Immunology
Chapter 4
Overview of the Immune System Transplantation Immunology
Characteristics of Innate Versus Adaptive Immunity . . . . . . . . . . . . . . . . . . . . . . . . 88 Grafts Used in Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Overview of the Immune Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 Graft Rejection Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Cells of the Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89–90
Characteristics of Lymphoid Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 Immunology Techniques in Diagnosis
Generation of Receptor Diversity in B and T Lymphocytes . . . . . . . . . . . . . . . . . . 90
Human Major Histocompatibility Complex (MHC) Summary . . . . . . . . . . . . . . . . 91 Fluorescence Activated Cell Sorter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
Examples of HLA-Linked Immunologic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . 91
Superantigens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 Immunopharmacology
T-Helper Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
Effector Cells in Cell-Mediated Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 Recombinant Cytokines and Clinical Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Key CD Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 Immunosuppressant Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 Monoclonal Antibodies (MABs) and Clinical Uses . . . . . . . . . . . . . . . . . . . . . . . . . 110
The Basic Structure of Immunoglobulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Summary of the Biologic Functions of the Antibody Isotypes . . . . . . . . . . . . . . . . 95
Precipitation of Ab-Ag Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Inflammation
Acute Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Neutrophil Margination and Extravasation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Neutrophil Migration/Chemotaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Other Chemical Mediators of Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Phagocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
Defects of Phagocytic Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
Complement Cascade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
Deficiencies of Complement or Its Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Summary of Acute Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Chronic Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Clinical Immunology
Comparison of the Primary and Secondary Immune Responses . . . . . . . . . . . . 100
Types of Immunization Used in Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Summary of Bacterial Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Summary of Viral Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Defects of Humoral Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Defects of T Cells and Severe Combined Immunodeficiencies . . . . . . . . . . . . . . 102
Association Between Immunodeficiency Disease and
Developmental Blocks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Acquired Immunodeficiency Syndrome (AIDS) . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Opportunistic Infection and Common Sites of Infection in AIDS Patients . . . . . 104
Other Complications of AIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
HIV Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Hypersensitivity Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Important Autoimmune Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106–107
87
Overview of the Immune System
GENERAL PRINCIPLES │ 4. Immunology ►►Characteristics of Innate versus Adaptive Immunity
The immune system can be divided into two complementary arms: the innate (native, natural) immune system and the adaptive (acquired,
specific) immune system. These two arms work in concert with each other through soluble substances, such as antibodies, complement,
and cytokines.
Characteristics Innate Adaptive
Specificity For structures shared by groups of microbes For specific antigens of microbial and nonmicrobial agents
Diversity Limited High
Memory No Yes
Self-reactivity No No
Components Innate Adaptive
Anatomic and Skin, mucosa, chemicals (lysozyme, Lymph nodes, spleen, mucosal-associated lymphoid
chemical barriers interferons α and β), temperature, pH tissues
Blood proteins Complement Antibodies
Cells Phagocytes and NK cells Lymphocytes (other than NK cells)
►►Overview of the Immune Response
Antigen CD28 • Foreign materials are processed and
MHC Class II TCR presented to TH cells in the MHC
CD4 class II groove.
Antigen- TH0
Presenting Cell • E xtracellular pathogens stimulate pro-
duction of TH2 cells, which provide the
IL-4 CD40L costimulatory signal and cyto-
kines to induce B cells to differentiate
CD28 IL-12 into plasma cells, which produce anti-
body. Antibody may assist in phagocy-
CD40 TH2 TH1 tosis (opsonization) or complement-
IL-10 inhibits proliferation IFN-γ mediated lysis.
Cytokines
inhibits • I ntracellular pathogens stimulate pro-
IL-4, IL-5, IL-6 proliferation duction of TH1 cells, which stimu-
late the effector cells of cell-mediated
immunity.
Activated B cell Cytokines • M acrophages are induced to become
IFN-γ more effective intracellular killers of the
IL-2 bacteria they ingest.
TNF-β
• Cytotoxic T cells kill virus-infected cells
Effector Cells of CCyDto8t+oxCicelTl NK NK by recognition of peptides presented in
Cell-Mediated CD16+ CD16+ the MHC class I molecule.
Cytotoxicity CD56+ CD56+
• Natural killer (NK) cells kill cells devoid
Proliferating B cells CD16 of MHC class I that are infected with
some viruses or have undergone
Macrophage CD8 malignant transformation.
Activation
• I n antibody-dependent cell-mediated
IL-1, IL-6, IL-8, TNF-α Virus- NK Target Cell Target Cells cytotoxicity (ADCC), abnormal surface
DTH Infected Cell ADCC molecules on infected or transformed
cells are recognized by antibodies
Plasma cells Serum Igs (CD16) and targeted for extracellular lysis by
Fc receptor NK cells, eosinophils, neutrophils, or
macrophages.
+ C3b receptor
C3b Phagocytosis
Complement
C3a, C5a, C4a
Inflammation
MAC
lysis
Definition of abbreviations: MHC, major histocompatibility complex; TCR, T cell receptor; TH, T helper.
88
►►Cells of the Immune System
Myeloid Cell Location Identifying Features Function
Monocyte Bloodstream, 0−900/μL Kidney bean-shaped nucleus, Phagocytic, differentiate into tissue GENERAL PRINCIPLES │ 4. Immunology
CD 14 (endotoxin receptor) macrophages
positive
Macrophage Tissues Ruffled membrane, cytoplasm with Phagocytosis, secretion of cytokines
vacuoles and vesicles (CD14+)
Dendritic cell Epithelia, tissues Long, cytoplasmic arms Antigen capture, transport, and
Neutrophil presentation
Bloodstream, Multilobed nucleus; small pink (There are also plasmacytoid dendritic
1,800−7,800/µL granules cells that look like plasma cells and
produce interferon-α.)
Phagocytosis and activation of
bactericidal mechanisms
Eosinophil Bloodstream, 0−450/µL Bilobed nucleus; large pink Killing of antibody-coated parasites
granules
Basophil Bloodstream, 0−200/µL Bilobed nucleus; large blue Nonphagocytic, release
granules pharmacologically active substances
during allergy
Mast cell Tissues, mucosa, and Small nucleus; cytoplasm packed Release of granules containing
epithelia
with large blue granules histamine, etc., during allergy
(Continued)
89
►►Cells of the Immune System (Cont'd.)
Lymphoid Cell Location Identifying Features Function
GENERAL PRINCIPLES │ 4. Immunology Lymphocyte Bloodstream, Large, dark nucleus, small rim of B cells produce antibody
1,000−4,000/µL, cytoplasm TH (CD3+CD4+) cells regulate
lymph nodes, spleen,
submucosa, and immune responses
epithelia Cytotoxic T cells (CTLs: CD3+CD8+)
kill altered or infected cells
Natural killer (NK) Bloodstream, ≤10% of Lymphocytes with large Kill tumor/virus cell targets or
lymphocyte lymphocytes cytoplasmic granules, antibody-coated target cells
CD16+CD56+
Plasma cell Lymph nodes, spleen, Small dark nucleus, intensely End cell of B-cell differentiation,
mucosal-associated staining Golgi apparatus produce antibody
lymphoid tissues, and
bone marrow
►► Characteristics of Lymphoid Cells
Comparison of B- and T-lymphocyte Antigen Receptors
Property B-Cell Antigen Receptor T-Cell Antigen Receptor
1
Idiotypes/lymphocyte 1 1 (α/β)
No
Isotypes/lymphocyte 2 (IgM and IgD) 1
Rigid
Is secretion possible? Yes CD3
Number of combining sites/molecules 2
Mobility Flexible (hinge region)
Signal transduction molecules Ig-α, Ig-β, CD19, CD21
►►Generation of Receptor Diversity in B and T Lymphocytes
Mechanism Cell in Which Expressed
Existence in genome of multiple V, D, J segments B and T cells
VDJ recombination (gene segments are selected and recom- B and T cells
bined randomly to generate unique variable domains)
N-nucleotide addition (TdT adds nucleotides randomly where B cells (only heavy chain), T cells (both chains)
V, D, and J are joined)
Combinatorial association of heavy and light chains B and T cells
Somatic hypermutation (mutations in variable domain coding B cells only, after Ag stimulation
occur during blastogenesis, and natural selection causes affin-
ity maturation)
Definition of abbreviation: Tdt, terminal deoxyribonucleotidyl transferase.
90
►►Human Major Histocompatibility Complex (MHC) Summary
MHC Class I MHC Class II GENERAL PRINCIPLES │ 4. Immunology
α1 Peptide-Binding Peptide-Binding
Groove Peptide-BindGinrgooGveroove
α1 α2
α3 ss α2
s β
s
α3
β2 Microglobulin α
s β2 Microglobulin
s
Cell Membrane
Cell Membrane
Names HLA-A, HLA-B, HLA-C Figure II-3-3. Left) The ClHasLsAI-MDHPC, HMLoAle-cDuQle, aHnLdA-DR
Tissue distribution right) X-Ray Crystallographic Image of Class I MHC Peptide-Binding Groove
Recognized by
Peptides bound All nucleated cells, platelets B and T lymphocytes, antigen-presenting cells
Function
Cytotoxic T cells (CD8+) Helper T cells (CD4+)
Invariant chain
β2-microglobulin Endogenously synthesized Exogenously processed
Elimination of abnormal (infected) host cells Presentation of foreign antigen to helper
by cytotoxic T cells T cells
No Yes
Yes No
►►Examples of HLA-Linked Immunologic Diseases
Disease HLA Allele
Rheumatoid arthritis DR4
Insulin-dependent diabetes mellitus DR3/DR4
Multiple sclerosis, Goodpasture syndrome DR2
Systemic lupus erythematosus DR2/DR3
Ankylosing spondylitis, psoriasis, inflammatory bowel B27
disease, Reiter syndrome
Celiac disease DQ2 or DQ8
Graves disease B8
91
GENERAL PRINCIPLES │ 4. Immunology ►► Superantigens
(Staphylococcal Enterotoxins, Toxic-Shock Syndrome Toxin-1, and Streptococcal Pyrogenic Exotoxins)
• Superantigens cross-link the variable β domain of a T-cell receptor to an α chain of a class II MHC molecule.
• They cause life-threatening overproduction of inflammatory cytokines (IL-1, IL-6, IFN-γ, and TNF-α).
• Endotoxin acts by direct stimulation of macrophages to produce IL-1, IL-6, and TNF-α in the absence of TH participation.
►►T-Helper Cells
• Naive TH cells (TH0) differentiate into TH1 cells when a strong initial innate immune response leads to production of IL-12 from
macrophages or IFN-γ from NK cells.
• Differentiation of a TH0 cell into a TH2 cell occurs in the absence of an innate immune response. TH1 cells secrete cytokines that
stimulate cell-mediated immunity (CMI). TH2 cells produce cytokines that stimulate humoral immunity (HMI). IFN-γ, produced by TH1,
inhibits TH2. IL-4 and IL-10, produced by TH2, inhibit TH1.
• TH17 cells increase inflammation and produce IL-17.
• Treg cells decrease inflammation and produce IL-10.
• T cells that are exposed to antigen presenting cells in the absence of costimulatory signals will become anergic.
TReg Pre-TH TH17
IL-10 IL-17
Intracellular pathogens Extracellular pathogens
TH0
IL-12 IL-4
IFN-γ
IFN-γ, IL-2, IL-4, IL-5, IL-6
TH1 TH2
IFN-γ, IL-2, TNF-β IL-4, IL-5, IL-6, IL-10, IL-13, TGFβ
Help for CMI Help for IgG, IgA, IgE
IL-4 and IL-10 inhibit TH1
IFN-γ inhibits TH2
92
►►Effector Cells in Cell-Mediated Immunity
Effector Cell CD Markers Antigen MHC Recognition Effector Molecules GENERAL PRINCIPLES │ 4. Immunology
Recognition Required for Killing
Perforin, cytokines (TNF-
CTL TCR, CD3, Specific, TCR Yes, class I β, IFN-γ)
Perforin, cytokines (TNF-
CD8, CD2 β, IFN-γ)
NK cell CD16, CD56, ADCC: specific by IgG, No, MHC I recognition Intracellular mechanisms
CD2 otherwise recognizes inhibits
lectins
Macrophage CD14 Nonspecific No
►►Key CD Markers
CD Designation Cellular Expression Known Functions
CD2 (LFA-2) T cells, thymocytes, NK cells Adhesion molecule
CD3 T cells, thymocytes Signal transduction by the TCR
CD4 TH cells, thymocytes, monocytes, and Coreceptor for MHC class II TH-cell activation, receptor
macrophages for HIV
CD8 CTLs, some thymocytes Coreceptor for MHC class I−restricted T cells
CD14 (LPS receptor) Monocytes, macrophages, granulocytes Binds LPS
CD16 (Fc receptor) NK cells, macrophages, mast cells Immune complex-induced cellular activation, ADCC
CD19 and 20 B cells Coreceptor with CD21 for B-cell activation
CD21 (CR2, C3d Mature B cells, follicular dendritic cells Receptor for complement fragment C3d, forms coreceptor
receptor) complex with CD19, Epstein-Barr virus receptor
CD25 Activated TH cells and TReg Alpha chain of IL-2 receptor
CD28 T cells T-cell receptor for costimulatory molecule B7
CD40 B cells, macrophages, dendritic cells, Binds CD40L, starts isotype switch
endothelial cells
CD56 NK cells Not known
Definition of abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; CTL, cytotoxic T lymphocytes; LPS, endotoxin
(lipopolysaccharide); NK, natural killer; TCR, T-cell receptor.
93
GENERAL PRINCIPLES │ 4. Immunology ►►Cytokines Source Activity
Monocytes, macrophages
Cytokine TH cells Stimulates cells, endogenous pyrogen
Interleukin-1 TH cells, NK cells
Interleukin-2 TH2 cells Induces proliferation, enhances activity
Interleukin-3
Interleukin-4 Supports growth and differentiation of myeloid cells
Interleukin-5 TH2 cells Stimulates activation, differentiation, class switch to IgG1
and IgE
Interleukin-6 Monocytes, macrophages,
Interleukin-7 TH2 cells Stimulates proliferation and differentiation, class switch to IgA; in
bone marrow, stimulates eosinophil production
Primary lymphoid organs
Second endogenous pyrogen, promotes differentiation into
Interleukin-8 Macrophages, endothelial plasma cells, induces acute phase response
Interleukin-10 cells
Stimulates progenitor B- and T-cell production in
TH2 cells bone marrow
Interleukin-11 Bone marrow stroma Chemokine (chemotactic for neutrophils)
Interleukin-12 Macrophages
Interleukin-17 TH17 cells Suppresses cytokine production of TH1 cells; diminishes
inflammation
Interferon-α and -β Leukocytes, fibroblasts
Interferon-γ TH1, CTLs, NK cells ↑ platelet count
Tumor necrosis factor-α and -β CMI cells Stimulates CMI
Granulocyte and granulocyte- Macrophages and TH cells ↑ inflammation and tissue damage associated with
monocyte colony-stimulating some autoimmune diseases
factors (G-CSF and GM-CSF)
Inhibits viral protein synthesis by acting on uninfected cells
Stimulates CMI, Inhibits TH2, increases expression of
class I and II MHC
Enhances CMI
Induce proliferation in bone marrow; counteract neutropenia
following ablative chemotherapy
Definition of abbreviation: CMI, cell-mediated immunity.
►►The Basic Structure of Immunoglobulin Immunoglobulin
Epitopes
Antigen
Binding (Idiotype)
Sites
Variable Light Variable γ Heavy Chain Domain Allotypepolymorphic
Chain Domain Constant γ Heavy Chain Domain differences between
members of species
Constant light (see lines in Fc region)
Chain Domain
Light Chain κ Hinge Isotypedeterminants
FAb (one antigen or λ Class Region common to constant
domains of heavy and
binding site, or Complement defines isotype light chains
Binding Region (constant domains)
aFn(Atibg’e)2n if two Idiotypedeterminants
binding Fc unique to the antigen
combining site
sites still joined.
Cell Receptor
Binding Region
94
►►Summary of the Biologic Functions of the Antibody Isotypes
IgM IgG IgA IgD IgE
δ ε
Heavy chain µ g α Trace Trace GENERAL PRINCIPLES │ 4. Immunology
40−345 mg/dL 650−1,500 mg/dL 75−390 mg/dL
Adult serum levels − −
++ − − −
Functions −+ − − −
Complement activation, classic pathway −+ −
− −
Opsonization −+ − + −
+− − − +
Antibody-dependent, cell-mediated −+ +
cytotoxicity (ADCC) − +
−− −
Placental transport
Naive B-cell antigen receptor
Memory B-cell antigen receptor
(one only)
Trigger mast cell granule release
►►Precipitation of Ab-Ag Complexes
Antigen-Excess Equivalence Antibody-Excess
Zone Zone Zone
{Supernatants Excess Ag ++++ + ++ ++ Prozone phenomenon—formation of suboptimal
Excess Ab amount of precipitate in antibody excess
(secondary syphilis)
Ag/Ab Precipitate
Window period (hepatitis B)—the equivalence
zone for HBsAg/HBsAb combination
Antibody Added
Figure II-16-1. Precipitation of Ag–Ab Complexes
During Titration of Ag with Ab
95
Inflammation
GENERAL PRINCIPLES │ 4. Immunology ►►Acute Inflammation
Acute inflammation is an immediate response to injury, associated with redness, heat, swelling, pain, and loss of function. Understand the
sequence of events of acute inflammation (extravasation, chemotaxis, phagocytosis, intracellular killing) and how these events set the
stage for the subsequent adaptive immune response.
Hemodynamic changes • Transient initial vasoconstriction, followed by massive dilation (mediated by histamine, bradykinin, and
Cellular response prostaglandins)
• Increased vascular permeability (due to endothelial cell contraction and/or injury)histamine,
serotonin, bradykinin, leukotrienes (e.g., LTC4, LTD4, LTE4)
• Blood stasis due to increased viscosity allows neutrophils to marginate
• Neutrophils: (segmented) polymorphonuclear leukocytes (PMNs) are important mediators in acute
inflammation
• Neutrophils have primary (azurophilic) and secondary (specific) granules:
– Primary granules contain: myeloperoxidase, phospholipase A2, lysozyme, acid hydrolases,
elastase, defensins, and bactericidal permeability increasing protein (BPI)
– Secondary granules contain: phospholipase A2, lysozyme, leukocyte alkaline phosphatase (LAP),
collagenase, lactoferrin, vitamin B12–binding proteins
►►Neutrophil Margination and Extravasation
Rolling Activation Arrest/adhesion Transendothelial Neutrophil Margination
migration and Adhesion
Endothelium • A t sites of inflammation,
endothelial cells increase
Neutrophil expression of E-selectin
and P-selectin, allowing
Chemokine or Chemokine Integrin neutrophils to bind weakly.
chemoattractant
receptor Ig-superfamily • Then neutrophils are
CAM stimulated by chemokines
Mucin-like to express their integrins.
CAM
• Tight adherence of the
E-selectin neutrophil to the endothelial
cell allows migration
through the basement
membrane toward the
inflammatory stimulus
(chemotaxis).
Step 1 Step 2 Step 3
Figure II-5-1. The Steps of Phagocyte Extravasation
96
►►Neutrophil Migration/Chemotaxis
Chemoattractive Molecule Origin
Chemokines (IL-8) Tissue mast cells, platelets, neutrophils, monocytes, macrophages, eosinophils, baso- GENERAL PRINCIPLES │ 4. Immunology
phils, lymphocytes
Complement split product C5a Endothelial damage → activation Hageman factor → plasmin activation
Leukotriene B4 Membrane phospholipids of macrophages, monocytes, neutrophils, mast cells → arachi-
donic acid cascade → lipoxygenase pathway
Formyl methionyl peptides Released from microorganisms
►►Other Chemical Mediators of Inflammation
Monoamine Sources Effects Triggers for Release
Histamine Basophils, platelets, and Vasodilation and increased • IgE-mediated mast cell reactions
mast cells vascular permeability • Physical injury
• Anaphylatoxins (C3a and C5a)
• Cytokines (IL-1)
Serotonin Platelets Platelet aggregation
Enzyme Arachidonic Acid Effects Comments
Product
Cyclooxygenase Thromboxane A2 Vasoconstriction, Produced by platelets
platelet aggregation
Prostacyclin (PGI2) Vasodilation and inhibits platelet Produced by vascular endothelium
aggregation
Lipoxygenase PGE2 Pain
PGE2, PGD2, PGF2
LTB4 Vasodilation
Neutrophil chemotaxis,
increased vascular
permeability, vasoconstriction
or vasodilation*
LTC4, LTD4, LTE4 Bronchoconstriction, Slow-reacting substance of anaphylaxis
increased vascular
permeability,
vasoconstriction or
vasodilation*
Kinin System
• Bradykininvasoactive peptide produced from kininogen by family of enzymes called kallikreins; degraded by different peptidases,
including angiotensin-converting enzyme (ACE)
• Activated Hageman factor (factor XII) converts prekallikrein → kallikrein
• K allikrein cleaves high molecular weight kininogen (HMWK) → bradykinin (produces increased vascular permeability, pain,
vasodilation, bronchoconstriction)
*Can be tissue specific (e.g., vasoconstriction in kidneys and heart; vasodilation in skin and nasal mucosa)
97
GENERAL PRINCIPLES │ 4. Immunology ►►Phagocytosis
• Several steps of phagocytosis: engulfment, fusion of the phagosome and lysosome, and digestion.
• Mechanisms of intracellular killing: NADPH oxidase-dependent, myeloperoxidase-dependent, and lysosome-dependent.
• Opsonization is the enhancement of phagocytosis with IgG and/or C3b.
Oxygen-Independent Killing Oxygen-Dependent Killing
Lysosome contains Myelo-
peroxidase
Lysozyme
Defensins 1
Lactoferrin Toxic
Hydrolytic Oxidants
enzymes NADPH
oxidase
Phagosome Cell
Membrane Membrane
►►Defects of Phagocytic Cells
Disease Molecular Defect(s) Symptoms
Chronic granulomatous Deficiency of NADPH oxidase (any one Recurrent infections with catalase-positive
disease (CGD) of four component proteins); failure to bacteria and fungi
generate superoxide anion, other O2
radicals Recurrent infection with bacteria: chemotactic and
degranulation defects; absent NK activity, partial
Chédiak-Higashi syndrome Granule structural defect albinism
Leukocyte adhesion deficiency Absence of CD18common β chain of the Recurrent and chronic infections, failure to form
leukocyte integrins pus, does not reject umbilical cord stump
►►Complement Cascade
• T he complement system is a set of interacting serum proteins that enhance inflammation (C3a, C4a, C5a) and opsonization (C3b) and
cause lysis of particles (e.g., gram-negative bacteria) via C5b-9.
• The alternative pathway is initiated by surfaces of pathogens.
• The classical pathway is activated by Ag/Ab complexes.
1 2 3 Alternative
Recruitment Opsonization Cascade
of Inflammatory of Pathogens Killing
C3b of Pathogens C3 + Factors C3, 5, 6, 7, 8, 9 lysis
Cells B+D
C3a Bacteria C5b membrane
Clearance of Microbial attack
C4a Immune Complexes 6 7 8 999 Surface
complex
C5a Membrane Attack
Complex → Puts
Holes in Membrane
Classical Ab
Cascade +
C1 + 2 + 4
Immune Complexes
C3b
Figure II-7-10. Three Functions of the Complement System
98
►►Deficiencies of Complement or Its Regulation
Deficiencies in Complement Deficiency Signs/Diagnosis GENERAL PRINCIPLES │ 4. Immunology
Components
Classical pathway C1q, C1r, C1s, C2, C4 Marked increase in immune complex diseases, increased
infections with pyogenic bacteria
Alternative pathway Factor B, properdin Increased neisserial infections
Both pathways C3 Recurrent bacterial infections, immune complex disease
C5, C6, C7, or C8 Recurrent meningococcal and gonococcal infections
Deficiencies in complement C1-INH (hereditary Serum depletion of C1, C2, C4
regulatory proteins angioedema) Edema at mucosal surfaces
►►Summary of Acute Inflammation Tissue
Blood
Monocyte
Histamines Complement activation
C5a
Prostaglandins
Leukotrienes
Mast cell Tissue damage
C5a
Neutrophil Chemotaxis Chemokines Bacteria
IL-8 Chemotaxis
Lymphocyte IL-1, IL-6, TNF-α Endothelial damage
Plasmin
Prostaglandins
Leukotrienes
Bradykinin Fibrin
Firinopeptides
Activated
macrophage
LFA-1
ICAM-1
Figure II-5-2. The Acute Inflammatory Response
99
►►Chronic Inflammation Important Cell Types
Causes
GENERAL PRINCIPLES │ 4. Immunology Macrophages
• F ollowing a bout of acute Derived from blood monocytes. During inflammation, macrophages are mainly recruited from the blood
inflammation (circulating monocytes). Macrophages contain acid hydrolases, elastase, and collagenase, secrete
monokines.
• Persistent infections
Chemotactic factors: C5a, MCP-1, MIP-1-α, PDGF, TGF-α
• Infections with certain Tissue-based macrophages:
organisms (viruses,
mycobacteria, • Connective tissue (histiocyte)
parasites, fungi) • Lung (pulmonary alveolar macrophages)
• Liver (Kupffer cells)
• Bone (osteoclasts)
• Brain (microglia)
• Kidney (mesangial cells)
• A utoimmune diseases Lymphocytes (e.g., B cells, plasma cells)
• Response to foreign • T cells
material • Lymphocyte chemokine: lymphotaxin
Eosinophils
Play an important role in parasitic infections and IgE-mediated allergic reactions
• Eosinophilic chemokine: eotaxin
• Granules contain major basic protein, which is toxic to parasites
Basophils
• Tissue-based basophils are called mast cells, present in high numbers in the lung and skin
• Play an important role in IgE-mediated reactions (allergies and anaphylaxis), release histamine
Clinical Immunology
►►Comparison of the Primary and Secondary Immune Responses
Feature Primary Response Secondary Response
Time lag after immunization 5−10 days 1−3 days
Peak response Small Large
Antibody isotype IgM then IgG Increasing IgG, IgA, or IgE
Antibody affinity Variable to low High (affinity maturation)
Inducing agent All immunogens Protein antigens
Immunization protocol High dose of antigen (often with Low dose of antigen (often without adjuvant)
adjuvant)
100
►►Types of Immunization Used in Medicine
Adjuvants increase immunogenicity nonspecifically. They are given with weak immunogens to enhance the response. GENERAL PRINCIPLES │ 4. Immunology
Type of Immunity Acquired Through Examples
Natural Passive means Placental IgG transport, colostrum
Natural Active means Recovery from infection
Artificial Passive means Immunoglobulins or immune cells given
Artificial Active means Vaccination
►►Summary of Bacterial Vaccines
Organism Vaccine Vaccine Type
C. diphtheriae DTaP Toxoid
B. pertussis DTaP Toxoid
C. tetani DTaP Toxoid
H. influenzae Hib Capsular polysaccharide and protein
S. pneumoniae PCV 13 capsular serotypes and protein
Pediatric
PPV 23 capsular serotypes
Adult
N. meningitidis MCV-4 4 capsular serotypes (Y, W-135, C, A) plus protein
►►Summary of Viral Vaccines
Killed Vaccines Live Viral Vaccines Component Vaccines
Mnemonic: RIP-A (Rest In Peace All but adenovirus are attenuated Hepatitis B
Always—the killed viral vaccines): HPV (human papilloma virus)
(mnemonic: Mrr. V.Z. Mapsy)
Rabies (killed human diploid Mumps
cell vaccine) Rotavirus
Rubella
Influenza Varicella – Zoster
Measles
Polio (Salk) Adenovirus (pathogenic
[not attenuated] respiratory strains
A Hepatitis given in enteric coated capsules)
Polio (Sabin)
Small Pox
Yellow Fever
101
►►Defects of Humoral Immunity
Disease Molecular Defect Symptoms/Signs
GENERAL PRINCIPLES │ 4. Immunology Bruton X-linked Deficiency of a tyrosine kinase Low immunoglobulin of all classes, no circulating B cells,
hypogammaglobulinemia blocks B-cell maturation pre-B cells in bone marrow in normal numbers, normal
cell-mediated immunity
Selective IgA deficiency Deficiency of IgA (most common)
Repeated sinopulmonary and gastrointestinal infections,
X-linked hyper-IgM syndrome Deficiency of CD40L on activated ↑ atopic allergy
T cells
High serum titers of IgM without other isotypes
Common variable B-cell maturation defect and Normal B- and T-cell numbers, susceptibility to extracellular
immunodeficiency hypogammaglobulinemia bacteria and opportunists
Both sexes affected, childhood onset, recurrent bacterial
infections and increased susceptibility to Giardia
Increased risk later in life to autoimmune disease, lymphoma,
or gastric cancer
►►Defects of T Cells and Severe Combined Immunodeficiencies
Category Disease Defect Clinical Manifestation
Selective T-cell DiGeorge syndrome Failure of formation of Facial abnormalities, hypoparathyroidism,
deficiency (velocardiofacial syndrome) third and fourth pharyngeal cardiac malformations, depression of T-cell
pouches, thymic aplasia numbers and absence of T-cell responses
MHC class I deficiency Failure of TAP 1 molecules CD8+ T cells deficient, CD4+ T cells
to transport peptides to normal, recurring viral infections, normal
endoplasmic reticulum DTH, normal Ab production
MHC class II deficiency Bare lymphocyte T cells present and responsive to
syndrome nonspecific mitogens, no GVHD, deficient
in CD4+ T cells, hypogammaglobulinemia;
presents as SCID
Combined partial B- Wiskott-Aldrich syndrome Defect in cytoskeletal Defective responses to bacterial
and T-cell deficiency glycoprotein, X-linked polysaccharides and depressed IgM,
gradual loss of humoral and cellular
responses, thrombocytopenia and
eczema
Ataxia telangiectasia Defect in kinase involved in Ataxia (gait abnormalities), telangiectasia
the cell cycle (capillary distortions in the eye), deficiency
of IgA and IgE production
Complete functional B- Severe combined Defects in common γ chain Chronic diarrhea; skin, mouth, and throat
of IL-2 receptor (also present lesions; opportunistic (fungal) infections;
and T-cell deficiency immunodeficiency (SCID) in receptors for low levels of circulating lymphocytes; cells
IL-4, -7, -9, -15) X-linked unresponsive to mitogens
Adenosine deaminase
deficiency (results in toxic
metabolic products in cells)
Defect in signal transduction
from T-cell
IL-2 receptors
102
►►Association Between Immunodeficiency Disease and Developmental Blocks
DiGeorge MHC II GENERAL PRINCIPLES │ 4. Immunology
Syndrome deficiency
SCID Chronic
IL-2R Mucocutaneous
Candidiasis
In Thymus
Helper T lymphocyte
NK cell T progenitor Thymocyte
MHC I
Pre-B Immature B
deficiency
Cytotoxic T lymphocyte
Severe Combined Lymphoid B progenitor B Lymphocyte Plasma cell
Immunodeficiency stem cell X-linked Common variable hypogammaglobulinemia,
Selective Ig deficiency, Hyper IgM Syndrome
ADA Agammaglobulinemia
deficiency
Pluripotent
stem cell
Dendritic cell
Monocyte
Chronic Granulomatous Granulocyte/ Neutrophil Macrophage
Disease and Monocyte
progenitor
Chediak Higashi
Myeloid
stem cell
103
►►Acquired Immunodeficiency Syndrome (AIDS)
Definition When a patient is HIV-positive with CD4 count less than 200/mm3 or HIV-positive with an AIDS-defining disease
GENERAL PRINCIPLES │ 4. Immunology Transmission • Sexual contact: homosexual > heterosexual in U.S.
– Cofactors: herpes and syphilis
• Parenteral transmission:
– Intravenous drug abuse
– Hemophiliacs
– Blood transfusions
– Accidental needle sticks in hospital workers
• Vertical transmission (mother to child)
Pathogenesis • Human immunodeficiency virus (HIV; an enveloped retrovirus containing reverse transcriptase)
• HIV infects CD4+ cells (gp120 binds to CD4)
– CD4+ T cells (with CCR5 chemokine coreceptor)
– Macrophages (with CXCR4 chemokine coreceptor)
• Persons who are homozygous CCR5 defective cannot be infected
• Entry into cell by fusion requires gp41 and coreceptors
Diagnosis and • Initial screening: Serologic, ELISA
Monitoring • Confirmation: Serologic, Western blot
• Detection of virus in blood (evaluate viral load): RT-PCR
• Detect HIV infection in newborns of HIV+ mother (provirus): PCR*
• Early marker of infection: p24 antigen
• Evaluate progression of disease: CD4:CD8 T-cell ratio
Treatment • Combination antiretroviral treatment
• Reverse transcriptase inhibitors
• Protease inhibitors
• Prophylaxis for opportunistic infections based on CD4 count
• Fusion inhibitors
• Integrase inhibitors
*RT-PCR tests for circulating viral RNA and is used to monitor the efficacy of treatment. PCR detects integrated virus (provirus DNA).
Viral load has been demonstrated to be the best prognostic indicator during infection.
►►Opportunistic Infection and Common Sites of Infection in AIDS Patients
Opportunistic Infection Common Sites of Infection
Pneumocystis jiroveci (carinii) Lung (pneumonia), bone marrow, start prophylaxis at < 200 CD4
Histoplasma capsulatum Lung, disseminated, start prophylaxis at < 100 CD4 in endemic area
Toxoplasma gondii CNS, start prophylaxis at < 100 CD4
Mycobacterium avium-intracellulare Lung, gastrointestinal tract, disseminated, start prophylaxis at < 50 CD4
Cytomegalovirus Lung, retina, adrenals, and gastrointestinal tract, start prophylaxis at < 50 CD4
Cryptosporidium parvum Gastrointestinal tract, start prophylaxis at < 50 CD4
Cryptococcus neoformans CNS (meningitis), start prophylaxis at < 50 CD4
Coccidioides immitis Lung, disseminated
Giardia lamblia Gastrointestinal tract
Herpes simplex virus Esophagus and CNS (encephalitis)
Candida albicans Oropharynx and esophagus
Aspergillus spp. CNS, lungs, blood vessels
JC virus CNS (progressive multifocal leukoencephalopathy)
Mycobacterium tuberculosis Lung, disseminated
104
►►Other Complications of AIDS
Hairy leukoplakia Associated with Epstein-Barr virus (EBV)
Kaposi sarcoma Associated with human herpes virus 8 (HHV8) GENERAL PRINCIPLES │ 4. Immunology
Common sites: skin, GI tract, lymph nodes, and lungs
Non-Hodgkin lymphoma Tend to be high-grade B-cell lymphomas
Extranodal CNS lymphomas common
Miscellaneous Cervical cancer
HIV wasting syndrome
AIDS nephropathy
AIDS dementia complex
►►HIV Therapies
Anti-HIV therapy usually involves three or more anti-retroviral agents including antimetabolite inhibitors of retroviral reverse transcriptase
and viral protease. These aggressive drug combinations (highly active antiretroviral therapy, HAART) are typically initiated early after
HIV infection and will often reduce viral load, preserve CD-4 counts, and limit opportunistic infections. Drug combinations also slow the
development of resistance to drugs as opposed to monotherapy.
Drug Mechanism of Action Side Effects and Comments
Nucleoside reverse transcriptase inhibitors (NRTIs)
Abacavir (ABC) Converted to nucleoside Dose-limiting pancreatitis (ddI)
Didanosine (ddI) triphosphates, which inhibit Dose-limiting peripheral neuropathy (ddC, ddI, d4T)
Emtricitabine (FTC) reverse transcriptase, leading Hypersensitivity reactions (ABC)
Lamivudine (3TC) the inhibition of viral replication by Lactic acidosis (ddI, d4T)
Stavudine (d4T) chain termination Fanconi syndrome (TDF)
Tenofovir (TDF) Dose-limiting BMS (ZDV)
Zalcitabine (ddC) Minimal toxicity (FTC, 3TC)
Zidovudine (ZDV, AZT) Least toxic and also used for hepatitis B (3TC)
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Delavirdine (DLV) Inhibit reverse transcriptase Rash (occasional Steven-Johnson syndrome)
Efavirenz (EFV) noncompetitively Adverse CNS effects (EFV)
Etravirine (ETR) P450 interactions
Nevirapine (NVP) Increased transaminase levels (DLV, EFV)
Protease inhibitors
Atazanavir (ATV) Inhibits aspartate protease (HIV- Inhibit CYP3A4 (especially ritonavir)
Darunavir (DRV) 1 protease encoded by pol gene), Crystalluria (indinavir, maintain hydration)
Fosamprenavir (FPV) blocking structural protein Elevated transaminases
Indinavir (IDV) formation of the Lopinavir is only available in combination with ritonavir
Nelfinavir (NFV) mature virion core
Ritonavir (RTV)
Saquinavir (SQV)
Lopinavir + Ritonavir
(LPV/r)
Fusion inhibitor
Enfuvirtide Binds gp41 and inhibits fusion Local injection reactions (100% patients)
of HIV-1 to CD4+ cells Hypersensitivity reactions
CCR5 antagonist
Maraviroc (MVC) Blocks CCR5 receptor, Hepatotoxicity, orthostatic hypotension
preventing HIV entry into target
cells
Integrase inhibitor
Raltegravir (RAL) Inhibits integrase, thus blocking CPK elevation
viral integration
105
►►Hypersensitivity Reactions
Type Antibody Complement Effector Cells Examples
GENERAL PRINCIPLES │ 4. Immunology I (immediate) IgE No Basophil, mast Hay fever, atopic dermatitis, insect venom sensitivity,
cell anaphylaxis to drugs, some food allergies, allergy to
animals and animal products, asthma
II (cytotoxic) IgG, IgM Yes PMN, Autoimmune or drug-induced hemolytic anemia, transfusion
macrophages, NK reactions, HDNB, hyperacute graft rejection, Goodpasture
cells disease, rheumatic fever
II (noncytotoxic) IgG No None Myasthenia gravis, Graves disease, type 2 diabetes
mellitus
III (immune IgG, IgM Yes PMN, SLE, polyarteritis nodosa, poststreptococcal
complex) macrophages glomerulonephritis, Arthus reaction, serum sickness
IV (delayed, None No CTL, TH1, Tuberculin test, tuberculosis, leprosy, RA, Hashimoto
DTH) macrophages thyroiditis, poison ivy (contact dermatitis), GVHD, IDDM
Definition of abbreviations: GVHD, graft-versus-host disease; HDNB, hemolytic disease of the newborn; IDDM, insulin-dependent diabetes
mellitus; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.
►►Important Autoimmune Diseases
Autoantibodies Clinical Features Comments
Systemic lupus erythematosus: chronic systemic autoimmune disease characterized by a loss of self-tolerance and production
of autoantibodies
Antinuclear antibody • Hemolytic anemia, thrombocytopenia, • Females >> Males (M:F = 1:9), peak age 20–45
(ANA) (>95%): leukopenia years, African American > Caucasian
Anti-dsDNA (40–60%) • Arthritis • Mechanism of injury: type II and III
Anti-Sm (20–30%) • Skin rashes (including classic malar hypersensitivity reactions
rash) • Treatment: steroids and other
• Renal disease immunosuppressants
• Libman-Sacks endocarditis
• Serositis
• Neurologic symptoms
Sjögren syndrome: an autoimmune disease characterized by destruction of the lacrimal and salivary glands, resulting in the inability to
produce saliva or tears
Antiribonucleoprotein antibodies: • Keratoconjuctivitis sicca (dry eyes) and • Females > males; age range: 30−50 years
corneal ulcers • Often associated with rheumatoid arthritis and
Anti-SS-A (Ro)
Anti-SS-B (La) • Xerostomia (dry mouth) other autoimmune diseases (e.g., SLE)
• Increased risk of developing lymphoma
• Mikulicz syndrome: enlargement of the
salivary and lacrimal glands (Continued)
106
►►Important Autoimmune Diseases (Cont’d.)
Autoantibodies Clinical Features Comments
Scleroderma (progressive systemic sclerosis): characterized by fibroblast stimulation and deposition of collagen in the skin and internal GENERAL PRINCIPLES │ 4. Immunology
organs; females > males; age range: 20−55 years; activation of fibroblasts by growth factors/cytokines leads to fibrosis
Diffuse Scleroderma
Anti-DNA topoisomerase I anti- Widespread skin involvement Raynaud phenomenon is seen in almost all patients
bodies (Scl-70) (70%) Early involvement of the visceral organs and often preceeds other symptoms.
• Esophagus—dysphagia Treatment: vasodilators, ACE inhibitors, NSAIDs,
• GI tract—malabsorption steroids, d-penicillamine
• Pulmonary fibrosis—dyspnea on
exertion
• Cardiac fibrosis—arrhythmias
• Kidney fibrosis—renal insufficiency
Limited scleroderma (e.g., CREST syndrome)
Anticentromere antibodies • Skin involvement of the face (Calcinosis, Raynaud phenomenon, Esophageal
and hands dysmotility, Sclerodactyly, Telangiectasia)
• Late involvement of visceral organs
(relatively benign clinical course)
Transplantation Immunology
►►Grafts Used in Medicine
Grafts Definition
Autologous (autografts) Tissue is moved from one location to another in the same individual
Isograft Transplants between genetically identical individuals (monozygotic twins)
Allograft Transplants between genetically different members of the same species
Xenograft Transplants between members of different species
►►Graft Rejection Reactions
Type of Rejection Time Taken Cause
Preformed anti-donor antibodies and complement (type II hypersensitivity)
Hyperacute Minutes to hours Reactivation of sensitized T cells
Primary activation of T cells
Accelerated Days Causes are unclear: antibodies, immune complexes, slow cellular
Acute Days to weeks reaction, recurrence of disease (type IV hypersensitivity)
Grafted bone marrow T cells attack host (type IV hypersensitivity)
Chronic Months to years
Graft versus host Weeks to months
107
Immunology Techniques in Diagnosis
GENERAL PRINCIPLES │ 4. Immunology ►►Fluorescence Activated Cell Sorter
Anti-CD4 Anti-CD8
Anti-CD3 Anti-CD20
Cells with • Complex mixtures of cells are
fluorescent treated with fluorescent dye-
antibody labeled antibodies and run through
the apparatus.
Fluorescence Sheath fluid
detector Laser • T he fluorescence activated cell
Light scatter beam sorter (FACS) separates the
detector cells into populations based on
+ their level of fluorescence with a
– Deflection plates particular dye.
Computer-Generated Graphs • Each dot on the diagram
represents a cell that has bound to
Double stainedAnti-CD8 (increasingDouble stained a fluorescent-labeled antibody.
intensity of
fluorescence) • Increasing fluorescence intensity
with one dye is represented as a
Anti-CD4 rise on the y-axis, and increasing
Anti-CD20 fluorescence with the other dye
occurs as you move right on the
x-axis.
• D ouble-labeled cells are always
found in the upper right quadrant.
• C ells that have only background
fluorescence with either dye are
found in the lower left quadrant.
The results of flow cytometry are often
shown for question analysis. Be sure
to know the key CD markers and the
biologic functions of the cells that
possess them.
Anti-CD3 Anti-CD3 Anti-CD3
(increasing intensity
of fluorescence)
108
Immunopharmacology
►►Recombinant Cytokines and Clinical Uses GENERAL PRINCIPLES │ 4. Immunology
Cytokine Clinical Uses
Aldesleukin (IL-2) ↑ Lymphocyte differentiation and ↑ NKs—used in renal cell cancer and metastatic melanoma
Oprelvekin (IL-11) ↑ Platelet formation—used in thrombocytopenia
Filgrastim (G-CSF) ↑ Granulocytes—used for bone marrow recovery
Sargramostim (GM-CSF) ↑ Granulocytes and macrophages—used for bone marrow recovery
Erythropoietin Anemias, especially associated with renal failure
Thrombopoietin Thrombocytopenia
Interferon-α Hepatitis B and C, leukemias, malignant melanoma, Kaposi sarcoma
Interferon-β Multiple sclerosis
Interferon-γ Chronic granulomatous disease →↑ TNF
►►Immunosuppressant Agents
Drug Mechanism Uses
Autoimmune diseases (e.g., SLE, rheumatoid
Azathioprine Converted to mercaptopurine, whose metabolites arthritis) and immunosuppression in renal allografts
inhibit purine metabolism
Cancer, organ transplants
Cytotoxic to proliferating lymphocytes (especially T
cells) • Autoimmune diseases, bone marrow transplants
• Similar cytotoxic drugs: cytarabine, dactinomycin,
Corticosteroids ↓ synthesis of prostaglandins, leukotrienes,
cytokines; inhibit T-cell proliferation; at methotrexate, vincristine
immunosuppressive doses, they are cytotoxic to • DOC in organ or tissue transplantation
some T cells
(± mycophenolate ± steroids ± cytotoxic drugs)
Cyclophosphamide Cytotoxic to proliferating lymphocytes (especially B • Side effects: peripheral neuropathy, nephrotoxicity,
cells)
hyperglycemia, hypertension, hyperlipidemia,
Cyclosporine Antibiotic that binds to cyclophilin → inhibits hirsutism, gingival overgrowth, cholelithiasis
calcineurin (cytoplasmic phosphatase) → ↓
activation of T-cell transcription factors → ↓
IL-2, IL-3, and interferon-γ
Tacrolimus Antibiotic that binds to FK-binding protein (FKBP); • U sed alternatively to cyclosporine in renal and
Sirolimus (rapamycin) also inhibits calcineurin (similar to cyclosporine) liver transplants
Mycophenolate
RhD immune globulin Inhibits T-cell activation and proliferation in • Side effects similar to cyclosporine
(RhoGAMTM) response to IL-2 by binding to mTOR
Inhibits de novo purine synthesis Immunosuppression after kidney transplantation in
conjunction with cyclosporine and corticosteroids
Antibody to red cell RhD antigens
• Kidney, liver, heart transplants
• Used with cyclosporine in renal transplants to ↓
cyclosporine dose
Administer to RhD mother within 72 h of
Rh ⊕ delivery to prevent hemolytic disease of
newborn in subsequent pregnancy
109
►►Monoclonal Antibodies (MABs) and Clinical Uses
MAB Clinical Uses
GENERAL PRINCIPLES │ 4. Immunology Abciximab Antiplatelet (acute coronary symptoms, post-angioplasty)—antagonist of IIb/IIIa receptors
Daclizumab Kidney transplants—blocks IL-2 receptors
Infliximab Rheumatoid arthritis and Crohn disease—binds TNF-α
Muromonab Allograft rejection block in renal transplantsbinds CD3 on T cells
Palivizumab Respiratory syncytial virus—blocks RSV fusion protein
Rituximab Non-Hodgkin lymphoma—binds to CD20 antigen on B-cell surface protein
Trastuzumab Breast cancer—antagonist to HER2/neu receptor
110
Microbiology
Chapter 5
General Principles of Microbiology Virology
Comparison of Medically Important Microbial Groups . . . . . . . . . . . . . . . . . . . . 112 Viral Structure and Morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
DNA Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
Bacteriology RNA Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Double-Stranded RNA Viruses: Reoviridae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Bacterial Growth Curve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 Positive-Sense RNA Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Features of Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 Negative-Sense RNA Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
Normal Flora Organisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 Viral Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
Bacterial Toxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 Antiviral Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135–136
Major Exotoxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Important Pathogenic Factors and Diagnostic Enzymes . . . . . . . . . . . . . . . . . . . . 116 Mycology
Unusual Growth Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
Bacterial Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 Mycology: Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
Nonsystemic Fungal Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
Antibacterial Agents Systemic Fungal Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
Opportunistic Fungi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Mechanisms of Action of Antibacterial Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 Antifungal Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
Cell Wall Synthesis Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118–119
Summary of Mechanisms of Protein Synthesis Inhibition . . . . . . . . . . . . . . . . . . . 119
Protein Synthesis Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
Folic Acid Synthesis Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
DNA Replication Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Parasites
Obligate Intracellular Parasites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
Facultative Intracellular Parasites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
Protozoans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
Protozoan Parasites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Free-Living Amebae That Occasionally Infect Humans . . . . . . . . . . . . . . . . . . . . 123
Plasmodium Life Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
Plasmodium Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Antimalarial Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Adverse Effects of Antimalarial Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Hemoflagellates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Miscellaneous Apicomplexa Infecting Blood or Tissues . . . . . . . . . . . . . . . . . . . . 127
Major Protozoal Infections and Drugs of Choice . . . . . . . . . . . . . . . . . . . . . . . . . 127
Metazoans: Worms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Trematode (Fluke) Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
Gastrointestinal Cestodes (Tapeworms) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Roundworms (Nematodes) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
Roundworms (Nematodes) Transmitted by Eggs . . . . . . . . . . . . . . . . . . . . . . . . . 130
Roundworms (Nematodes) Transmitted by Larvae . . . . . . . . . . . . . . . . . . . . . . . 131
Filarial Nematodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Drugs for Helmiathic Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
111
General Principles of Microbiology
GENERAL PRINCIPLES │ 5. Microbiology ►►Comparison of Medically Important Microbial Groups
Characteristic Viruses Bacteria Fungi Parasites
Diameter Minute (0.02–0.3 µ) Small (0.3–2 µ) 3–10 µ 15–25 µ
(trophozoites)
Cell type Acellularno nucleus Prokaryotic cells Eukaryotic cells
• DNA or RNA • DNA and RNA • DNA and RNA
• 1 nucleocapsid, except in • 1 chromosome • More than one chromosome
• No histones
segmented or diploid viruses
Replicates in host cells DNA replicates continuously G and S phases
Exons, no introns Introns and exons
Some have polycistronic mRNA Mono- and polycistronic Monocistronic RNA
and post-translational cleavage mRNA
Uses host organelles; obligate No membrane-bound Mitochondria and other membrane-
intracellular parasites organelles bound organelles
No ribosomes 70S ribosomes 80S ribosomes (40S+60S)
(30S+50S)
Replication Make and assemble viral Binary fission Cytokinesis with mitosis/meiosis
components (asexual)
Cellular membrane Some are enveloped, but no Membranes have Ergosterol is Sterols, such
membrane function no sterols, except major sterol as cholesterol
Mycoplasma, which have
cholesterol
Cell wall No cell wall Peptidoglycan Complex No cell wall
carbohydrate
cell wall: chitin,
glucans, or
mannans
Note: Prions are infectious proteins (contain no nucleic acids). They are the agents of kuru, mad cow disease, etc.
Bacteriology
Log Number of Cells►►Bacterial Growth Curve Death Lag Phase:
Phase • Detoxifying medium
Stationary Phase • Turning on enzymes to utilize medium
Log Phase Log Phase:
(Logarithmic or • Rapid exponential growth
• Generation timetime it takes one cell to divide into two
Exponential) • This is determined during log phase
Lag Stationary Phase:
Time • Nutrients used up
• Toxic products begin to accumulate
• Number of new cells = the number of dying cells
Death Phase:
• Nutrients gone
• Toxic products kill cells
• Number of cells dying exceeds the number of cells dividing
112
►►Features of Bacteria Outer Membrane LPS GENERAL PRINCIPLES │ 5. Microbiology
Protein O-Antigen
Capsule
Cell Wall Core OM
Teichoic Acid Lipid-A Envelope
Membrane Porin
Lipoteichoic Acid Lipoprotein
Cell Surface
Peptidoglycan
Proteins
Peptidoglycan Periplasmic space
Cytoplasmic Cytoplasmic IM
Membrane Membrane
Gram + Cell Wall Synthesizing Enzymes Gram –
(Penicillin Binding Proteins—PBPs)
Envelope Structure Gram ⊕ or – Chemical Composition Function
Both Gram ⊕ and Gram –
Capsule (nonessential) Polysaccharide gel • Antiphagocytic
= slime (except B. anthracis: • Immunogenic (except S. pyogenes
= glycocalyx poly-D-glutamate)
and N. meningitidis, type B)
Outer membrane Gram – only Phospholipid/proteins Hydrophobic membrane:
LPS: • LPS = endotoxin
• Lipid A • Lipid A = toxic moiety
• Polysaccharide • PS = immunogenic portion
Outer membrane proteins Attachment, virulence, etc.
Protein porins Passive transport
Cell wall = Gram ⊕ (thick) Peptidoglycanopen 3-D • Rigid support, cell shape, and protection
peptidoglycan Gram – (thin) net of: from osmotic damage
• N-acetyl-glucosamine • Synthesis inhibited by penicillins and
cephalosporins
• N-acetyl-muramic acid
• Confers Gram reaction
• Amino acids (including
DAP)
Gram ⊕ only Teichoic acids • Immunogenic, induces TNF-α, IL-1
• Attachment
Acid-fast only Mycolic acids • Acid-fastness
• Resistance to drying and chemicals
Periplasmic space Gram – only “Storage space” between the • Enzymes to break down large molecules
inner and outer membranes (b-lactamases)
• Aids regulation of osmolarity
Cytoplasmic membrane Gram ⊕ Phospholipid bilayer with many • Hydrophobic cell “sac”
= inner membrane Gram – embedded proteins • Selective permeability and active
= cell membrane
= plasma membrane transport
• Carrier for enzymes for:
– Oxidative metabolism
– Phosphorylation
– Phospholipid synthesis
– DNA replication
– Peptidoglycan cross linkage
• Penicillin binding proteins (PBPs)
Definition of abbreviation: DAP, diaminopimelic acid; LPS, lipopolysaccharide.
113
►►Normal Flora Organisms
GENERAL PRINCIPLES │ 5. Microbiology Most infectious disease vignettes begin with the necessity to rule out the normal flora organisms that are cultured from the patient. Make
sure you know those organisms that can confound a simple Gram-stain type of diagnosis, e.g., notice in the oropharynx and vagina,
normal flora organisms cannot be indistinguishable from pathogens by Gram stain alone!
Common or Medically Important
Site Organisms Less Common but Notable Organisms
Blood, None, generally sterile
internal organs
Cutaneous surfaces Staphylococcus epidermidis Staphylococcus aureus, Corynebacteria (diphtheroids),
streptococci, anaerobes, e.g., peptostreptococci,
Candida spp.
Nose Staphylococcus aureus S. epidermidis, diphtheroids, assorted streptococci
Oropharynx Viridans streptococci, including Assorted streptococci, nonpathogenic Neisseria, nontypeable
Streptococcus mutans Haemophilus influenzae, Candida albicans
Gingival crevices Anaerobes: Bacteroides, Prevotella,
Fusobacterium, Streptococcus,
Actinomyces
Stomach None
Colon Adult: Bacteroides/Prevotella Eubacterium, Fusobacterium, Lactobacillus, assorted gram-
(microaerophilic/ (predominant organism), Escherichia, negative anaerobic rods
anaerobic) Bifidobacterium
Enterococcus faecalis and other streptococci
Vagina Lactobacillus Assorted streptococci, gram-negative rods,
diphtheroids, yeasts, Veillonella (gram-negative diplococcus)
►►Bacterial Toxins
Endotoxin
Endotoxin (lipopolysaccharide = LPS) is part of the gram-negative outer membrane. It is encoded on the chromosome.
• The toxic portion is lipid A. LPS is heat stable and not strongly immunogenic, so it cannot be converted to a toxoid.
• LPS activates macrophages, leading to release of TNF-α, IL-1, IL-6, and nitric oxide (NO). IL-1 is a major mediator of fever. Damage
to the endothelium from bradykinin-induced vasodilation leads to shock. Coagulation (DIC) is mediated through the activation of
Hageman factor. NO production causes hypotension, which contributes to shock.
Exotoxin
Exotoxins are protein toxins, generally quite toxic, and secreted by bacterial cells. They are encoded on plasmids or in lysogenic phage
genomes.
• Exotoxins can be modified by chemicals or heat to produce a toxoid that still is immunogenic, but no longer toxic, so it can
be used as a vaccine.
• Most are A-B (or two) component protein toxins. B component binds to specific cell receptors to facilitate the internalization of A (the
active [toxic] component)
114
►►Major Exotoxins
Organism (Gram) Toxin Mode of Action Role in Disease GENERAL PRINCIPLES │ 5. Microbiology
Diphtheria toxin Inhibits eukaryotic cell
Protein Corynebacterium diphtheriae • ADP ribosyl transferase protein synthesis
synthesis (⊕) inactivates eEF-2
inhibitors Inhibits eukaryotic cell
• T argets: heart, nerves, protein synthesis
Pseudomonas aeruginosa ( Exotoxin A epithelium
–) • Inhibits protein synthesis
• A DP ribosyl transferase in eukaryotic cells
Shigella dysenteriae ( – ) Shiga toxin inactivates eEF-2
• E nterotoxic, cytotoxic, and
Enterohemorrhagic Verotoxin • Target: liver neurotoxic
E. coli (EHEC) (– ) (shiga-like)
Interferes with 60S Inhibits protein synthesis in
ribosomal subunit eukaryotic cells
Interferes with 60S
ribosomal subunit
Neurotoxins Clostridium tetani (⊕) Tetanus toxin Blocks release of glycine Inhibits neurotransmission
Superantigens Clostridium botulinum (⊕) Botulinum toxin and GABA in inhibitory synapses
cAMP inducers Staphylococcus TSST-1
aureus (⊕) Blocks release of Inhibits cholinergic synapses
Cytolysins Exotoxin A, also acetylcholine
Streptococcus called erythrogenic Fever, increased susceptibility
pyogenes (⊕) or pyrogenic toxin • Induces IL-1, IL-6, to LPS, rash, shock, capillary
Enterotoxigenic Escherichia Heat labile TNF-α, IFN-γ leakage
coli (– ) toxin (LT)
• Decreases liver Fever, increased susceptibility
Vibrio cholerae (– ) Cholera toxin clearance of LPS to LPS, rash, shock, capillary
Bacillus anthracis (⊕) Anthrax toxin leakage, cardiotoxicity
(3 proteins Similar to TSST-1
Bordetella pertussis (– ) make 2 toxins) Both LT and ST promote
LT stimulates an secretion of fluid and
Clostridium perfringens (⊕) Pertussis toxin adenylate cyclase by ADP electrolytes from intestinal
Staphylococcus aureus (⊕) ribosylation of GTP- epithelium
Alpha toxin binding protein
Profuse, watery diarrhea
Alpha toxin Similar to E. coli LT
• Decreases phagocytosis
• E F = edema factor = • Causes edema, kills cells
adenylate cyclase
• Histamine sensitizing
• LF = lethal factor • L ymphocytosis promotion
• P A = protective antigen
(inhibits chemokine
(B component for both) receptors)
• Islet activation
ADP ribosylates Gi,
the negative regulator of • Damages cell membranes
adenylate cyclase, leading • Myonecrosis
to increased cAMP
Membrane becomes leaky
Lecithinase
Pore former
Definition of abbreviations: TSST-1, toxic shock syndrome toxin-1
115
►►Important Pathogenic Factors and Diagnostic Enzymes
GENERAL PRINCIPLES │ 5. Microbiology Factor Function Organisms
All capsules Antiphagocytic Streptococcus pneumoniae, Klebsiella pneumoniae, Haemophilus
influenzae, Pseudomonas aeruginosa, Neisseria meningitidis,
Cryptococcus neoformans (mnemonic: some killers have pretty
nice capsules) and many more
M protein Antiphagocytic Group A streptococci
A protein Binds Fc of IgG to inhibit Staphylococcus aureus
opsonization and phagocytosis
Lipoteichoic acid Attachment to host cells All gram-positive bacteria
All pili Attachment Many gram-negatives
Pili of N. gonorrhoeae Antiphagocytic, antigenic N. gonorrhoeae
variation
Hyaluronidase Hydrolysis of ground Group A streptococci
substance
Collagenase Hydrolysis of collagen Clostridium perfringens, Prevotella melaninogenica
Urease Increases pH of locale, Proteus, Ureaplasma, Nocardia, Cryptococcus, Helicobacter
contributes to kidney stones (mnemonic: PUNCH)
Kinases Hydrolysis of fibrin Streptococcus, Staphylococcus
Lecithinase Destroys cell membranes Clostridium perfringens
Heparinase Thrombophlebitis Bacteroides
Catalase Destroys hydrogen peroxide • Most important: Staphylococcus, Pseudomonas, Aspergillus,
(major problem for CGD Candida, Enterobacteriaceae
patients)
• Most anaerobes lack catalase
IgA proteases Destroy IgA, promote Neisseria, Haemophilus, Streptococcus pneumoniae
colonization of mucosal
surfaces
Oxidase Cytochrome c oxidase is the Neisseria and most gram-negatives, except the Enterobacteriaceae
terminal electron acceptor
Coagulase Produces fibrin clot Staphylococcus aureus and Yersinia pestis
►►Unusual Growth Requirements
Requirements in Culture Organism
Factors X and V Haemophilus
Cholesterol Mycoplasma
High salt Staphylococcus aureus, group D enterococci and Vibrio
Cysteine Francisella, Legionella, Brucella, and Pasteurella
(mnemonic: the 4 Sisters “ELLA” worship in the Cysteine Chapel)
High temperature (42° C) Campylobacter
Lower than atmospheric oxygen pressure Campylobacter and Helicobacter
(microaerophilic); special CO2 incubator
116
►►Bacterial Genetics
Recombination Homologous: The one-to-one exchange of linear extrachromosomal DNA for homologous alleles within the GENERAL PRINCIPLES │ 5. Microbiology
chromosome, using recombinase A
Site-specific: The incorporation of extrachromosomal circles of DNA into another molecule of DNA using
restriction endonucleases
Conjugation The donation of chromosomal or plasmid genes from one bacterium to another through a conjugal
bridge.
• F+ cells have a fertility factor plasmid and serve as donors of plasmid DNA
• F– cells do not have fertility factors and serve as the recipients of DNA in any cross.
• Hfr cells have incorporated a fertility factor plasmid (now called episome) into their chromosome by site-
specific recombination and serve as donors of chromosomal DNA
• Conjugation is the most important means of transfer of drug resistance genes in gram-negative bacilli
Transduction The delivery of bacterial genes from one bacterium to another via a virus vector.
• Generalized transduction: Transfer of any genes from one bacterium to another via an accident in the
assembly of a virus with a lytic life cycle.
• Specialized transduction: The transfer of bacterial chromosomal genes located near the insertion site
of a temperate phage from one bacterium to another via an accident of excision.
• Transduction has been shown to be the means of transfer of drug resistance to methicillin (MRSA) and
imipenem (Pseudomonas).
Transformation The uptake and incorporation of free DNA from the environment by competent cells followed by
homologous recombination.
• Transformation is an important means of transfer of traits in bacteria that are naturally competent
(Streptococcus pneumoniae, Helicobacter, Neisseria, and Haemophilus influenzae)
Lysogeny The stable association of DNA molecules between a bacterium and a temperate phage.
• It imparts the important traits: C = Cholera toxin, O = Salmonella O antigen, B= Botulinum toxin,
E = Erythrogenic toxin of Streptococcus pyogenes, D = Diphtheria toxin, S = Shiga toxin. Mnemonic:
COBEDS: when 2 people share a bed, someone gets a little bit pregnant (with phage).
• Bacterial cells with stably integrated temperate phage DNA are said to have undergone lysogenic
conversion.
Transposon A mobile genetic element capable of movement within a cell.
• They move by a variation of site-specific recombination and are responsible for the formation of multiple
drug-resistance plasmids.
• VRSA has arisen because Enterococcus donated a multi-drug resistance plasmid, produced by
transposition, to MRSA.
Antibacterial Agents
►►Mechanisms of Action of Antibacterial Agents
Mechanism of Action Antibacterial Agents
Inhibition of bacterial cell-wall synthesis Penicillins, cephalosporins, imipenem/meropenem, aztreonam, vancomycin
Inhibition of bacterial protein synthesis Aminoglycosides, chloramphenicol, macrolides, tetracyclines, streptogramins, linezolid
Inhibition of DNA replication or transcription Fluoroquinolones, rifampin
Inhibition of nucleic acid synthesis Trimethoprim, flucytosine
Inhibition of folic acid synthesis Sulfonamides, trimethoprim, pyrimethamine
117
►►Cell Wall Synthesis Inhibitors
GENERAL PRINCIPLES │ 5. Microbiology Class/Example Mechanism of Spectrum Toxicity/Notes
Action/Resistance
Penicillins
Resistant staph emerging
Narrow spectrum, Mechanism: Gram-positives “MRSA”
β-lactamase sensitive: inhibit cross-linking Clostridia
penicillin G, penicillin V of peptidoglycan Syphilis
component of cell wall by
Very narrow spectrum, transpeptidases; action Gram-positives, especially S. aureus
β-lactamase resistant: mediated by binding of
methicillin, nafcillin, oxacillin penicillin-binding proteins
(PBPs)
Broad spectrum, Resistance: production Gram-positives, enterococci, Activity may be augmented
aminopenicillins, of β-lactamases, which H. influenzae with penicillinase
β-lactamase sensitive: cleave the β-lactam ring β-lactamase inhibitors
ampicillin, amoxicillin structure; change in L monocytogenes (e.g., clavulanic acid,
PBPs; change in porins M. catarrhalis sulbactam, and tazobactam)
Extended spectrum, E. coli
antipseudomonal,
β-lactamase sensitive: • Gram-negatives, including
mezlocillin, piperacillin, Pseudomonas
carbenicillin, ticarcillin,
azlocillin • Gram-positives, including enterococci
(mezlocillin and piperacillin)
First generation:
cefazolin, cephalexin Cephalosporins
Second generation: Mechanism: inhibition of Gram-positives • Cross-allergenicity with
cefotetan, cefoxitin, cell wall formation similar Proteus mirabilis penicillins occurs in 5%
cefuroxime, cefaclor to penicillins E. coli
Klebsiella pneumoniae • Anaphylaxis, but not
Third generation: Resistance: same as rash, a contraindication in
ceftazidime, cefoperazone, penicillins Less gram-positive activity and more penicillin-sensitive pt.
cefotaxime, ceftriaxone gram-negative activity than first
generation • Disulfiram-like effects
Fourth generation: • B. fragilis (cefotetan)
cefepime • H. influenzae
• M. catarrhalis • Most penetrate blood-
• P. mirabilis brain barrier (not
• E. coli cefoperazone)
• K. pneumoniae
• Neisseria, Enterobacter • Reserved for serious
infections
Less gram-positive activity and more
gram-negative activity than second • Disulfiram-like effects
generation (cefoperazone)
• Serratia sp. More resistant to
β- lactamases
• Borrelia burgdorferi
(Continued)
• H. influenzae
• Neisseria
• Enterobacter
Some have anti-Pseudomonas activity
More gram-negative activity while
retaining first-generation gram-positive
activity
118
►►Cell Wall Synthesis Inhibitors (Cont’d.)
Mechanism of
Action/Resistance
Class/Example GENERAL PRINCIPLES │ 5. MicrobiologySpectrumToxicity/Notes
nd Carbapenems and Monobactams
Carbapenems (meropenem, Similar mechanism Gram-positives, gram-negative rods, • Nephrotoxic
imipenem) to penicillins and anaerobes
cephalosporins • GI distress
• Rash
• CNS toxicity
• Cilastatin administered
concurrently with
imipenem increases the
drug’s half-life and reduces
nephrotoxicity
• Beta-lactamase resistant
Monobactams (aztreonam) Gram-negative rods • GI distress with
superinfection, vertigo,
headache
• Synergistic with
aminoglycosides
• Beta-lactamase resistant
Non-Beta Lactam Cell Wall Synthesis Inhibitors
Vancomycin Binds cell wall Drug resistant gram-positives, e.g., • Chills, fever, ototoxicity,
precursors (D-ala-D-ala MRSA sepsis (IV) or C. difficile (oral [not nephrotoxicity
muramyl pentapeptide), absorbed from lumen])
preventing • Flushing or “red man
polymerization, syndrome” upon rapid
peptidoglycan elongation infusion
• Resistant strains (VRSA,
VRE) emerging
Definition of abbreviations: VRE, vancomycin-resistant enterococcus; VRSA, vancomycin-resistant Staphylococcus aureus.
►►Summary of Mechanisms of Protein Synthesis Inhibition
p eptide bo *4 #2 = initiating amino acid
*3 #1 = amino acid in peptide sequence
#1 Translocation = tRNA, specific for each amino acid
50 S *1 "A"
*2
m RNA "P"
30 S sites
Event Antibiotics and Binding Sites Mechanism
1. Formation of initiation complex
Aminoglycosides (30S) Interfere with initiation codon functions—block association
Linezolid (50S) of 50S ribosomal subunit with mRNA-30S (bacteriostatic);
misreading of code—incorporation of wrong amino acid
2. Amino-acid incorporation Tetracyclines (30S) (bactericidal)
Dalfopristin/quinupristin (50S)
3. Formation of peptide bond Block the attachment of aminoacyl tRNA to acceptor site
4. Translocation Chloramphenicol (50S) (bacteriostatic)
Macrolides and clindamycin (50S) Inhibit the activity of peptidyltransferase (bacteriostatic)
Inhibit translocation of peptidyl tRNA from acceptor to donor
site (bacteriostatic)
119
►►Protein Synthesis Inhibitors
GENERAL PRINCIPLES │ 5. Microbiology Drug/Class Site of Spectrum Mechanisms Toxicities Notes
Inhibition of Resistance • Toxicity limits
Plasmid-mediated • “Gray baby”
Chloramphenicol 50S Wide spectrum, acetyltransferases syndrome (↓ clinical use
including: that inactivate the glucuronyl transferase • Reserved for
• H. influenzae drug in neonates)
• N. meningitidis severe Salmonella
• Bacteroides Plasmid-mediated • Aplastic anemia/bone and bacterial
• Rickettsia efflux pumps and marrow suppression meningitis in b-
• Salmonella reduced uptake via lactam–sensitive
transport systems • GI irritation patients
Tetracyclines: 30S Gram ⊕ and Gram – : • Fanconi
• tetracycline • Rickettsia Methylation of • GI irritation syndrome
• doxycycline • Chlamydia binding site on 50S; • Tooth enamel with expired
• minocycline • Mycoplasma increased efflux from tetracycline
• H. pylori multidrug exporters dysplasia • Oral absorption
• Brucella • Bone growth limited by
• Vibrio Many macrolide- multivalent cations
resistant strains irregularities
Macrolides: 50S Gram ⊕, some are susceptible to • Hepatotoxicity Useful in atypical
• erythromycin, Gram – : ketolides • Photosensitivity pneumonia
• azithromycin Methylation of • Vestibular toxicity
• clarithromycin • Chlamydia binding site on 50S Its use is limited
• Mycoplasma • GI irritation because of toxicity
Ketolides 50S • Ureaplasma Plasmid-mediated • Cholestasis
• Telithromycin • Legionella group transferases • Hepatitis
• Campylobacter • Skin rashes
Resistance rare • ↓ CYP3A4 (except Neomycin for bowel
Similar spectrum to prep (stays in bowel
macrolides azithromycin) lumen)
Clindamycin 50S Narrow spectrum: • Severe hepatotoxicity No cross-resistance
Gram ⊕, anaerobes • Visual disturbances with other protein
• Fainting synthesis inhibitors,
Aminoglycosides: 30S Gram – rods, aerobic so often reserved for
• gentamicin 50S only • GI irritation resistant infections
• neomycin • Skin rash
• tobramycin Gram ⊕ cocci • C. difficile
• streptomycin
superinfection
Oxazolidinones:
• linezolid Ototoxicity,
nephrotoxicity
• Thrombocytopenia,
neutropenia, esp. in
immunocompromised
• MAO inhibition (dietary
and drug restrictions)
120
►►Folic Acid Synthesis Inhibitors Trimethoprim and GENERAL PRINCIPLES │ 5. Microbiology
pyrimethamine inhibit
Sulfonamides inhibit
Dihydropteroate Dihydrofolate
Synthase Reductase
Pteridine + PABA Dihydropteroic Dihydrofolic Tetrahydrofolic
Acid
Acid + Acid
Glutamate
Class/Drug Mechanism Spectrum Mechanism Toxicity Notes
Sulfonamides of Action of Resistance
Gram – , gram • Hypersensitivity Combined with
Trimethoprim PABA antimetabolite ⊕, Chlamydia, Decreased • Hemolytic anemia trimethoprim for
inhibits bacterial Nocardia accumulation of increased efficacy
dihydropteroate drugs, decreased in G6PD-deficient
synthase, thus affinity of drug for • Nephrotoxicity • Adverse effects
curbing folate dihydropteroate • Kernicterus in may be reduced by
synthesis synthase concurrent folinic
newborns acid
Inhibits bacterial H. influenzae Production
dihydrofolate M. catarrhalis of bacterial • Megaloblastic • Good for UTIs
reductase, thus dihydrofolate anemia because it is
inhibiting folate reductase with excreted in urine
synthesis decreased affinity • Leukopenia unchanged
for drug • Granulocytopenia
►►DNA Replication Inhibitors
Class/Drug Mechanism Spectrum Mechanism Toxicity Notes
of Action of Resistance
• GI distress Contraindicated
Fluoroquinolones: Interfere with Gram – rods, • Decreased intracellular • Skin rash in pregnancy
• ciprofloxacin bacterial DNA Neisseria, drug concentrations • Superinfection due to cartilage
• ofloxacin topoisomerase occasional through efflux pumps • Tendonitis and formation
• levofloxacin II and IV (DNA gram ⊕ and altered porins abnormalities in
• moxifloxacin gyrase), resulting tendon rupture animal studies
in inhibition of DNA • Alteration of drug’s
synthesis binding site
►►Miscellaneous
Class/Drug Mechanism Spectrum Mechanism Toxicity Notes
of Action of Resistance
Metronidazole When reduced, Anaerobes Rare plasma- • GI distress • Strong metallic taste
interferes with (except mediated
nucleic acid Actinomyces) resistance • Disulfiram-like • DOC in
synthesis reaction with pseudomembranous
(bactericidal) alcohol colitis
• Peripheral
neuropathy, ataxia
Definition of abbreviations: DOC, drug of choice; G6PD, glucose-6-phosphate dehydrogenase; PABA, para-aminobenzoic acid; UTI,
urinary tract Infection.
121
GENERAL PRINCIPLES │ 5. Microbiology Parasites
►►Obligate Intracellular Parasites
• Cannot be cultured on inert media. Intracellular organisms (both obligate and facultative) are protected from antibody and
complement. Intracellular pathogens tend to elicit cell-mediated immune responses, so end pathologic lesion is frequently a
granuloma
• All rickettsiae, chlamydiae, Mycobacterium leprae
• All viruses
• Plasmodium, Toxoplasma gondii, Babesia, Leishmania, Trypanosoma cruzi (amastigotes in cardiac muscle)
►►Facultative Intracellular Parasites
Live inside phagocytic cells in the body, but can be cultured on inert media
• Francisella tularensis
• Listeria monocytogenes
• Mycobacterium tuberculosis
• Brucella species
• Nontuberculous mycobacteria
• Salmonella typhi
• Legionella pneumophila
• Yersinia pestis
• Nocardia
• Borrelia burgdorferi
• Histoplasma capsulatum
►►Protozoans Amebae Flagellates Apicomplexa (Intracellular)
Common Name Entamoeba Luminal (Gut, UG) Blood/Tissue
Important genera Naegleria Trichomonas Plasmodium
Acanthamoeba Giardia Toxoplasma
Babesia
Hemoflagellates
Leishmania Intestinal
Trypanosoma Cryptosporidium
Isospora
122
►►Protozoan Parasites
Species Disease/Organs Most Form/Transmission Diagnosis GENERAL PRINCIPLES │ 5. Microbiology
Affected • Trophozoites or cysts (with 4 nuclei)
• Cysts
Entamoeba • Amebiasis: dysentery • Fecal-oral transmission: in stool
histolytica
• Inverted, flask-shaped water, fresh fruits, and • Nuclei have sharp central karyosome
lesions in large intestine with vegetables and fine chromatin “spokes”
extension to peritoneum and • Travel to tropics
liver, lungs, brain, and heart
• Blood and pus in stool
• Liver abscesses
• Serology
Giardia lamblia Giardiasis: Ventral sucking disk • Cysts • Trophozoites or cysts in stool or fecal
attaches to lining of duodenal antigen test (replaces “string” test)
wall, causing a fatty, foul- • Fecal (human, beaver,
smelling diarrhea (diarrhea → muskrat, etc.), oral • “Falling leaf” motility
malabsorption in duodenum, transmission: water, food, day
jejunum) care, oral-anal sex
• Campers and hikers
Cryptosporidium Cryptosporidiosis: transient • Cysts Acid fast oocysts in stool: biopsy
spp. diarrhea in healthy; severe in shows dots (cysts) in intestinal glands
immunocompromised hosts • Undercooked meat, water;
not killed by chlorination
Trichomonas Trichomoniasis: frothy green, • Trophozoites Motile trophozoites in methylene blue
vaginalis unpleasant smelling vaginal • Sexual wet mount
(urogenital) discharge, itching, burning
vaginitis
►►Free-Living Amebae That Occasionally Infect Humans
Species Disease/Locale Form/Transmission Diagnosis
Naegleria Primary amebic • Free-living amebae picked up • Motile trophozoites
meningoencephalitis (PAM): while swimming or diving in in CSF
severe prefrontal headache, very warm fresh water
nausea, high fever, often an • Culture on plates seeded with gram
altered sense of smell; often fatal • Penetrates cribriform plate – bacteria; amebae will leave trails
Acanthamoeba Keratitis; GAE in • Free-living amebae in • Star-shaped cysts
immunocompromised patients; contaminated contact lens on biopsy; rarely seen in CSF
insidious onset but progressive solution (airborne cysts)
to death • Culture as above
• Not certain for GAE;
inhalation or contact with
contaminated soil or water
Definition of abbreviations: CSF, cerebrospinal fluid; GAE, granulomatous amaebic encephalitis.
123
GENERAL PRINCIPLES │ 5. Microbiology ►►Plasmodium Life Cycle
Each Plasmodium has two distinct hosts:
• A vertebrate, such as the human (intermediate host), where asexual phase (schizogony) takes place in the liver and red blood cells
• An arthropod (definitive) host (Anopheles mosquito), where gametogony (sexual phase) and sporogony take place
Disease is caused by a variety of mechanisms, including metabolism of hemoglobin and lysis of infected cells, leading to anemia and to
agglutination of the infected RBCs. Paroxysms (chills, fever spike, and malarial rigors) occur when the infected RBCs are lysed, liberating
a new crop of merozoites.
Cycle in
Mosquito
Ruptured Migrate to Sporozoites migrate Exoerythrocytic
oocyst salivary gland into the bloodstream
Stomach Sporozoites invade the Hypnozoites
Lumen parenchymal cells (sleeping forms)
of the liver P. vivax+
Zygote Penetrates P. ovale
stomach wall Liver reLapse
and divides
Division to form
Fertilization primary tissue
schizont
Liver
Maturation Division
Gambyettohceymteossiqnugietosetesd Some merozoites Blood
differentiate into
sexual forms Erythrocytic
Schizont
Asexual cycle Cycle in
determines the Trophozoite Humans
time between Invasion of Erythrocyte
febrile episodes
Erythrocytic
Definition of abbreviation: RBCs, red blood cells.
124
►►Plasmodium Species
Species Disease Important Features Blood Smears Liver Stages GENERAL PRINCIPLES │ 5. Microbiology
Plasmodium vivax Benign tertian 48-hour fever spikes Enlarged host cells; Persistent hypnozoites
ameboid trophozoites Relapse*
Plasmodium ovale Benign tertian 48-hour fever spikes Oval, jagged, infected Persistent hypnozoites
RBCs Relapse
Plasmodium malariae Quartan or malarial 72-hour fever spikes; Bar and band forms; No persistent stage*
recrudescence* rosette schizonts
Plasmodium Malignant tertian Irregular fever spikes; Multiple ring forms No persistent stage*
falciparum causes cerebral malaria; crescent-shaped
most dangerous gametes
Definition of abbreviations: PO, by mouth; RBCs, red blood cells.
*Recrudescence is a recurrence of symptoms from low levels of organisms remaining in red cells. Relapse is an exacerbation from liver
stages (hypnozoites).
†Use quinine sulfate plus pyrimethamine-sulfadoxine.
►►Antimalarial Drugs
1. Suppressive (to avoid infection)
2. Therapeutic (eliminate erythrocytic)
3. Radical cure (eliminate exoerythrocytic)
4. Gametocidal (destruction of gametocytes)
Successful treatment is accomplished with chloroquine followed by primaquine. Chloroquine therapy is
suppressive, therapeutic, and gametocidal, whereas primaquine eliminates the exoerythrocytic form.
Chloroquine-Sensitive Malaria
P. falciparum Chloroquine
P. malariae Chloroquine
P. vivax Chloroquine plus primaquine
P. ovale Chloroquine plus primaquine
Chloroquine-Resistant Malaria
Prophylaxis: mefloquine; backup drugs: doxycycline, atovaquone-proguanil
Treatment: quinine ± either doxycycline, clindamycin, or pyrimethamine
►►Adverse Effects of Antimalarial Drugs
Drug Side Effects Contraindications and Cautions
Chloroquine, GI distress, pruritus, headache, dizziness, hemolysis, Avoid in psoriasis
hydroxychloroquine retinopathy
Mefloquine NVD, dizziness, syncope, extrasystoles, CNS effects (rare) Avoid in seizures, psychiatric disorders, and
in cardiac conduction defects
Primaquine GI distress, headache, dizziness, neutropenia, Avoid in pregnancy, G6PD deficiency,
hemolysis and autoimmune disorders
Quinine GI distress, cinchonism, CNS effects, hemolysis, Avoid in pregnancy
hematotoxicity
Definition of abbreviations: CNS, central nervous system; GI, gastrointestinal; G6PD, glucose-6-phosphate dehydrogenase; NVD,
nausea, vomiting, diarrhea.
125
GENERAL PRINCIPLES │ 5. Microbiology ►►Hemoflagellates Trypomastigote Amastigote
Hemoflagellates (Trypanosomes and Leishmania) infect blood and Flagellar pocket
tissues. They are found in:
• H uman blood as trypomastigotes with flagellum and an Nucleus
undulating membrane.
• I ntracellular as amastigotes (oval cells having neither the
flagellum nor undulating membrane). Leishmania spp.
have only amastigotes in the human.
Species Disease Vector/Form/ Diagnosis
Transmission
Trypanosoma • Chagas disease Reduviid bug Blood films, trypomastigotes
cruzi* (American (kissing or cone
trypanosomiasis) bug) passes
trypomastigote
• Latin America in feces
• Swelling around
eye (Romaña’s
sign): common
early sign
• Cardiac
muscle (dilated
cardiomyopathy),
megaesophagus,
megacolon
Trypanosoma • African sleeping Trypomastigote in • Trypomastigotes in blood films, CSF
brucei sickness (African saliva of tsetse fly • High immunoglobulin levels in CSF
gambiense trypanosomiasis)
Trypanosoma b. • Antigenic
rhodesiense variation
Leishmania • Visceral Sandfly bite Amastigotes in macrophages in bone marrow, liver, spleen
donovani† leishmaniasis
complex
• Kala-azar
Leishmania Cutaneous Sandfly bite Amastigotes in macrophages in cutaneous lesions
(about 15 different leishmaniasis
species) (Oriental sore, etc.)
Leishmania Mucocutaneous Sandfly bite Same
braziliensis leishmaniasis
complex
Definition of abbreviations: CSF, cerebrospinal fluid.
*T. cruzi: An estimated 0.5 million Americans are infected, creating some risk of transfusion transmission in the United States. In babies,
acute infections are often serious and involve the CNS. In older children and adults, mild acute infections may become chronic with the
risk of development of cardiomyopathy and heart failure.
† All Leishmania: intracellular, sandfly vector, stibogluconate
126
►►Miscellaneous Apicomplexa Infecting Blood or Tissues
Species Disease/Locale of Origin Transmission Diagnosis GENERAL PRINCIPLES │ 5. Microbiology
Giemsa stain of blood
Babesia (primarily a Babesiosis (hemolytic, malaria-like) • Ixodes tick smear
disease of cattle)
Same range as Lyme: N.E., N. Central, • Coinfections with Borrelia Serology:
Humans: Babesia California, and N.W. United States and Ehrlichia High IgM or rising IgM
microti, WA1 and acute infection
MO1 strains
Toxoplasma gondii • Most common parasitic disease Cat is essential definitive
host; many other animals are
• Infections after birth are most commonly intermediate hosts
asymptomatic or mild; may mimic
mononucleosis Mode:
• Raw meat in U.S.; pork is
• Produces severe disease in AIDS or other
immunocompromised (ring-enhancing #1
lesions in brain) • Contact with cat feces
• Primary maternal infection during
pregnancy may infect fetus:
− Severe congenital infections
(intracerebral calcifications,
chorioretinitis, hydro- or microcephaly,
seizures) if Toxoplasma crosses the
placenta early
− Later term congenital infection may
produce progressive blindness
►►Major Protozoal Infections and Drugs of Choice
Infection Drug of Choice Comments
Amebiasis Metronidazole Diloxanide for noninvasive intestinal amebiasis
Giardiasis Metronidazole or furazolidone
Trichomoniasis Metronidazole Treat both partners
Toxoplasmosis Pyrimethamine and sulfadiazine TMP-SMX is also prophylactic against Pneumocystis
jiroveci in AIDS
Leishmaniasis Stibogluconate
Trypanosomiasis • Nifurtimox (Chagas disease)
• Arsenicals, pentamidine, suramin (African sleeping
sickness)
►►Metazoans: Worms*
Phylum Flatworms (Platyhelminthes) Roundworms (Nemathelminthes)
Class (common name) Trematodes (flukes) Cestodes (tapeworms) Nematodes† (roundworms)
Genera Fasciola Diphyllobothrium Necator
Fasciolopsis Hymenolepis Enterobius
Paragonimus Taenia W uchereria/Brugia
Clonorchis Echinococcus Ascaris and Ancylostoma
Schistosoma OTonxcohcoacrear,cWTarichuris, and Trichinella
Dracunculus
Eyeworm (Loa loa)
Strongyloides
*Metazoans also include the Arthropoda, which serve mainly as intermediate hosts (the crustaceans) or as vectors of disease
(the Arachnida and Insecta).
†Nematodes mnemonic (turn the “W” upside down)
127
►►Trematode (Fluke) Diseases
GENERAL PRINCIPLES │ 5. Microbiology Trematodes:
• Are commonly called flukes, which are generally flat and fleshy, leaf-shaped worms
• Are hermaphroditic, except for Schistosoma, which has separate males and females
• Have complicated life cycles occurring in two or more hosts
• Have operculated eggs (except for Schistosoma)
• The first intermediate hosts are snails
Organism Common Name Acquisition Progression Important Ova
in Humans
Schistosoma mansoni Intestinal Contact with water; skin Skin penetration
S. japonicum schistosomiasis penetration (itching) → mature in
veins of mesentery →
eggs cause granulomas
in liver (portal
hypertension and
liver fibrosis in chronic
cases)
Schistosoma Vesicular Contact with water; skin Skin penetration
haematobium schistosomiasis penetration (itching) → mature in
bladder veins; chronic
infection has high
association with bladder
carcinoma
in Egypt and Africa
Nonhuman Swimmer’s itch Contact with water; Penetrate skin,
schistosomes skin penetration (Great producing dermatitis
Lakes) without further
development in humans;
Raw fish ingestion itching is most intense
at 2 to 3 days
Raw crabs, crayfish
Clonorchis sinensis Chinese liver fluke Inflammation Operculated eggs
of biliary tract,
pigmented gallstones,
cholangiocarcinoma
Paragonimus Lung fluke Hemoptysis, secondary Operculated eggs
westermani bacterial infection of lung
128
►►Gastrointestinal Cestodes (Tapeworms)
• Consist of three basic portions: the head or scolex; a “neck” section, which produces the proglottids; and the segments or proglottids, GENERAL PRINCIPLES │ 5. Microbiology
which mature as they move away from the scolex
• Are diagnosed by finding eggs or proglottids in the feces
• Have complex life cycles involving extraintestinal larval forms in intermediate hosts; when humans are intermediate host, these
infections are generally more serious than intestinal infections with adult tapeworms
Cestode Form/ Human Disease/Organ Involvement/
(Common Name) Transmission Host Symptoms (Sx)
Type
Diagnosis
Taenia solium (pork Water, vegetation, IH Cysticercosis/eggs → larva Biopsy
tapeworm) food contaminated develop in brain, eye, heart, lung, Proglottids or eggs in feces
with eggs etc. Epilepsy with onset after age Biopsy
IH: swine; rare: humans 20
Autoinfection Proglottids or eggs in feces
DH: humans,developing • Intestinal tapeworm Imaging, serology
and Slavic countries Rare/raw pork • Sx: same as for Taenia saginata
containing the
cysticerci ingested by DH
humans
Diphyllobothrium latum Drinking pond water IH Sparganosis/larvae penetrate
(fish tapeworm) containing copepods DH intestinal wall
(crustaceans) carrying and encyst
2 IHs: crustaceans → the larval forms or
fish; rare: humans frog/snake poultices Intestinal tapeworm (up to
10 meters)/small intestine,
DH: humans/mammals; Rare, raw pickled megaloblastic anemia
cool lake regions fish containing a
sparganum
Echinococcus Ingestion of eggs IH Hydatid cyst disease; liver and
granulosus lung, where cysts containing brood
capsules develop
IH: herbivores; rare:
humans
DH: carnivores in sheep-
raising areas
Definition of abbreviations: IH, intermediate host; DH, definitive host.
129
GENERAL PRINCIPLES │ 5. Microbiology ►►Roundworms (Nematodes)
Roundworms are transmitted by:
• Ingestion of eggs (Enterobius, Ascaris, or Trichuris)
• Direct invasion of skin by larval forms (Necator, Ancylostoma, or Strongyloides)
• Ingestion of meat containing larvae (Trichinella)
• Infection involving insects transmitting the larvae with bites (Wuchereria, Loa loa, Mansonella, Onchocerca, and Dracunculus)
►►Roundworms (Nematodes) Transmitted By Eggs
Disease/Organs Form/Transmission
Most Affected
Species Diagnosis
Enterobius vermicularis Pinworms, large intestine, • Eggs/person to person • Scotch tape swab of
perianal itching • Autoinfection perianal area
(Most frequent helminth
parasite in U.S.) • Ova have flattened side with
larvae inside
Trichuris trichiura Whipworm cecum, Eggs ingested Barrel-shaped eggs with
appendicitis, and rectal bipolar plugs in stools
prolapse
Ascaris lumbricoides Ascariasis Eggs ingested Bile stained, knobby eggs
(Most common helminth Ingest egg → larvae migrate
worldwide; largest roundworm) through lungs (cough) and
mature in small intestine; may
obstruct intestine or bile duct
Toxocara canis or cati Visceral larva migrans Eggs ingested/from handling Adult 35 to 40 cm
(Dog/cat ascarids) puppies or from eating dirt in
Larvae wander aimlessly until yard (pica) Clinical findings
they die, cause inflammation and serology
130
►►Roundworms (Nematodes) Transmitted by Larvae
Species Disease/Organs Form/Transmission Diagnosis GENERAL PRINCIPLES │ 5. Microbiology
Fecal larvae (up to 13 mm) and
Necator americanus Hookworm infection Filariform larva penetrates
(New World hookworm) Lung migration → pneumonitis intact skin of bare feet ova: oval, transparent with
Bloodsucking → anemia 2–8 cell-stage visible inside
Fecal occult blood may be
Ancylostoma braziliense Cutaneous larva migrans/ Filariform larva penetrates present
Ancylostoma caninum (dog intense skin itching, snake-like intact skin but cannot mature in Usually a presumptive
tracks humans diagnosis; exposure
and cat hookworms)
Strongyloides stercoralis Threadworm strongyloidiasis: Filariform larva penetrates Larvae in stool, serology
Early: pneumonitis, abdominal intact skin; autoinfection
Trichinella spiralis leads to indefinite infections Muscle biopsy; clinical findings:
pain, diarrhea unless treated fever, myalgia, splinter
Later: malabsorption, ulcers, hemorrhages, eosinophilia
Viable encysted larvae in
bloody stools meat are consumed: wildgame
meat
Trichinosis: larvae encyst in
muscle → pain
►►Filarial Nematodes
Species Disease Transmission/Vector Diagnosis
Mosquito
Wuchereria bancrofti; Brugia Elephantiasis Microfilariae in blood,
malayi Chrysops, mango flies eosinophilia
Loa loa Pruritus, calabar swellings Blackflies Microfilariae in blood,
(African eye worm) eosinophilia
River blindness, itchy Drinking water with infected
Onchocerca “leopard” rash copepods Skin snips from calabar
volvulus Creeping eruptions, swellings
ulcerations, rash
Dracunculus medinensis Increased IgE;
(Guinea worm, worm eruption
fiery serpent) from skin
►►Drugs for Helminthic Infections
Most intestinal nematodes (worms) • Mebendazole (↓ glucose uptake and ↓ microtubular structure)
• Pyrantel pamoate (NM agonist → spastic paralysis)
Most cestodes (tapeworms) and • Praziquantel (↑ Ca2+ influx, ↑ vacuolization)
trematodes (flukes)
131
Virology
GENERAL PRINCIPLES │ 5. Microbiology ►►Viral Structure and Morphology Icosahedral Viral Structure Helical
The Basic Virion Naked capsid virus Nucleocapsid (No naked
helical viruses)
DNA or RNA + Structural proteins =
Nucleocapsid (naked capsid virus)
Nucleocapsid + Host membrane Enveloped icosahedral Enveloped
with viral specified glycoproteins* capsid virus helical virus
= Enveloped virus
Lipid
*c ritical for infectiousness of viral bilayer
progeny Glycoprotein
►►DNA Viruses
General Comments About DNA Viruses:
• All are double-stranded except Parvo
• All are icosahedral except Pox, which are brick-shaped complex
• All replicate in the nucleus except Pox
Virus Family DNA Type Polymerase Envelope Area of Replication Major Viruses
Parvovirus ssDNA No Naked Nucleus B19
Papilloma dsDNA No Naked Nucleus Papilloma
Circular
Polyomavirus dsDNA No Naked Nucleus Polyoma
Circular
Adenovirus dsDNA No Naked Nucleus Adenovirus
Linear
Hepadnavirus Partially dsDNA Yes Enveloped Nucleus via RNA HBV
Circular intermediate
Herpesvirus dsDNA No Enveloped Nucleus, assembled HSV, VZV, EBV, CMV
Linear Nuclear in nucleus HHV-6, HHV-8
Poxvirus dsDNA Yes Enveloped Cytoplasm Variola, vaccinia
Linear Molluscum contagiosum
Definition of abbreviations: CMV, cytomegalovirus; ds, double-stranded; EBV, Epstein-Barr virus; HBV, hepatitis B virus; HSV, herpes
simplex virus; ss, single-stranded; VZV, varicella-zoster virus.
Note: Viruses are listed from top to bottom in order of increasing size. If you know them in this order, then you can remember that the
smallest 4 are naked (wearing more clothing makes you larger).
Mnemonic: Pardon PaPa As He Has Pox
Mnemonic: Naked viruses PAPP (you need to be naked for a Pap smear)
132
►►RNA Viruses GENERAL PRINCIPLES │ 5. Microbiology
General Comments About RNA Viruses:
• All are single-stranded except Reo
• Most are enveloped. Only naked ones are Hepe, Calici, Pico, and Reo (Mnemonic: Help! CPR!)
• Some are segmented; Mnemonic: ROBA: Reo, Orthomyxo, Bunya, and Arena – ROBA sounds like ROBOT
• Positive sense RNA = (+)RNA (can be used itself as mRNA)
• Negative sense RNA = (–)RNA
– Complementary to mRNA
– Cannot be used as mRNA
– Requires virion-associated, RNA-dependent RNA polymerase (as part of mature virus)
• Others that carry a polymerase are Reo, Arena, and Retro
►►Double-Stranded RNA Viruses: Reoviridae
RNA Structure Polymerase Envelope Shape Major viruses
Reovirus • Linear dsRNA Yes Naked • Icosahedral • Reovirus
• 10−11 segments • Double shelled • Rotavirus
►►Positive-Sense RNA Viruses
Family RNA Structure Polymerase Envelope Shape Area of Major Viruses
Calicivirus No Naked Icosahedral Replication
• ss⊕RNA, linear • Norwalk
• Nonsegmented Cytoplasm • Norolike
Hepevirus • ss⊕RNA, linear No Naked Icosahedral Cytoplasm Hepatitis E
• Nonsegmented
Picornavirus • ss⊕RNA, linear No Naked Icosahedral Cytoplasm • Polio, ECHO, Entero
• Nonsegmented • Rhino, coxsackie
• Hepatitis A
Flavivirus • ss⊕RNA, linear No Enveloped Icosahedral Cytoplasm Yellow fever, dengue,
• Nonsegmented SLE, hepatitis C, West
Nile virus
Togavirus • ss⊕RNA, linear No Enveloped Icosahedral Cytoplasm Rubella
• Nonsegmented WEE, EEE, VEE
Coronavirus • ss⊕RNA, linear No Enveloped Helical Cytoplasm Coronaviruses
• Nonsegmented SARS agent
Retrovirus • Diploid RNA- Enveloped Icosahedral Nucleus HIV
• ss⊕RNA, linear dependent or truncated HTLV
• Nonsegmented DNA conical Sarcoma
polymerase
Definition of abbreviations: EEE, eastern equine encephalitis; HIV, human immunodeficiency virus; HTLV, human T-cell lymphocytotropic
virus; VEE, Venezuelan equine encephalitis; WEE, Western equine encephalitis.
Mnemonic: Again from smallest (top) to largest (bottom): Call Henry, Pico, and Flo To Come Rightaway
Mnemonic: Picornaviruses: PEE Co Rn A viruses (Polio, Entero, Echo, Coxsackie, Rhino, Hep A)
133
►►Negative-Sense RNA Viruses
GENERAL PRINCIPLES │ 5. Microbiology Virus RNA Polymerase Envelope Shape Area Where Major Viruses
Paramyxovirus Yes Yes Helical Multiplies
• ss – RNA, linear Cytoplasm Mumps, measles
Rhabdovirus • Nonsegmented Yes Yes Bullet- RSV, parainfluenza
shaped, Cytoplasm
• ss – RNA, linear Rabies, VSV
• Nonsegmented helical
Filovirus • ss – RNA, linear Yes Yes Helical Cytoplasm Marburg, Ebola
• Nonsegmented
Orthomyxovirus • ss – RNA, linear Yes Yes Helical Cytoplasm Influenza
• 8 segments
and nucleus
Bunyavirus • ss – RNA, linear to Yes Yes Helical Cytoplasm California and
circular
LaCrosse
• 3 segments,
ambisense encephalitis,
Hantavirus
Arenavirus • ss – RNA, circular, Yes Yes Helical Cytoplasm Lymphocytic
• 2 segments: 1 – choriomeningitis
sense, 1 ambisense
virus, Lassa fever
Definition of abbreviations: ds, double-stranded; RSV, respiratory syncytial virus; ss, single-stranded; VSV, vesicular stomatitis virus.
Mnemonic (in order of increasing size): Pain Results From Our Bunions Always (Pain is a negative thing!)
Or, to remind you of life-cycle: Bring A Polymerase Or Fail Replication
►►Viral Genetics
Phenotypic mixing • Related viruses coinfect cell (virus A and virus B)
• Resulting proteins on the surface are a mixture capsid of AB around nucleic acid of either A or B
Phenotypic masking • Related viruses coinfect cell (virus A and virus B)
• Capsid of proteins of virus A form around nucleic acid of B
Complementation • Two related defective viruses infect the same cell; if they are defective in different genes, viral progeny
(still with mutated DNA) will be formed
• If they are defective in the same gene, no progeny will be formed
• Coinfection of hepatitis B and D is a clinical example of complementation where HBV supplies
the needed surface antigen for hepatitis D
Genetic reassortment • Two different strains of a segmented RNA virus infect the same cell.
(genetic shift)
• Major new genetic combinations are produced through “shuffling,” resulting in stable and
dramatic changes
• This results in pandemics of disease
Genetic drift • Minor antigenic changes from mutation
• Occurs in many viruses, particularly RNA types
• Most noted in HIV and influenza
Viral vectors • Recombinant viruses are produced that have combinations of human replacement genes with the
defective viral nucleic acid
134
►►Antiviral Agents
As viruses rely on host machinery to produce viral products, selectivity must be achieved by targeting minute differences in viral enzymes. GENERAL PRINCIPLES │ 5. Microbiology
This may be accomplished at any stage in the viral “life cycle” including adsorption, penetration, nucleic acid synthesis, late protein
synthesis, protein processing, viral product packaging, and viral release.
Class/Agent Mechanism of Action Spectrum/Clinical Mechanism(s) Toxicity/Notes
Applications of Resistance
ANTIHERPETICS
Acyclovir Inhibit viral DNA HSV, VZV (esp. Decreased activity • Fairly well-tolerated
Famciclovir polymerases famciclovir, valacyclovir) or loss of thymidine (esp. oral), some
Valacyclovir kinase/DNA nausea/vomiting
Activated by viral thymidine polymerase
kinase (TK); • IV use associated
with seizure, delirium,
• F amciclovir is oral prodrug crystalluria (maintain
converted to penciclovir hydration)
• V alacyclovir is oral prodrug • F amciclovir and
of acyclovir valacyclovir have
much greater oral
• Mechanism of penciclovir bioavailability and
same as acyclovir longer t1/2 than
acyclovir
Ganciclovir Similar to acyclovir CMV (e.g., CMV Similar to acyclovir Dose-limiting leukopenia,
retinitis), HSV, VZV thrombocytopenia;
crystalluria (maintain
hydration)
Foscarnet Inhibits DNA and RNA • C MV retinitis in • Dose limiting
polymerases; does not AIDS patients nephrotoxicity
ANTI-INFLUENZA require activation by kinases
DRUGS (may be effective in acyclovir-, • A cyclovir-resistant • Electrolyte imbalance
Amantadine ganciclovir-resistant strains) mucocutaneous (can lead to seizures)
Rimantadine HSV in immuno
compromised patients
Oseltamivir
Zanamivir Block viral penetration/ • Influenza A Current isolates are • A taxia
uncoating of influenza A (prophylaxis) resistant • I ncreased seizure
virus via interaction with
viral M2 protein • Amantadine also used Resistance due activity
in Parkinson disease to mutations in • Dizziness &
Inhibit neuraminidases to stimulate dopamine M2 protein (no
made by influenza A and B release cross resistance hypotension
(enzymes that promote virion to neuraminidase • R imantadine better
release and prevent clumping Prophylaxis, but may ↓ inhibitors)
of these virions), decreasing duration of flu symptoms tolerated in elderly
viral spread by 2-3 days Mutations to viral
neuraminidase Oseltamivir: oral prodrug;
GI discomfort
Zanamivir: inhalational
drug; cough,
bronchospasm in
asthmatics
Ribavirin Inhibits viral RNA synthesis by Influenza A & B, Dose-dependent
altering the nucleotide pools Parainfluenza, hemolytic anemia
and normal messenger RNA RSV, paramyxoviruses Unknown
formation HCV (combined with (Continued)
α−interferon), HIV
135
The words you are searching are inside this book. To get more targeted content, please make full-text search by clicking here.
[libribook.com] MedEssentials for the USMLE Step 1 14th Edition
Discover the best professional documents and content resources in AnyFlip Document Base.
Search
[libribook.com] MedEssentials for the USMLE Step 1 14th Edition
- 1 - 50
- 51 - 100
- 101 - 150
- 151 - 200
- 201 - 250
- 251 - 300
- 301 - 350
- 351 - 400
- 401 - 450
- 451 - 500
- 501 - 550
- 551 - 587
Pages: