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Host-microbe interactions BIO475 - Dieter M. Schifferli - 11.19.03 • Encounter of the host and the microbe – Travel (host and/or microbe) – Environmental conditions – Transmission • Aerosol • Faecal-oral • Venereal • Vectors • Productive interaction - Microbial adhesion to host surface molecules – Microbial ligand (environment/gene expression: infectious dose) – Appropriate host/surface and receptor (host's genetic constitution, age) • Potential progression - Colonization of the host surface (local multiplication) – Nutrients – Resistance to new environment (IgA protease) • Invasion of epithelial barriers (inter- or intracellular) – Ligand-receptor interaction – Microbe-induced invasion • Invasion of subepithelial tissue/inflammatory response – Polar movements and exit at the baso(lateral) epithelial surface – Adaptation to environment ( Fe2+) – Extracellular resistance to complement and PMN degranulation products – inhibition of phagocytic uptake • inhibition of chemotaxis • inhibition of opsonization • inhibition of adsorption • binding to surface molecules which do not trigger the uptake • cytocidal (hemolysin, leucotoxin) • Uptake by phagocytic cell (PMN leucocyte, macrophage) – opsonization (complement, antibodies) – non-opsonic phagocytosis/ lectinophagocytosis • Intraphagocytic survival – Inhibition of degranulation (no vacuolar fusion) – Diversion of lysosomal vacuoles to the cytoplasm (cytolysis) – Resistance to lysosomal products ( pH) – Resistance to oxydative burst (catalase) – Macrophage • Resistance to NO • Escape the phagosome, to RER, cytoplasm (nutrient rich, multiplication) • Local or directed dissemination – Spreading factors/enzymes (interstitial tissue) – Tissue tropism (e.g. nerves) • Dissemination to/through the lymphatic system – Strong antiphagocytic activity (extracellular survival) – Intraphagocytic hiding and survival (Trojan horse) • Entering blood vessels - primary bacteremia – Via lymphatic system or subepithelial blood vessels – Direct (bite, trauma) • Uptake by reticuloendothelial cells (liver, spleen) - secondary bacteremia (septicemia) – Resistance to clearance by RE cells – Resistance to specific immune response • • • • • • • • • High microbial multiplication rate Tolerance (poor antigen,prion) Microbial mimicry of host antigens Immunosuppression Inhibition of cytokine or receptor synthesis/activity Inhibition of antigen presentation by MHC Induction of non-protective response Release of soluble "decoy" antigen Antigenic variation • Adhesion/invasion of endothelial cells/tissue – Toxic damage to endothelial cells • Damage to the tissue – Multiplication (competition, apoptosis) – Microbial toxins (cytotoxic or cytotonic) • Extracellular – Catabolic enzymes » Proteases (elastase) » Glycosidases (hyaluronidase) » Lipases (phospholipases) » Activation of host enzymes – Pore-forming (hemolysins) – Mitogens (T-cells- superantigens) • Intracellular – B(inding) + A(ctive) toxins or injected toxins – Modifying enzymes » ADP-ribosylating ( protein synthesis or actin polymerization, adenylate cyclase) » Glycosylation, or » Deamidation of Rho family GTPases » Specific N-glycosidase ( protein synthesis) » Adenylate cyclase – Catabolic enzymes (endoproteases) – Mimicking of GTPase exchange factors/ activating proteins (GEF/GAP) • Intracellular microbe • Synergism • Cell-associated toxins (LPS) • Inflammatory response from the host • Immunopathological reactions (CMI) • Secondary damages (liver, coagulation) • Persistent infection – Temporal carrier ± symptoms/shedding (poorly accessible loci of infection for the host's defenses: bile, urine, saliva, milk) – Temporally/spatially contained until reactivation (latency) – Noncultivable "dormant" forms of microbes • Exit from the host – Direct – Excretory or secretory organs (through epithelial cells – Transplacental Enterotoxigenic E. coli (ETEC) watery diarrhea • Colonizing factors - fimbriae,pili,adhesin – Host and receptor specificity – Associated with certain O-serogroups • Enterotoxins (plasmid) – Heat-labile toxins - 1 A & 5 B subunits • cAMP - Cl- secretion, Na+ resorption, H2O efflux – Heat-stable toxins - peptides • STa: cGMP Uropathogenic E. coli (UPEC) Mulvey et al. PNAS, 2000, 97:8829 Prevalence of Bacteriuria P-fimbriaemediated pathogen-host cross-talk at the uroepithelial cell surface Neutrophil migration to infected mucosal sites Bacterial activation of epithelial cell cytokine responses Classical endocytic pathway of phagocytosis FimH-CD48 endocytic pathway of phagocytosis SLTEC Enteropathogenic E. coli (EPEC) Attaching and effacing E. coli (AEEC) • Fimbriae • Injection of bacterial molecules into host cells subverting – Cytoskeletal machinery – Signal transduction mechanisms Attaching and effacing lesions – Loss of microvilli of enterocytes – Effacement and cupping (polymerized actin under pedestal) Shiga-like toxin producing E. coli (SLTEC) (Verotoxigenic E. coli, VTEC) • Like EPEC: attaching & effacing • Shiga-like toxin (verotoxin) - 1 A & 5 B – Farm animals (cattle) as carriers – Hemorrhagic colitis (humans) – Humans - Enterohemorrhagic E. coli (EHEC, STEC), e.g. O157 • Hemolytic uremic syndrome (HUS) • Thrombotic thrombocytopenic purpura SALMONELLA Environmentally regulated virulence factors • Flagella • Fimbriae - intestinal epithelial cells - M cells (Peyer's patches) • Invasion - injection of bacterial proteins subverting – Cytoskeletal machinery – Signal transduction mechanisms resulting in macropinocytosis (formation of blebs, ruffles, splash) Salmonella spreading • Survival and multiplication in macrophages, apoptosis • Spreading - transport to regional lymph nodes, spleen, liver and hematogenous dissemination MØ 3 hrs. p.i. with wild-type S.tm.: apoptotic morphology, membrane blebbing, fragmentation, chromatin condensation (A), presence of apoptotic bodies (B). C: MØ with necrotic morphology. D: Uninfected macrophage Salmonellosis - gastroenteritis • Injected Salmonella proteins – Induce an inflammatory response • cytokines, infiltration of PMNs • prostaglandins ( cAMP, Na+ absorption , Cl- secretion ) – Stimulate Ca2+ and inositol polyphosphate fluxes • Cl- secretion Yersinia • Facultative intracellular pathogens • Transcriptional activation of effector molecules (= to be injected into host cells) upon contact