MODULE 3 - Microbial Virulence Mechanisms Flashcards
how is adhesion important to an extracellular pathogen and give examples of these pathogens?
colonisation of host mucosal surfaces or artificial surfaces to allow for efficient delivery of exotoxins into the host cell
contact to surface of cell allows most effective toxin action
first step of biofilm formation is adherence to surface
e.g. Neisseria spp, S. aureus, uropathogenic E. coli, enteropathogenic E. coli
how is adhesion important to intracellular pathogens and what microbes do this?
critical step that precedes internalisation - adhesion first step to get the microbe inside cell where its safe
bacteria - listeria
protozoa - toxoplasma, plasmodium
what are the three things adhesion can be mediated by?
multi-component structures (pili)
single protein adhesins
a receptor derived from bacterium
what is a pili?
multicomponent structures made of lots of proteins, with the one at the tip mediating adhesion
they have lots of roles including in conjugation and adhesion
what is a P-pili expressed by and allow adherence to?
expressed by uropathogenic E. coli (UPEC) which colonise the urinary tract and infect the kidney
mediate bacterial adherence to epithelial cells of the bladder and kidney
responsible for 80% UTIs
what is the structure of the P-pilus?
PapG: adhesion that binds to a receptor on the surface of the human cell
PapA: the major structural component of the pilus
PapC: outer membrane protein that forms a channel that other P-pilus components are transported through (important for assembly of pilus)
PapD: chaperone that binds P-pilus components in the periplasm; prevents these proteins from being degraded and presents them to the PapC channel, helps with assembly of pilus
how does assembly of the p-pilus occur?
occurs in ordered fashion starting with tip protein PapG and ending with PapA and PapH
different components of pilus synthesised in periplasm, when in periplasm PapD chaperon keeps them folded correctly
no chaperon they get misfolded and degraded, PapG first protein to go through channel
what are pilicides and why could they be effective for treating UTIs?
chemicals that bind and inhibit the function of chaperones like PapD. Pilicides block P-pilus assembly and could eventually be developed into effective drugs to treat UTIs
what is the human surface receptor for the P-pilus?
globoside (a galactose containing glycolipid)
it contains polysaccharides and lipids and PapG binds to the polysaccharide component of the receptor
why might someone with UPEC not be responding well to antibiotics?
UPEC makes intracellular biofilms
after time this biofilm matures and some bacteria can disperse and go infect other cell
what is a Type IV pili mediate binding to?
mediate binding of bacteria to protein or glycolipid receptors on the surface of host cells (e.g. Neisseria, enteropathogenic E. coli (EPEC))
in the case of some bacteria e.g. Neisseria, type IV pili also promote internalisation of bacteria into human cells
what is Neisseria species?
gram negative diplococcus which commonly colonises nasopharynx (N. meningitidis) or urethra/cervix (N. gonorrheae)
causes meningitis and septic shock
causes gonorrhoea
outline the pathogenesis of N. meningitidis?
type IV pilis plays a critical role in bacterial internalisation into epithelial cells in nasopharynx ultimately resulting in spread to blood and then maybe even spread across blood-brain barrier
describe the structure of the Neisseria type IV pilus?
pilus extends from inner membrane through periplasm then outward
the pilus is dynamic in that it can grow and retract (this is ATP dependent)
PilE (pilin subunit) composes most of it
PilC binds host CD46 receptor
growth involves new pilin subunits being added onto base and retraction involves piling subunits being removed and this is done by ATPase
what is twitching motility mediated by type IV pili?
pili are dynamic and extend or retract due to addition or removal of new PilE subunits at the base (polymerisation and depolymerisation)
this results in twitching motility, which may bring adherent bacteria into close contact with the human cell
what are adhesins?
single proteins which will bind tightly to allow adhesion
binding often leads to bacterial internalisation in the case of many adhesins
what are two examples of single protein adhesins?
invasin protein of yersinia enterocolitica
InlA protein of listeria monocytogenes
these adhesins are bacterial surface proteins that bind to host surface receptors (usually proteins)
how does yersinia enterocolitica get internalised?
there is a receptor on the surface of intestinal M cells (NOT epithelial) which the invasin can target
once inside binds to macrophages which spread them around the blood and then they can go infect other shit
internalisation into M cells contributes to localised inflammation and bacterial dissemination
what is intimin?
single protein adhesion from enteropathogenic E. coli (EPEC)
in this case both the adhesion and the receptor for the adhesion come from the bacterium (it injects receptor into cell)
what is Tir?
the receptor for intimin which EPEC injects into host cell
interaction between intimin and Tir leads to actin filaments forming below Tir creating a pedestal which EPEC sits on on the cell
Tir is in the plasma membrane of human cell
what do EPEC pedestals do?
mediate tight and persistent adhesion to the intestinal epithelium
outline the two-step process that is EPEC adhesion to human intestinal epithelial cells?
step 1: binding of a type IV ‘bundle forming pilus’ to host cell
step 2: bacterial injection of Tir into the host cell plasma membrane. EPEC then binds to Tir through it’s bacterial outer membrane protein intimin. Tir/intimin interaction elicits the formation of a ‘pedestal’
degradation of microvilli is one thing which allows it to get closer to the cell for internalisation
is Tir essential for bacterial colonisation of intestine?
yeah
what are the three general mechanisms of invasion?
interaction with host surface receptors (active participation of both bacterium and host cell e.g. listeria)
injection of bacterial effectors into host cytosol (active participation of both both bacterium and host cell e.g. salmonella)
active penetration into the host cell (active participation of parasite only; host cell is passive e.g. toxoplasma, plasmodium (protozoans))