Transcript Host microbe interactions BIO475 Dr. Dieter M. Schifferli

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