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Microbiology - Immune Evasion
Lectures 20-21
57
Microbiology
Professional
09/21/2010

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Term
3 distinct phases of infection
Definition
innate immunity (immediate: 0-4 hrs)

early induced response (early: 4-96)

adaptive immune response (late: >96hrs)
Term
innate immunity phase of infection
Definition
recognition of NONSPECIFIC effectors (physical/physiological barriers and alternative pathway of complement)
Term
early induced response phase of infection
Definition
inflammation by phagocytic leukocytes (macs and neutrophils)

infection --> recruitment of effector cells (macs and neutrophils) --> recognition, activation of effector cells --> removal of infectious agent
Term
adaptive immune response phase of infection
Definition
>96hrs

antigen-specific response involving lymphocytes

infection --> transport of antigen to lymphoid organs --> recognition by naive B and T cells --> clonal expansion and differentiation to effector cells --> removal of infectious agent
Term
latency
Definition
ability of a pathogen to reside in its host without attracting the attention of the immune system
Term
ex's of latent pathogens
Definition
herpes simplex virus

human immunodeficiency virus
Term
reactivation
Definition
period of active replication and disease that pathogens enter after being latent

ex - herpes simplex virus (outbreaks)
Term
herpes simplex virus (an example of latent evasion)
Definition
prior to complete clearance by immune system, virus enters sensory neurons

neurons - long lived, express little MHC

thus, neurons containing virus are overlooked by immune system; don't activate CTLs - virus enters latent state

reactivation occurs by the likes of stress-induced hormonal changes or other infections

cold sores
Term
latent human immunodeficiency virus
Definition
hides in mostly T lymphocytes and macrophages

retrovirus (uses reverse transcriptase to copy and add its RNA genome to host cell's)
Term
alternative complement pathway
Definition
activated by numerous bacterial and fungal products; one of the first defenses to infection

lipopolysaccharide (LPS) in gram negative and lipoteichoic acid in gram positive bacteria are two potent complement activators

pathogen surfaces --> C3, B, D --> C3 convertase
Term
lipopolysaccharide (LPS)
Definition
characteristic of gram negative bacteria's cell walls

activates complement
Term
lipoteichoic acid
Definition
characteristic of gram positive bacterial cell walls
Term
3 ways to evade alternative complement pathway
Definition
long-chain polysaccharides on "smooth" strains of Salmonella (O-Antigens)

sialic acid in lipopolysaccharide of Neisseria gonorrhea (LOS - sialic acid terminal sugar in LPS - grabs factor H)

M-protein expressed by Streptococcus pyogenes (virulence factor that binds factor H)
Term
"smooth" strains of Salmonella avoid activating complement how?
Definition
differ from "rough strains" that have short chained polysaccharides

also known to evoke strong immunogenic responses

these "O-Antigens" avoid complement binding
Term
Neisseria gonorrheae avoids activation of complement how?
Definition
sialic acid is an inhibitor of complement (grabs factor H)

sialic acid is the terminal sugar of neisseria gonorrheae's LPS - collectively called LOS (lipooligosaccharide)
Term
Streptococcus pyogenes avoids activation of complement how?
Definition
expresses M-protein

M-protein binds to factor H

C3b is cleaved; complement activation avoided
Term
Proteins associated with complement activation regulation (regulators of complement activation - RCA)

in other words, proteins that prevent host cells from being destroyed by complement pathway
Definition
factor H

C4b-binding protein (C4bBP)

complement receptor type 1 (CR1) and membrane cofactor protein (MCP)

decay-acelerating factor (DAF)

CD59
Term
Factor H
Definition
inhibits complement activation by activating factor I on C3b

factor I (once activated) cleaves C3b

C3b-mediated opsonization prevented

also prevents C3b from joining the complex that forms the C5 convertase that leads to formation of highly destructive Membrane Attack Complex
Term
C4b-binding protein (C4bBP)
Definition
co-factor in the CLEAVAGE of C4b by factor I

this inhibits it from interacting with C2a in the formation of C3 convertase
Term
Complement receptor type 1 (CR1) and Membrane cofactor protein (MCP)
Definition
both cofactors for the factor I cleavage of both C4b and C3b
Term
Decay-accelerating factor (DAF)
Definition
binds C3 convertase of bot the classical and alternative pathways

this results in disassociation of the convertase complex
Term
CD59
Definition
inhibits the formation of the MAC by interfering with the deposition of C9 molecules

deposition = settling on surface
MAC = membrane attack complex
Term
evasion of phagocytes by surrounding pathogens with protective barriers (fibrin barriers and capsules)
Definition
coagulase/Staphylokinase produced by Staphylococcus aureus (wall of fibrin made with help from COAGULASE - promotes clot formation and STAPHYLOKINASE - digests clot)

Polysaccharide capsule expressed by Streptococcus pneumoniae (90 diff polysaccs on cell surface create thick slimy wall - CAPSULE)
Term
Staphylococcus aureus evades phagocytosis how?
Definition
Coagulase/Staphylokinase production

Coagulase - generates a fibrin clot around cell (prothrombin --> thrombin)

Staphylokinase - digests fibrin clot when pathogen is ready to spread

** can also kill phagocytes with PVL**
Term
Streptococcus pneumoniae evades phagocytosis how?
Definition
has 90 different polysaccharides on its surface that collectively form a slimy wall - CAPSULE

many of these polysaccharides are immunogenic, however
Term
Streptococcus pyogenes avoids phagocytosis by inhibiting what? how?
Definition
it produces C5a peptidase that inhibits phagocyte chemotaxis (following of phagocyte)

C5a peptidase - cleaves the potent leukocyte chemoattractant C5a (side product of complement activation)

C5a (together with C3a) are ANAPHYLOTOXINS (increase vascular permeability - easy diapedisis)
Term
C5a peptidase
Definition
cleaves C5a

C5a is important attractant
C5a is a crucial chemoattractant produced by complement activation

phagocytes use C5a to track down pathogens

this makes C5a peptidase production very useful to pathogens wanting to escape phagocytes
Term
Leukocidins
Definition
an exotoxin produced by bacteria with selectivity for neutrophils and/or macrophages

panton-valentine leukocidin (S. aureus)

YOPs proteins (Yersinia pestis)
Term
Panton-Valentine leukocidin (PVL)
Definition
produced by Staphylococcus aureus

it is a pore-forming cytotoxin produced by some strains of S. aureus

increases virulence

present in the majority of community-associated methicillin-resistant S. aureus (CA-MRSA)
Term
YOPs
Definition
Yersinia Outer Proteins of Yersinia pestis

bacteria is agent of plaque

YOP B/D - forms pores in the cell membranes of host macrophages and have been linked to cytolysis

YOP J - injected into cytoplasm of host cells via type III secretion and interfere with signaling pathways required for various phagocytic activities, activation of cytokine genes, and can also trigger apoptosis
Term
give an example of a pathogen that evades phagocytosis by inhibiting lysosome-phagosome fusion
Definition
Legionella pneumophila

causes atypical pneumonia referred to legionellosis (Legionnaire's diseases)

readily enters and grows within human alveolar macrophages
Term
how does Legionella pneumophila evade a macrophage?
Definition
it inhibits lysosome-phagosome fusion by entering the host cell by a specialized phagocytic process involving coiling of a single pseudopod around the bacterium

incomplete signaling results in modification of the membranes of the phagosomes that inhibits their fusion with lysosomal granules
Term
give four examples of pathogens that can evade phagocytosis by PHYSICAL/CHEMICAL RESISTANCE to LYSOSOMAL DAMAGE
Definition
Mycobacterium tuberculosis (Hydrophobic shield)

Bacillus anthracis (unnatural substrate for protease)

Salmonella typhimurium (PhoP-PhoQ Regulon)

Staphylococcus aureus (contains catalase)
Term
how does hydrophobic shield protect M. tuberculosis
Definition
Mycobacterium tuberculosis, cause of tuberculosis, lives inside macrophages

thick waxy hydrophobic cell wall components, MYCOLIC ACIDS, are not easily attacked by lysosomal enzymes or penetrated by reactive oxygen products

surface lipids with long and short-chain fatty acids - trehalose dimycolic acid (cord factor)
Term
how does Bacillus anthracis avoid being destroyed by lysosome?
Definition
it resists killing and digestion by means of its POLY D-GLUTAMATE capsule

isomeric D-configuration is not recognized by conventional proteases of lysosomes
Term
how does Salmonella typhimurium avoid digestion by lysosomes and allowed to live inside macrophages?
Definition
must avoid digestion by cationic lysosomal anti-microbial peptides (such as defensins) - these attack the negatively charged phosphoryl groups of lipopolysaccharide (LPS)

S. typhimurium possesses a genetic sensing system known as the PhoP-PhoQ Regulon

PhoQ senses presence of cationic anti-microbial peptide OR a drop in Mg++ ions (happens when lysosome-phagosome fusion occurs); it then is autophosphorylated and activates PhoP

PhoP - transcription factor that after being activated by PhoQ, it activates multiple genes (at least 30) who products interfere with various destructive processes in phagocytes (such as structural change in LPS, reduced cytokine responses, and decreased antigen presentation.
Term
PhoP-PhoQ Regulon
Definition
sensory of cationic anti-microbial peptides or drop in Mg++ ions activates PhoQ

PhoQ then activates PhoP

PhoP then activates multiple genes associated with releasing virulence factors that allow it to survive and multiply within macrophages (such as structural changes in LPS, reduced cytokine responses, and decreased antigen presentation
Term
How does Staphylococcus aureus avoid digestion by lysosomes?
Definition
it has CATALASE - enzyme that breaks down H2O2 (hydrogen peroxide)

H2O2 is essential in oxidative respiratory burst
Term
describe the only example of evasion by ESCAPING from phagosome (Listeria monocytogenes)
Definition
L. monocytogenes relies on several molecular species for early LYSIS of PHAGOSOME -
1. Pore-forming Hemolysin (listeriolysin O)
2. Two forms of phopholipase C

ACTIN-BASED MOTILITY in cytoplasm - Listeria interacts with host cell's actin cytoskeletal system, turning it into its own form of transportation

Listeria induces its own movement through the host's cytoplasm using cell actin polymerization and formation of microfilaments (cell-to-cell transmission)

this method of spreading btwn cells protects pathogen from antibodies and other extracellular antimicrobial substances
Term
what are the two examples of evasion by MISDIRECTING the IMMUNE RESPONSE
Definition
depletion of antigen-specific T cells by superantigens (Streptococcus pyogenes and Staphylococcus aureus)

skewing the TH1 vs. TH2 balance (Mycobacterium leprae)
Term
how do superantigens allow pathogens to misdirect the immune response and evade late-inducible adaptive defenses?
Definition
Streptococcus pyogenes and Staphylococcus aureus

superantigens activate a large # of pro-inflammatory T-cells (TH1 and TH17)

responses are polyclonal and involve as many as 20-40% of all CD4+ T cells - so many can lead to toxic shock syndrome

T cell arm of immune system = state of paralysis
Term
what are the three superantigens of S. aureus and S. pyogenes and what are their respective pathologies?
Definition
Staphylococcal enterotoxin (staph food poisoning)

Staph Toxic Shock Snydrome Toxin (TSST-1) - Toxic Shock Syndrome

Streptococcal exotoxin (scarlet fever; shock)
Term
how does Mycobacterium leprae misdirect the immune response and thus evade the adaptive immune system?
Definition
M. leprae disrupts the balance of TH1 vs. TH2

lepromatous leprosy - ABSENCE of cell-mediated immunity (low/absent T-cell responsiveness = no response to M. leprae antigens)

tuberculoid leprosy (less harmful) - patients demonstrate cell-mediated immunity (inflammation cytokines) but little TH2 cells
Term
describe how lepromatous leprosy and tuberculoid leprosy are different
Definition
lepromatous leprosy - no TH1 cells (inflammatory helper cells); thus, no IL-2, IFN-gama, and TNF-beta; do have TH2 cell presence

tuberculoid leprosy - no TH2 (antibody formation helpers) cell activity/presence, thus, no IL-4, IL-5, and IL-10
Term
describe host-parasite mimicry and give an example
Definition
evasion mechanism is to coat a pathogen with host products so that the immune system recognizes it as "self"

Treponema pallidum - agent of syphilis; binds host FIBRONECTIN, serves 2 purposes
1. bridges pathogen to host tissues
2. cloaks pathogen (makes invisible to immune system)
Term
give 2 examples of pathogens that INTERFERE WITH ANTIBODY FUNCTION
Definition
Staphylococcus aureus - neutralizes opsonizing antibodies with Staphylococcal Protein A

Neisseria meningitis - contains IgA protease (IgA - mucosal antibody)
Term
describe how Staphylococcus aureus interferes with antibody function
Definition
it has staphylococcal protein A - binds IgG through its Fc region; after binding, IgG loses its complement fixing and opsonizing abilities.
Term
describe how Neisseria meningitis interferes with antibody function
Definition
*causes baterial meningitis, in which, pathogen associates with mucosal boundaries thus stimulating mostly the secretion of IgA

IgA protease present in N. meningitis - breaks down IgA and uses its fragments to also defend against IgG
Term
describe how Streptococcus pneumoniae avoids adaptive immunity through ANTIGENIC VARIATION
Definition
antigenic variation = antigen "switching"

S. pneumoniae - each strain carries slightly different polysaccharide antigens in capsules

immunity to one strain leaves individual unprotected to other pneumococcus strains of other "SEROTYPES" (over 90 serotypes!)
Term
describe antigenic DRIFT in the influenza virus
Definition
influenza = RNA virus w/ complex genome (prone to mistakes resulting in generation of point mutations);

Mutations often in genes that code for HEMAGGLUTININ and NEURAMINIDASE proteins

small changes to the genome = small changes in protein epitopes

slight epitope changes = diminished ability for previous antibody to recognize the virus
Term
describe antigenic SHIFT of influenza virus
Definition
shifts are due to INFREQUENT REASSORTMENTS OF GENOMIC SEGMENTS

usually from different host populations such as humans, pigs and birds, etc

MAJOR DIFFERENCES in antigen expression rapidly occur - could result in PANDEMIC
Term
how does Trypanosoma brucei express antigenic variation?
Definition
T. brucei - African sleeping sickness

VARIABLE SURFACE GLYCOPROTEINS - only one VSG protein can be expressed at one time

*can rearrange VSG genes through GENE CONVERSION (gene in expression site removed and replaced by another VSG gene of similar, but not identical sequence)

host goes through waves of typanosome VSG variants
Term
describe how Neisseria gonorrhea incorporates antigenic variation
Definition
N. gonorrhea is bacterial agent of gonorrhea (obviously)

expresses a PILUS STRUCTURE (allows pathogen to bind to host epithelial cells)

numerous variations of this protein, called PILIN, that compose the pilus structure

like trypanosome's VSGs, N. gonorrhea's pilin variations are "switched" in and out - once immune system targets one variation (lets say, pilin A), then GENE REARRANGEMENT takes place and the pathogen begins to express a different variation of pilin (lets say, pilin B)
Term
describe how some pathogens evade adaptive immunity through DECREASED EXPRESSION of MHC molecules
Definition
many of these examples interfere with class I MHC molecules (to prevent apoptosis of their host cells)

no antigen presenting molecules = reduced CTL recognition and elimination

3 examples
1. HIV -1
2. Cytomegalovirus (CMV)
3. Adenovirus
Term
describe mechanism in which HIV avoids adaptive response with MHC manipulation
Definition
down-regulates MHC class I and beta2m transcription

blocks TAP transport of peptides into the ER

Increases MHC class I turnover via endocytosis (allele-specific)

effects on MHV class I appear to have specificity for certain class I molecules; that is, significant down-regulation of HLA-A and HLA-B is observed, but there is little impact on the expression of HLA-C and HLA-E. Since HLA-E is involved in NK cell inactivation, this selectivity allows HIV-1-infected cells to escape lysis by NK cells.
Term
Cytomegalovirus (CMV) avoids adaptive immune response through manipulation of MHC molecules, describe this mechanism
Definition
produces MHC class I homolog that competes for beta2m

binds TAP in ER and inhibits peptide translocation

**CMV encodes an MHC class I heavy chain homolog; this heavy chain mimic can bind beta2m, thus preventing the association with the real heavy chain necessary for transport to the surface. Displaced MHC heavy chains are "ejected" into the cytoplasm where they are fed to proteosomes for degradation.

The CMV heavy chain mimic also inhibits TAP, thereby blocking peptide loading of HLA-A, -B, and -C molecules, but not HLA-E; this preservation of HLA-E ensures protection against NK cells
Term
describe mechanism in which adenovirus avoids adaptive immune response via manipulation of MHC molecules
Definition
it retains MHC molecules in the ER

prevents TAP association with tapasin
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