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87 Cards in this Set

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Describe regular, commensal E. coli strains.
Abundant part of microflora in the intestine
Rarely cause disease
Some strains are used as probiotics
What kind of diseases do pathogenic E. coli cause?
Diarrhea
Dysentery
Hemolytic uremic syndrome (kidney)
Urinary tract infections
Septicemia
Pneumonia
Meningitis
IBD (inflammatory bowel disease)
How do you keep tract of/differentiate between different strains?
Serotyping reactivity of surface antigens to antibodies
What is a serogp?
O: O-Ag of LPS
160 serogps, most are normal flora
What is a serotype?
H: hauch=flagellum
Describe regular, commensal E. coli strains.
Abundant part of microflora in the intestine
Rarely cause disease
Some strains are used as probiotics
What kind of diseases do pathogenic E. coli cause?
Diarrhea
Dysentery
Hemolytic uremic syndrome (kidney)
Urinary tract infections
Septicemia
Pneumonia
Meningitis
IBD (inflammatory bowel disease)
How do you keep tract of/differentiate between different strains?
Serotyping reactivity of surface antigens to antibodies
What is a serogp?
O: O-Ag of LPS
160 serogps, most are normal flora
What is a serotype?
H: hauch=flagellum
What is K?
Capsular antigen
(K1 is the leading G- organism that cuases neonatal meningitis)
What is virotyping based on?
Virulence factors
How is virotyping determined?
DNA hybridization or PR virulence factor genes
What are some virulence ass't characteristics?
Attachment to host cells
Effects of attachment
Toxins
Invasiveness
What are common virotypes of E. coli?
ETEC: enterotoxigenic
EAggEC/EAEC= enteroaggregative
EPEC: enteropathogenic
EHEC:enteroheorrhagic
DAEC: diffusely adhering
EIEC: enteroinvasive
UPEC: uropathogenic
AIEC: adherent/invasive
How many serogps/types does 1 virotype usually have?
More than 1
What is the most common EHEC strain?
O157:H7
How are E.coli clasified by adherence?
Localized adherence: ETEC, EHEC, EPEC
Stacked brick: EAEC
How are E. colis classified in an outbreak situation?
Isolate organism from samples of infeted patients
Antibiotic resistance profile
serological evidence
Genotyping
How do E. coli strains become pathogenic?
Acquisition of virulence factors
What defines a virulence factor?
Confers increased ability to colonize/survive/persist/cuase disease in the host
Includes toxins, adhesins, secreted factors, iron acquisition systems
What are Falkows postulates about virulence factors?
1) Gene encoding factor present in strains of bacteria that cause the disease
2) Not present in avirulent strains
3) Disrupting the gene reduces virulence
4) Re-introduction of gene restores virulence
5) The gene is expressed during infection
6) Specific immune response to gene protects (not necessarily)
How does E. coli acquire virulence factors?
1) Gain of genes from mobile genetic elements
2) Black holes: loss of genes that cause increased virulence (not that common)
What are the mobile elements that cause gain of genes? For which strain of E. coli?
Plasmids: ETEC toxin genes
Transposons: ETEC heat-stable toxin (ST)
Pathogenicity islands: EPEC, EHEC
Bacteriophages: EHEC shiga toxin (Stx)
What is the difference btw a pathogenic EHEC strain and K12?
EHEC has extra 1.3 Mb
->Pathogenic strain has extra DNA compared with the non-pathogenic strains
Do all E.coli strains have the smae mode of pathogenesis?
No
What does ETEC do?
Cause watery diarrhea in ppl who aren't previously exposed
-One of the most common bacterial cause of diarrhea in kids in the developing world
-Traveller's diarrhea
-Can cuase death in children
How many ETEC bacteria are needed to cause disease in a healthy person?
10^8 - 10^10
What is required to recover from this infection?
Generally just wait it out and drink water
Don't need hospital or antbiotics
How does ETEC cause infection?
Adheres to intestinal mucosa
Does NOT invade cells
Produces toxins that act on mucosal cells, causing diarrhea
What is required for ETEC adherence?
Colonization factor Ags (CFAs)
-Fimbriae mainly found in ETEC strains
More than 20types
CFA/I/II/III/IV ass't with ETEC strains that cause human disease
What are the ETEC enterotoxins?
LT: heat labile toxin
ST: heat-stabile toxin
ETEC strains can have one or both of these
How are these enterotoxins encoded?
In plasmids
Describe ETEC's LT.
AB toxin
Closely related to cholera toxin
has 1 A subunit and 5 B subunits
Describe the mechanism of action of LT-1.
B component binds a receptor on the host (GM1 ganglioside surface receptor)
A subunits is engulfed
A (catalytic domain) ADP-ribosylates stimulatory G ptns (Gs)
-Gs regulates adenylate cyclase
ADP-ribosylation of Gs constitutively activated a.c.
-inc cAMP and cAMP dependent kinases
-Activates CFTR (main Cl- channel of epithelial cells)
**-Inc Cl- secretion**
-Ion imbalance: loss of control over water= diarrhea
What are the 2 heat stable toxins?
In what do they cause disease?
STa and STb
STa: human disease
STb: animal disease
Describe STa (aa-wise, how many as a precursor etc)
What is its receptor?
72 aa precursor in periplasm
54 aa peptide to extracellular fluid
17 aa mature form
Receptor: guanylate cyclase
Causes increase in cGMP, activates kinases, get fluid loss
What is the end result of ETEC toxins?
Secretion of water into the intetinal lumen
Inhibition of NaCl absorption
=> Watery diarrhea
What therapy can be used for ETEC?
Oral rehydration
->Illness is self-limiting
What does EAggEC/EAEC cause?
Persistent diarrhea in children and AIDS patients
Causes traveller's diarrhea
Resembles ETEC in clinical presentation and response to antibiotics
Where does EaggEC bind?
Small intestine
What form does it take when it binds?
Stacked brick appearance
->clumps when it binds small intestine
What is the adhesin of EAggEC?
Aggregative Adherence Fimbriae (this is in many, but not all EAEC strains)
Is EAggEC an invasive species?
No
What kind of toxins does EAggEC have?
No single virulence factor has been irrefutably ass't with EAggEC virulence
-> very heterogeneous gp
Some toxins: ST-like toxin, ShET, hemolysin etc
What other group is EIEC (enteroinvasive) closely linked to?
Shigella
(would be the same gp if classified today)
What disease do both Shigella and EIEC cause?
Dysentery: abdominal cramps, diarrhea, vomiting, fever, chilld and generalized malaise
How many organisms are required to cause infection?
<10
Describe the pathogenesis of EIEC
Invasion
Escape from vacuole
Actine based cytoplasmic movement
Cell-cell spreading
Do EIEC species produce toxins?
No, whole bact gets engulfed into the cell
What kind of secretion system does EIEC use?
T3SS
Describe the T3SS of EIEC
Encoded by ~20 genes
Present in many G- pathogens
Absent from non-pathogenic bacteria
Secretion triggered by contact with host cells
->though the genes used to create the secretion system are similar between different species, the ptns secreted vary a lot
What do T3SS look like?
Molecular syringe
What is pWR100?
Virulence plasmid
Found in EIEC and Shigella
What does pWR100 encode?
T3SS
What happens if there is no T3SS?
Can't invade host cekk
What do the effector ptns secreted by the T3SS cause?
Actin cytoskeleton rearrangements
What does the cytoskeleton consist of?
Actin microfilaments
Microtubules
Intermediate filaments
What is the actin cytoskeleton important for?
Cell shape
Microvilli
Cell migration
Cell/cell interactions
Cell/ECM interactions
Phagocytosis
Cell division (cytokinesis
etc
.: good target for many pathogens
How does actin exist? (what form)
Monomer (G-actin)
Polymerized into filaments (F-actin)
How are filaments organized?
Where are monomers added?
Filaments are directional, have a + and - end
Monomers added at the + end
->Highly regulated process
What complex stimulates actin polymerization?
Arp2/3
Formins can also nucleate actin polymerization
What activates Arp2/3?
WASP family ptns
Which host family ptn regulates this process?
Rho family
What does the Rho family do?
Acts as a switch btw GTP and GDP
When Rho is attached to GTP, it is active and causes a downstream response, usually linked to the actin-cytoskeleton
When Rho is linked to GDP, it is inactive
What happens when activated Ras is injected into a cell?
Lamellipodia (2D sheet-like projections)
What happens when activated Rho is injected into a cell?
Stress fibers = contractile bundles of actin and mysoin II
What happens when activated Cdc42 is injected into a cell?
Filopodia= 1D projections
What is actin used for by the bacteria?
Uptake and cytoplasmic movement within the host
Describe Shigella invasion (similar to salmonella invasion)
Use many T3SS effectors
IpgB1, VirA: activate Rac
IpgB2: activates Rho
IpgD: causes disconnection of actin from PM
=>These regulate actin cytoskeleton
=> Cause mb ruffles around bacterial point of entry
What happens if IpgB1/IpgB2 is KO?
Decrease invasion
How does Shigella escape from the vacuole?
T3SS, but mechanism is unknown
Mb fragments releast from the vacuole act as DAMPs and trigger host cell signalling responses including cytokine producton, autophagy and pyroptosis
How do EIEC/Shigella spread from cell to cell?
Hijack host cell's actin cytoskeleton and use it to spread within and between cells
pWR100 plasmid encoded IcsA binds and activates N-WASP (which activates Arp2/3 which activates actin)
IcsA is expressed at one pole of the bacterial cell
Actin polymerization behind the bacteria gives it a propulsive force
What happens if you KO IcsA?
IcsA is what Shigella binds, in order to activate actin polymerization
Won't be able to leave cell
What kind of disease is EPEC (enteropathogenic) responsible for?
Neonatal diarrhea in developing world
What are the 3 stages of EPEC host cell interaction?
1) non-intimate binding (bundle forming pili) Bfp
2) Type III secretion
3) Intimate binding (pedastal formation*)
Does EPEc enter the host?
No, stays extracellular
->Uses its T3SS to inject effectors into the host
->Reprograms cell biology
What does EPEC secrete into the host through its T3SS?
TIR (translocated interim receptor)
Once in host, TIR integrates itself into the host cell mb and serves as a receptor for effector ptns
->EPEC has its own receptor for tight injection, .: it can infect many different types of cells
What are teh main players in EPEC pedastal formation?
Locus for Enterocyte Effacement (LEE) pathogenicity island
This PI encodes:
-a T3SS
-T3SS effector ptn Tir
-Outer mb ptn Intimin
What are the steps to pedastal formation?
1) EPEC Tir is inserted into the host cell plasma mb in a hairpin configuration
2)Extracellular loop binds intimin on bacteria
3) Intracellular tyrosine is P and initiates actin polymerization
4) P of Tir: allows binding of NCK (adaptor): which binds many things, including P Tir and N-WASP
What happens to the host cell once the T3SS is in place?
Microvilli disappear
Form a pore in the host using T3SS (this pore is a conduit btw the host cell cytoplasm and bacterial cytoplasm)
Tir goes into host
Bacteria bind internin on the surface
Tir important for clustering on cell
Get directional polymerization of actin due to NCK
->Cause pedastal formation
Why does this bacteria form a pedastal?
Strong, tight interaction with host
->Will be flushing of the system soon, so if bacteria tightly bound, won't get flushed out of host
What is EspF important for?
Tight junction disruption during EPEC infection
(EspF is a T3SS effector ptn)
Why is it important to disrupt the tight junctions?
Can invade between cells, instead of through them
What is occludin?
Tight jct ptn
What happens to occludin during infection with WT EHEC?
Lose them
Get disruption
Bacteria can get to the tissue
How does EPEC cause disease once it attaches to the host?
Unclear
Effacement of microvilli: loss of absorptive surface
Destruction of tight jcts btw intestinal epithelial cvells
Signal transduction in host cells
Leading to alterations in wate and electrolyte absorption and secretion (change amount of ions that can go into and come out of the cells)