diarrhea qa

8/13/2019 Diarrhea QA

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1. List the members of the Enterobacteriaceae or Vibrio known to produce disease in the

gastrointestinal tract (I combined 1 & 2)

2. Describe the general nature of the infections caused by these intestinal pathogens

Vibrio Cholerae- its toxin causes most dramatic watery diarrhea known leading to dehydration,

electrolyte imbalance, hypotension, and death. Rice-water stools- watery diarrhea with mucous flecks.

Pertinent negatives: no fever, no inflammation or direct bowel mucosal injury; no pus or blood in stools.

Enterobacteriaceae: mostly in lower GI of humans and animals; can exist in nature living free in water

E. coli Strains: all below types start with mild, watery diarrhea 2-4 post-ingestion

ETEC (enterotoxigenic E. coli)- travelers diarrhea; diarrhea remains watery; self-limiting in days

-leading cause of m&m in children up to 2y in developing countries

EPEC (enteropathogenic)- accounts for ~20% of diarrhea in bottle-fed children under1y in

developing countries; primarily attacks small intestine; diarrhea remains watery; self-limiting in days

EHEC (enterohemorrhagic)- a significant cause of bloody diarrhea in industrialized countries

(outbreaks associate with unpasteurized juices and hamburger); usual serotype O157:H7; primarily

attacks colon;

-begins as usual followed within 1-2d by intense abdominal pain + bloody diarrhea; resolves

in 3-10d; no prominent fever

-HUS (from circulating Shigatoxin) can accompany this infection in about 10% of pt

experiencing hemorrhagic colitis and usually kids under 10y; Other Sx: oliguria, edema,

pallor, anemia, thrombocytopenia, renal failure

-Stx can bind to renal tissueglomerular swelling and fibrin + platelet deposition in

microvasculature

EIEC (enteroinvasive E.coli): disease mirrors Shigella in almost every way; usually affects kids

under 5y in developing countries

Shigella:classic cause of dysentery; spread under poor sanitary conditions (both developed and developing

countries); begins as watery diarrheaintense colitis with frequent, small volume stools (dysentery- blood

and puss); infection usually confined to intestinal tract; worldwide, one of the most common causes of

infectious diarrhea; S. dysenteriae, type 1 most severe infection (makes Stx)

-febrile dysentery syndrome- triad of cramps, tenesmus (painful straining to pass stool), and

frequent, small-volume, bloody, mucoid discharge

Salmonella:

-S. enterica: 1-2 days post-ingestiondevelop abdominal pain, nausea, vomiting, and diarrhea

lasting 3-4 days (Salmonella gastroenteritis); mostly in industrialized countries; improper food

handling (allows animal to human infection).

-S. serotype Typhi: Causes enteric fever/typhoid fever; insidious onset and can last for weeks if

left untreated; gradually resolves (if humoral Ab and activated macs can clear infection) or can end

in death due to rupture of intestine (most significant and occurs at the site of necrotic Peyers patches

near terminal ileum) or spleen;feveris prominent feature, may see mild rash or enlarged spleen,diarrhea only occurs 1-2x if at all.

-seen less and less in developed countries due to improved mode of fecal disposal. Lovely.

3. For each pathogen list any unique virulence factors which relate to intestinal disease and

describe how they act.

Vibrio Cholerae-

(1) produces a colonizing factor called TCP (toxin-coregulated pilus for its coregulated expression

with CT, cholera toxin). All strains causing cholera have this.


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(2) CT- an A-B type ADP-rybosylating toxin with 2 toxic subunits (A1,A2) and 5 binding units (B)

that bind GM1-ganglioside receptors on many cell surfaces. Once bound to cell, A1 unit released and enters

cell via translocation. Then acts on G protein (Gs-alpha which regulates adenylate cyclase system) by

catalyzing ADP ribosylation of said G protein and thus keeping it from dissociating from the active

adenylate cyclase complex. This stuck ON setting continuously stimulates conversion of ATP to cAMP

causing excessive cAMP build-up at cell membrane. Result: hypersecretion of Cl, K, bicarb, and water from

cell = profuse diarrhea.**This dastardly bacteria controls the expression of the above virulence factors via a transmembrane protein

(ToxR) that senses environmental pH, osmolarity, and temp so it knows when to express factors (that is,

when it finds itself in a human hosts intestines.)

Enterobacteriaceae:

-E. coli:

-O Ag (outer membrane LPS)-K Ag (slime layer, or well-defined polysaccharide capsule

-H Ag (protein peritrichous flagella)

-Pili: mediators of attachment (Type 1 common pilibind D-mannose on many cells,

and specialized pilibind uroepithelial cells, P pili, and to human enterocytes)

-Toxins:-alpha hemolysin: pore forming cytotoxin that inserts into plasma membrane of

many host cells (like streptolysin O)

-Shiga toxin (Stx)- an A/B toxin released upon bacterial cell lysis

-B unit directs binding to host cell receptor; is internalized in vacuole

-A subunit crosses vacuolar membrane, enzymatically alters 28s rRNA of

60s subunit; prevents binding of tRNA to ribosomeblocks protein synth

-Labile toxin (LT): A/B toxin; B binds, A catalyzes ADP-ribosylation of regulatory

G protein (like cholera toxin)activation of membrane associated adenylate

cyclase systemstimulates Cl secretion from cellwater and electrolytes follow

into bowel lumen.

-Stable toxin (ST):binds to glycoprotein receptoractivation of membrane-boundguanylate cyclaseincrease in [cGMP]net secretion of fluid and electrolytes

into bowel lumen

ETEC: adherence to microvilli mediated by CFA (colonizing factor antigen) class of pili

required for effective toxin delivery to target gut cells; genes encoding ST, LT, CFA on

plasmids

EPEC: attachement and effacement (A/E) lesion (genetically controlled in PAI)-

attachmentto enterocyte via BFP (bundle forming pili) causing microcolony formation on

enterocyte surface; effacementof microvilli and changes in cell morphology forming

pedestals with bacteria at apex. Adorable.

-Intimin- major attachment protein

-Type III secretion system injects E. coli secretion proteinsin host cell (disrupt

intracellular signal transduction pathways); also injects intimin receptor

EHEC:-low infecting dose;

-distinguishing feature: produces both Stx (Shigatoxin) AND A/E lesions

EIEC: almost identical to Shigella (except higher infecting dose and lower person-to-person

transmission)

Shigella: low infecting dose (


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2. Bacteria activate apoptosis in M cells and phagocytes

3. Bacteria released from M cell begin invasion process via invasion protein antigens (IpaA,

IpaB, etc) injected by injection secretion system.

4. Each Ipa has its own action: attachment, cytoskeleton reorganization, actin

polymerization, apoptosis induction)

5. Bacteria orient in parallel with cell actin cytoskeleton, control polymerization of actin

fibrils to make an actin tail used to drive the microbe through cytoplasm (cometappearance)

6. When bacteria reach cell membrane, they push through to next cell in finger-like

projections that pinch off (like Listeria).

-S. dysenteriae type 1 is the most potent producer of Stx causing systemic effects as seen in EHEC

including HUS

Salmonella:1. S. Enterica: requires much higher infecting dose (10k +) than Shigella;

-invade enterocytes of lg and sm blowel, transcytose through basolateral membrane into

lamina propria causing profound inflammation; contact with mucosa alters normal

architecture in a matter of minutes

A.Surface adhesins react with host cell receptorfilamentous actin cytoskeletonrearrangement (membrane ruffling)

B.Bacteria pinocytosed in association with ruffles (like the chips? I suppose that

would make them more palatable, but really?)

C.Injection (type III secretion system)- multiple effector proteins injected into host

cell.

2.S. Typhi: infecting dose intermediate (btwn Shigella & S. enterica)- lowered by capsular Vi Ag

-ingestionreach small intestinetravers mucosaingested by macrophages

-bacteria survive in macrophagescarried through lymph to nodes, spleen, liver, BM

-multiplies, enters bloodstream (bacteremia)

-LPS endotoxin seeding causes fever

-bacteremia canurinary tract and biliary tree infection (can re-infect bowel)

-this cycle takes ~ 2wks-Cellular events:

1. bacteria bind M cells and get delivered to Peyers patches

2. S. Typhi invades macrophages and multiplies in membrane-bound vacuole that

fails to fuse with host cell organellesmacrophage dies

3. survival inside phagocytes is due to inhibition of oxidative metabolic burst

4. Describe how these intestinal pathogens are transmitted to humans and maintained in the

general population.

Vibrio Cholerae-

-usually via contaminated water in the setting of poor sanitation (Indian subcontinent and Africa-

endemic); can be found in inadequately cooked crab and shrimp

-2 day incubation period; infected people become part of propagating epidemic (feces in water

supply??)

-convalescent human carriage is brief

Enterobacteriaceae:

E. Coli:

ETEC: food or water contaminated by human cases or carriers; high infecting dose so little human

to human infection


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EPEC: reservoir is infant cases and adult carriers; fecal oral route

EHEC:common reservoir (cattle), modern meat packing plants that can infect meat from many

farms, low infecting dose (100-200 bacteria) even allows person-to-person transmission; manure

from fields adjacent to fruit and veg fields can lead to contamination.

EIEC:humans only known reservoir; higher infecting dose means less person-to-person

transmission than seen in Shigella.

Shigella: person-to-person under poor sanitary conditions or by contaminated food/water; fecal-oral route;

ehconly human disease (no animal reservoir)

Salmonella:

1. S. enterica: animal reservoir (poultry, exotic pets like turtles, raw milk); mishandling of food

allows transfer to humans; chronic carriers who are food handlers. Yummy. Ill never look at a

potluck the same way.

2. S. Typhi: strictly human disease; reservoir is chronic human carrier (Typhoid Mary); transmission

is fecal-oral when carriers contaminate food/water;

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