Diarrheal Enteric Bacterial Infections

Introduction

Diarrhea is major problem worldwide; In developing countries – leading cause of childhood morbidity and mortality

Microbial infections account for most instances of acute diarrhea (viral, bacterial, fungal and parasitic agents)

Prevalence of diarrheal infections related to socioeconomic status, hygiene practices, feeding patterns, storage and handling of food, quantity and quality of water supply, and animal reservoirs

Host risk factors – gastric acid, blood group, malnutrition, immunity

Mechanisms of bacterial infections – enterotoxin elaboration, mucosal invasion, cytotoxicity

Vibrio cholerae infection

Flagellated gram negative motile, curved rod, facultative anaerobes;

Two types – classical and El Tor; divided on basis of O Ag (139 serotypes) and 3 serogroups – Inaba, Ogawa, Hikojima

Occurs as pandemics (6 in 19^th cent.; 1961 due to El Tor strain) and endemics (caused by O1 serotype strain until 1992)

Inhabits brackish water and estuaries; sensitive to drying; fecal-oral transmission (sewage or food contamination)

shellfish, plankton are bacterium reservoirs; transmission vehicles include raw clams, oysters, mussels, shirmp, crab

Risk factors – Hypochlorhydria due to disease or medications, blood group O ppl and bottle feeding increases risk

Inoculum - >10⁸ if healthy; 10⁴ if coadministered with antacid; 10³ if administered directly into small intestine

Pathogenesis – adherence via pili (toxin-coregulated pilus for classic O1 type) to mucus layer and microvilli is essential Þ multiply and produce toxins (cholera toxin – 1 A and 5 B subunits) Þ B binds to GM1-gangliosides on brush border Þ A subunit enters cell Þ cleaved to A1 and A2 subunits Þ A1 catalyzes ADP ribosylation of GTP-binding domain of the G protein Þ increases cAMP levels Þ opening of Cl channels in crypt cells Þ Cl secretion Þ diarrhea (1L/hr), vomiting

other toxins – zona occludens toxin (ZOT) – cytoskeleton altering (increases pore size, permeability, secretion); accessory cholera enterotoxin (ACE); hemolysin (cytotoxin)

CTX genetic element – encodes virulence factors (ie toxins and pilus)

CTXj genome – can chromosomally integrate or replicate as a plasmid; uses TCP as receptor to gain entry into V. cholera

Infected individuals are usually asymptomatic; El Tor strain results in more asymptomatic individuals

Treatment – restoring or preventing fluid loss; antimicrobial disease decreases duration of disease; recovery leads to several years immunity; vaccine is 50% efficient

Enterotoxigenic Escherichia coli (‘traveler’s diarrhea’)

Inoculum level and patho. are similar to V. cholerae (Patho. dependent on colonization factor I to IV and toxin production)

Enterotoxins – heat labile toxin (LT1, LT2) and heat stabile toxin (STa,STb)

LT similar to cholera toxin but less potent

STa (mimics guanylin)binds guanylate cyclase and increases cGMP Þ activates PK-G or PK-A Þ increased Cl secretion and dimished Na/Cl absorption

STb allows calcium influx

Treatment – prevent and restore fluid loss by oral rehydration; Antibiotics decreases duration of diarrhea (but leads to resistant strains)

Shigella dysenteriae and other Shigella

4 species – dysenteriae, flexneri, boydii, sonnei

non-motile (no flagella); very small inoculum (10¹-10²) needed for infection; humans are only reservoir

Infection acquired via M-cells (distal colon), but can invade infiltrating phagocytes and other cells

Invasion determined by chromosomal and plasmid genetic elements

Bacteria multiply intracellularly and spread horizontally to neighboring epithelial cells

Shiga toxin – 1 A subunit and 5 B subunits Þ pentameric B subunit binds to globotriosylceramide Þ A subunit is internalized Þ (N-glycosidase activity) ribosylates adenine Þ ribosome inhibiting protein synthesis Þ cell death Þ diarrhea and dysentery (bloody stool) due to inflammatory response and loss of absorbing epithelium

Shigellosis – symptoms include fever, malaise, myalgia and anorexia; soon diarrhea and dysentery; rarely bacteremia, hemolysis, thrombocytopenia, acute renal failure, neurologic complications

Treatment – Antibiotics shorten illness and decreases mortality

Salmonella

Exists in humans and animals; occurs worldwide

Major types – typhoidal (S. typhi and S. paratyphi) and non-typhoidal (S. typhimurium and S. enteritidis)

High inoculum is characteristic

Invasion through M-cells of Peyer’s patches (ie distal ileum) Þ bacteria multiply within phagocytes and carried systemically Þ Diarrhea due to inflammatory reaction

Clinical Syndromes – typhoid fever, gastroenteritis, bacteremia, vascular infection, osteomyelitis and abscesses

prolonged and severe infections occur in immunosuppressed (ie AIDS) and in hemoglobinopathies (ie sickle cell)

Yersinia

Species – enterocolitica and pseudotuberculosis

Wide array of animals harbor these bacteria (swines, cows); fecal-oral transmission

Entry via M-cells

Virulence factors – (chromosomally encoded) – Invasin, enterotoxin (ST-like), sideropores, lipopolysaccharides; (plasmid encoded) – protein kinase, cytotoxin

Syndromes – diarrhea, fever, abdominal pain; appendicitis-like presentation, pharyngitis, arthritis, uveitis, bacteremia, septicemia

Campylobacter jejuni (enteritis)

Most common agent causing acute infective bacterial diarrhea in developed countries

Most infections are sporadic; bacteria are commensals in birds and mammals; Poultry is major source of infection

Inoculum size – as little as 500 organisms

Motility is essential for colonization and infection (role of adherence factors less clear); microaerophilic

Diarrhea may be watery, less frequent, bloody; symptoms – abdominal pain, fever, Guillain-Barre syndrome

Erythromycin is drug of choice

Clostridium difficile

Gram positive; motile; capsulated

Major infectious cause of diarrhea due to antimicrobial therapy – kills off normal flora; anaerobic spore-forming

Frequently present in healthy infants; widely distributed in hospital environment

Cytotoxins A and B cause diarrhea (severity and duration varies)

mucosal receptors for toxin A – CHO blood group antigens designated I, X, and Y on intestinal epithelial cells
Toxin B has effects mediated thru substance P receptors and enteric nervous system; has greater cytotoxicity and more potent in damaging human colonic mucosa
Toxins damage the cytoskeletal actin by monoglucosyltransferase activity against GTP-binding proteins

The disease affects the colon; protein losing enteropathy may ensue

Clinical aspect – asymptomatic, diarrhea, colitis, pseudomembranous colitis, fulminant colitis with megacolon

Treatment – metronidazole; oral vancomycin; relapse is common

Enterohemorrhagic Escherichia coli (‘hamburger diarrhea)

Cause of bloody diarrhea; major serotype = O157:H7

Outbreaks traced to foods of bovine origin (eg undercooked meats, contaminated milk, fresh apple cider)

Bug relatively tolerant to acid; animal reservoir

Inoculum – intermediate between that of Shigella and Vibrio cholerae

Pathogenesis – related to presence of adherence factors and production of Shiga-like toxins

Toxins (SLT-1, SLT-2) structure, receptors and activity similar to Shigella; adherence via intimin

Children more susceptible to severe disease; Hemolytic uremic syndrome occurs as a complication

Enteropathogenic E. coli

Certain serogroups isolated in infantile diarrhea

"attaching and effacing" lesions

intimin needed for attachment

attachment leads to skeletal rearrangements