Microbiology – Immune Evasion – Flashcards
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| 3 distinct phases of infection |
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| innate immunity (immediate: 0-4 hrs) early induced response (early: 4-96) adaptive immune response (late: >96hrs) |
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| innate immunity phase of infection |
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| recognition of NONSPECIFIC effectors (physical/physiological barriers and alternative pathway of complement) |
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| early induced response phase of infection |
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| inflammation by phagocytic leukocytes (macs and neutrophils) infection --> recruitment of effector cells (macs and neutrophils) --> recognition, activation of effector cells --> removal of infectious agent |
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| adaptive immune response phase of infection |
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| >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 |
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| latency |
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| ability of a pathogen to reside in its host without attracting the attention of the immune system |
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| ex's of latent pathogens |
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| herpes simplex virus human immunodeficiency virus |
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| reactivation |
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| period of active replication and disease that pathogens enter after being latent ex - herpes simplex virus (outbreaks) |
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| herpes simplex virus (an example of latent evasion) |
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| 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 |
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| latent human immunodeficiency virus |
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| hides in mostly T lymphocytes and macrophages retrovirus (uses reverse transcriptase to copy and add its RNA genome to host cell's) |
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| alternative complement pathway |
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| 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 |
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| lipopolysaccharide (LPS) |
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| characteristic of gram negative bacteria's cell walls activates complement |
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| lipoteichoic acid |
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| characteristic of gram positive bacterial cell walls |
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| 3 ways to evade alternative complement pathway |
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| 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) |
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| "smooth" strains of Salmonella avoid activating complement how? |
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| differ from "rough strains" that have short chained polysaccharides also known to evoke strong immunogenic responses these "O-Antigens" avoid complement binding |
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| Neisseria gonorrheae avoids activation of complement how? |
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| 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) |
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| Streptococcus pyogenes avoids activation of complement how? |
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| expresses M-protein M-protein binds to factor H C3b is cleaved; complement activation avoided |
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| 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 |
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| factor H C4b-binding protein (C4bBP) complement receptor type 1 (CR1) and membrane cofactor protein (MCP) decay-acelerating factor (DAF) CD59 |
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| Factor H |
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| 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 |
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| C4b-binding protein (C4bBP) |
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| co-factor in the CLEAVAGE of C4b by factor I this inhibits it from interacting with C2a in the formation of C3 convertase |
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| Complement receptor type 1 (CR1) and Membrane cofactor protein (MCP) |
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| both cofactors for the factor I cleavage of both C4b and C3b |
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| Decay-accelerating factor (DAF) |
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| binds C3 convertase of bot the classical and alternative pathways this results in disassociation of the convertase complex |
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| CD59 |
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| inhibits the formation of the MAC by interfering with the deposition of C9 molecules deposition = settling on surface MAC = membrane attack complex |
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| evasion of phagocytes by surrounding pathogens with protective barriers (fibrin barriers and capsules) |
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| 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) |
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| Staphylococcus aureus evades phagocytosis how? |
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| 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** |
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| Streptococcus pneumoniae evades phagocytosis how? |
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| has 90 different polysaccharides on its surface that collectively form a slimy wall - CAPSULE many of these polysaccharides are immunogenic, however |
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| Streptococcus pyogenes avoids phagocytosis by inhibiting what? how? |
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| 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) |
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| C5a peptidase |
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| 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 |
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| Leukocidins |
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| an exotoxin produced by bacteria with selectivity for neutrophils and/or macrophages panton-valentine leukocidin (S. aureus) YOPs proteins (Yersinia pestis) |
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| Panton-Valentine leukocidin (PVL) |
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| 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) |
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| YOPs |
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| 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 |
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| give an example of a pathogen that evades phagocytosis by inhibiting lysosome-phagosome fusion |
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| Legionella pneumophila causes atypical pneumonia referred to legionellosis (Legionnaire's diseases) readily enters and grows within human alveolar macrophages |
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| how does Legionella pneumophila evade a macrophage? |
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| 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 |
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| give four examples of pathogens that can evade phagocytosis by PHYSICAL/CHEMICAL RESISTANCE to LYSOSOMAL DAMAGE |
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| Mycobacterium tuberculosis (Hydrophobic shield) Bacillus anthracis (unnatural substrate for protease) Salmonella typhimurium (PhoP-PhoQ Regulon) Staphylococcus aureus (contains catalase) |
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| how does hydrophobic shield protect M. tuberculosis |
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| 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) |
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| how does Bacillus anthracis avoid being destroyed by lysosome? |
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| it resists killing and digestion by means of its POLY D-GLUTAMATE capsule isomeric D-configuration is not recognized by conventional proteases of lysosomes |
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| how does Salmonella typhimurium avoid digestion by lysosomes and allowed to live inside macrophages? |
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| 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. |
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| PhoP-PhoQ Regulon |
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| 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 |
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| How does Staphylococcus aureus avoid digestion by lysosomes? |
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| it has CATALASE - enzyme that breaks down H2O2 (hydrogen peroxide) H2O2 is essential in oxidative respiratory burst |
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| describe the only example of evasion by ESCAPING from phagosome (Listeria monocytogenes) |
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| 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 |
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| what are the two examples of evasion by MISDIRECTING the IMMUNE RESPONSE |
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| depletion of antigen-specific T cells by superantigens (Streptococcus pyogenes and Staphylococcus aureus) skewing the TH1 vs. TH2 balance (Mycobacterium leprae) |
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| how do superantigens allow pathogens to misdirect the immune response and evade late-inducible adaptive defenses? |
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| 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 |
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| what are the three superantigens of S. aureus and S. pyogenes and what are their respective pathologies? |
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| Staphylococcal enterotoxin (staph food poisoning) Staph Toxic Shock Snydrome Toxin (TSST-1) - Toxic Shock Syndrome Streptococcal exotoxin (scarlet fever; shock) |
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| how does Mycobacterium leprae misdirect the immune response and thus evade the adaptive immune system? |
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| 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 |
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| describe how lepromatous leprosy and tuberculoid leprosy are different |
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| 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 |
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| describe host-parasite mimicry and give an example |
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| 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) |
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| give 2 examples of pathogens that INTERFERE WITH ANTIBODY FUNCTION |
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| Staphylococcus aureus - neutralizes opsonizing antibodies with Staphylococcal Protein A Neisseria meningitis - contains IgA protease (IgA - mucosal antibody) |
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| describe how Staphylococcus aureus interferes with antibody function |
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| it has staphylococcal protein A - binds IgG through its Fc region; after binding, IgG loses its complement fixing and opsonizing abilities. |
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| describe how Neisseria meningitis interferes with antibody function |
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| *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 |
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| describe how Streptococcus pneumoniae avoids adaptive immunity through ANTIGENIC VARIATION |
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| 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!) |
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| describe antigenic DRIFT in the influenza virus |
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| 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 |
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| describe antigenic SHIFT of influenza virus |
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| 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 |
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| how does Trypanosoma brucei express antigenic variation? |
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| 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 |
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| describe how Neisseria gonorrhea incorporates antigenic variation |
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| 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) |
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| describe how some pathogens evade adaptive immunity through DECREASED EXPRESSION of MHC molecules |
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| 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 |
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| describe mechanism in which HIV avoids adaptive response with MHC manipulation |
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| 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. |
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| Cytomegalovirus (CMV) avoids adaptive immune response through manipulation of MHC molecules, describe this mechanism |
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| 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 |
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| describe mechanism in which adenovirus avoids adaptive immune response via manipulation of MHC molecules |
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| it retains MHC molecules in the ER prevents TAP association with tapasin |
