Professional Documents
Culture Documents
www.nature.com/clinicalpractice/gasthep
S U M M ARY INTRODUCTION
Enteric infections that cause diarrhea are a major
Infectious diarrhea is an important public health problem worldwide.
cause of morbidity throughout the world. In
Research has provided new insights into the mechanisms of diarrhea
developing countries, infectious diarrhea is fre-
caused by various pathogens that are classified as noninflammatory,
quently disabling and contributes substantially
inflammatory or invasive. These three groups of organisms cause two
to malnutrition, resulting in high morbidity and
diarrheal syndromesnoninflammatory diarrhea and inflammatory
diarrhea. The noninflammatory diarrheas are caused by enterotoxin-
mortality, particularly in infants and children. It
producing organisms such as Vibrio cholerae and enterotoxigenic has been estimated that 2billion to 4billion epi-
Escherichia coli, or by viruses that adhere to the mucosa and disrupt the sodes of infectious diarrhea occur annually in
absorptive and/or secretory processes of the enterocyte without causing developing countries, with the highest rates of
acute inflammation or mucosal destruction. Inflammatory diarrhea is infection occurring in children below the age
caused by two groups of organismscytotoxin-producing, noninvasive of 5years.1 At present, the life-time risk of con-
bacteria (e.g. enteroaggregative Escherichia coli, enterohemorrhagic tracting diarrheal disease is increased fivefold in
Escherichia coli and Clostridium difficile), or by invasive organisms (e.g. sub-Saharan Africa compared with developed
Salmonella spp., Shigella spp., Campylobacter spp., Entamoeba histolytica). countries (39.1% versus 7.2%, respectively).2 In
The cytotoxin-producing organisms adhere to the mucosa, activate fact, in 2001 the WHO reported that diarrheal dis-
cytokines and stimulate the intestinal mucosa to release inflammatory eases were the second leading cause of disability-
mediators. Invasive organisms, which can also produce cytotoxins, adjusted life-years lost, and contributed to
invade the intestinal mucosa to induce an acute inflammatory reaction, 2.2million deaths, making diarrheal diseases the
involving the activation of cytokines and inflammatory mediators. third leading cause of death worldwide.3
Regardless of the underlying mechanism they use, these various types of Although the morbidity and mortality associ-
pathogen have all successfully evolved to evade and modulate the host ated with infectious diarrhea is considerably less
defense systems. The mechanisms by which the different pathogens invade in Western countries, this disease is neverthe-
the host and cause infectious diarrhea are the topic of this Review. less a major cause of morbidity, physician visits,
Keywords diarrhea, enteric infection, enteropathogens, enterotoxin,
hospitalizations and absence from work or
infectious diarrhea school. In fact, physicians in the US are consulted
annually for 8.2million diarrheal episodes,
REVIEW CRITERIA including infectious and noninfectious types.4 In
In January 2008 MEDLINE was searched from 1962 to the present using the medical addition, infectious diarrheal diseases constitute
subject headings (MeSH) terms diarrhea, infectious diarrhea pathogenesis, and
mechanism, alone, and in combination with each other. Abstracts and full papers the most common health problem in Western
were considered. No language restrictions were placed on the search. Important persons who travel to developing countries.5
developments in molecular and genomic research, experimental reports from Our knowledge of infectious diarrheal disease
centers of excellence, and our own research developments were used to form the has expanded enormously over the past decade,
basis of this review article. The reference list was last updated in August 2008.
particularly with regard to understanding
U Navaneethan is a Resident in the Department of Internal Medicine, the pathogenesis of infectious diarrhea and the
and RA Giannella is the Mark Brown Professor of Medicine in the Division addition of new organisms to the existing reper-
of Digestive Diseases, at the University of Cincinnati College of Medicine, toire of agents that cause diarrhea. This Review
Cincinnati, OH, USA. presents our current understanding of the
mechanisms of important underlying infectious
Correspondence
*Division of Digestive Diseases, ML 0595, University of Cincinnati College of Medicine,
diarrheas, including host defense mechanisms
Cincinnati, OH 45267-0595, USA that provide protection against ingested infec-
ralph.giannella@uc.edu tious pathogens. In addition, the epidemiology
and clinical syndromes of infectious diarrheas
Received 27 March 2008 Accepted 20 August 2008 Published online 23 September 2008
www.nature.com/clinicalpractice
are discussed. Owing to space limitations, the
doi:10.1038/ncpgasthep1264 management of infectious diarrheas is not
november 2008 vol 5 no 11 nature clinical practice GASTROENTEROLOGY & HEPATOLOGY 637
review
www.nature.com/clinicalpractice/gasthep
considered; instead, the reader is referred to other Enteroinvasive E. coli (EIEC) infections are seen
articles that review various aspects of infectious predominantly in tropical countries including
diarrhea, including its management.69 Thailand,18 with occasional cases reported in the
US. Enterohemorrhagic E. coli (EHEC) are one
EPIDEMIOLOGY OF INFECTIOUS of the most common causes of bloody diarrhea
DIARRHEAS in the US19 and throughout the world, including
Virus-induced diarrheas account for 3040% Canada and Europe. Infection occurs primarily
of acute episodes of diarrhea in the US, with after ingestion of undercooked hamburgers and
norovirus (previously known as Norwalk meat patties. Enteroaggregative E.coli (EAEC)
virus) and rotavirus being the most common of affect children and adults of developing and
the diarrhea-causing viruses.10 In children in the developed countries. EAEC have been shown to
US, rotavirus is responsible for 35% of hospi- cause acute and/or persistent diarrhea in 1044%
talized cases and 1030% of community-based of patients with an HIV infection and are also a
cases of diarrhea.11 Norovirus affects people of major cause of travelers diarrhea.20,21
all ages and is responsible for approximately Among cases of infectious diarrhea caused by
40% of nonbacterial outbreaks of diarrhea invasive pathogens, shigellosis is common and
in the US.12 By contrast, in developing coun- accounts for 1020% of cases of enteric infec-
tries where there is relatively poor sanitation, tions throughout the world.22 Shigellosis is com-
enteric bacterial pathogens (e.g. Vibrio cholerae, monly seen in children younger than 5years of
enterotoxigenic Escherichia coli [ETEC] and age, although adults of all ages are susceptible.8
enteropathogenic E.coli [EPEC]), protozoa Non-typhoidal salmonellosis is also seen world-
and intestinal parasites are the predominant wide and is one of the most common causes of
causes of infectious diarrhea.8 food poisoning and diarrhea in the US. In fact,
V. cholerae is one of the most common causes close to 1.4million cases of salmonella food poi-
of diarrhea worldwide. Diarrhea associated with soning occur annually in the US.8 Campylobacter
cholera is predominantly seen in the Indian infection is also an important cause of diarrhea,
subcontinent, South East Asia, Africa and South with C. jejuni being the most common cause of
America.13 In the US, sporadic cases of V. cholerae- acute bacterial diarrhea in the US.8 Similarly to
induced diarrhea have been reported along salmonella infections, most C. jejuni infections
the Gulf coast.14 Vibrios are classified into O1 are related to the consumption of improperly
or non-O1 serogroups based on whether they cooked chicken.23
undergo agglutination by antisera against the One of the most important causes of diar-
O1 antigen (cell wall polysaccharide). Diarrhea rhea in the US is Clostridium difficile infection.
caused by the non-O1 toxigenic strain Vibrio The incidence of this infection has increased
0139 Bengal, which was described in 1992, dramatically and it is now recognized as the
started in southern India and Bangladesh and most common cause of nosocomial infectious
spread to other parts of Southeast Asia.15,16 At diarrhea in developed countries.24,25
present, Vibrio 0139 Bengal is present only in Intestinal protozoa are also important causes
Asia.15,16 Another Vibrio species, V. parahemo- of diarrhea in the developing world and are
lyticus, is more common than V. cholerae in the an increasingly common cause of diarrhea in
US, and V. parahemolyticus-induced diarrhea Western countries. Entamoeba histolytica is
occurs sporadically along the US coast.8 one of the most important causes of diarrhea
Pathogenic E. coli are another important and dysentery throughout the world, with an
cause of diarrhea worldwide, and are classi- estimated 3450million symptomatic infec-
fied according to their pathogenic mechanisms. tions occurring worldwide annually.26 Giardia
ETEC are among the most common causes of lamblia is the intestinal parasite most com-
diarrhea in children in developing countries monly implicated as a cause of diarrhea in the
including Mexico, Central and South America, US, where it is most commonly found in chil-
India, Southeast Asia and Africa, and affect dren in day-care facilities and in sexually active
1550% of travelers to these regions of the homosexual men, but is also common in the
tropics, making ETEC the most common cause general population.27 Cryptosporidium infec-
of travelers diarrhea.17 By contrast, ETEC tion is seen not only in HIV-infected indivi
infections are not common in the US or other duals but also in cases of self-limited diarrhea in
developed countries. immunocompetent persons.28
638 nature clinical practice GASTROENTEROLOGY & HEPATOLOGYNavaneethan and Giannella november 2008 vol 5 no 11
review
www.nature.com/clinicalpractice/gasthep
november 2008 vol 5 no 11 Navaneethan and Giannella nature clinical practice GASTROENTEROLOGY & HEPATOLOGY 639
review
www.nature.com/clinicalpractice/gasthep
Inflammatory diarrhea
Organisms that cause inflammatory diarrhea
infection by binding to the H type 1 oligo primarily target the lower bowel, particularly the
saccharide on gastric and duodenal epithelial distal ileum and colon. These organisms cause
cells, and the synthesis of H type 1 is contributed disease either by secreting noxious cytotoxins or
to, in part, by FUT2.46 In fact, a homozygous by invading the intestinal epithelium, resulting
inactivating mutation in FUT2 imparts resistance in an acute inflammatory reaction.68
to infection by norovirus.46 Cytotoxin-producing, noninvasive organisms
HLA gene polymorphisms, which influence include EAEC, EHEC and C. difficile. Patients
the T-cell immune response, have been impli- infected with these noninvasive organisms
cated in susceptibility to infections caused by usually present with watery diarrhea with or
E.histolytica and Cryptosporidium parvum.4749 without passage of blood or mucus, abdominal
Multiple susceptibility loci have also been identi pain, and low grade fever.68
fied on chromosomes 8, 11 and 13 and in the Invasive organisms including Shigella spp.,
STAT6 gene that might determine susceptibility Campylobacter spp., Salmonella spp., Yersinia
to infection by Ascaris spp.50,51 In addition, spp., EIEC and E. histolytica also cause an
the presence of the ApoE4 allele might protect inflammatory diarrheal syndrome that is
against the cognitive impairment that can be characterized by diarrhea (with or without dys-
caused by diarrhea in children.52 entery), abdominal pain and fever.8 Microbial
Thus, host genetic factors confer susceptibility invasion of the mucosa results in an acute
to various infections. Future research could help inflammatory reaction with disruption of the
predict the populations who might benefit from, epithelial barrier, resulting in the presence of
or require, vaccination and/or prophylaxis to mucus, red blood cells and polymorphonuclear
prevent diarrheal infections. leukocytes in the stool.7,8 Compared with non-
invasive organisms, invasive organisms can
CLINICAL SYNDROMES OF INFECTIOUS cause more-severe abdominal pain, more blood
DIARRHEA in stool, frank dysentery and a higher fever.8
Infectious diarrheas can be classified, based
on their clinical presentation, into two syn- MECHANISMS OF ENTERIC INFECTION
dromesnoninflammatory and inflammatory AND DIARRHEA
diarrheas. The characteristics of these two syn- Noninflammatory diarrhea
dromes are compared in Table 1. The clinical As mentioned earlier, a number of organisms
syndromes and mechanisms underlying these cause diarrhea by producing and secreting
two syndromes differ considerably and are, various proteins called enterotoxins. Most of
therefore, discussed separately. these enterotoxins induce intestinal secretion by
640 nature clinical practice GASTROENTEROLOGY & HEPATOLOGYNavaneethan and Giannella november 2008 vol 5 no 11
review
www.nature.com/clinicalpractice/gasthep
Vibrio cholerae
V. cholerae causes disease by producing cholera Toxin elaboration
toxin. All Vibrio strains, including Vibrio 0139
Bengal, produce the same enterotoxin. The clini-
cal features resulting from infection with Vibrio Toxin binding to enterocyte receptors
0139 Bengal resemble those produced by toxin-
producing V. cholerae 01 species (classical and
E1 Tor biotypes).53,54 A study from Bangladesh
Concentrations of intracellular mediators
comparing the clinical features of infection by ( cAMP, cGMP, Ca2+)
Vibrio 0139 versus V. cholerae 01 in two medical
centers found the clinical features to be largely
similar, but that the different species had differ-
ences in their antibiotic susceptibility.53 Vibrio Activation of targets of intracellular mediators
(protein kinases, etc.)
0139 was found to be susceptible to tetracycline
and furazolidone in more than 90% of infected
patients; by contrast, V. cholerae 01 was suscep-
tible to tetracycline and furazolidone in 2758% Alteration of transporter proteins and ion channels
of infected patients.55
Although cholera toxin can affect the whole
intestine, cholera is largely caused by toxin acti Diarrhea
vity in the proximal small intestine (e.g., the
duodenum and upper jejunum), which is typical Figure 1 Schema illustrating mechanisms of
of noninflammatory diarrhea.56 The adherence of pathogenesis for enterotoxin-mediated bacterial
the bacterium to the intestinal epithelium is criti- diarrheas. Bacterial enterotoxin (either ingested
cal for the survival of both enterotoxin-producing in food or produced by ingested pathogens)
binds to receptors on the surface of enterocytes.
and invasive bacteria.8 The attachment of
This receptor binding results in an increase in
V.cholerae is mediated by a fimbrial colonization concentrations of either cellular cAMP, cGMP,
factor, known as the toxin-coregulated pilus.55 or Ca2+, which causes the activation of various
Additional pilus structures, including the fucose- protein kinases. This kinase activation leads to
binding and mannose-binding hemagglutinins, altered electrolyte transport, resulting in the onset
also promote colonization by the classical and El of diarrhea.
Tor biotypes of V. cholerae 01, respectively.57
After adhesion, V. cholerae secretes cholera
toxin.56 Cholera toxin consists of two subunits, increase in intracytoplasmic cAMP concen
a single toxic active A subunit (CTA), and a tration leads to altered electrolyte transport by
Bsubunit pentamer (CTB), which is responsible enterocytes in the form of increased chloride
for binding of the toxin to the intestinal epithelial secretion by crypt cells and reduced absorption
cell via a ganglioside (GM1) receptor present on of sodium and chloride ions by villous cells,
the brush border membrane.57 The bound toxin which results in diarrhea.55 In addition, cholera
is internalized into the intestinal epithelial cell, toxin stimulates enterochromaffin cells to release
through either caveolin-coated vesicles, clathrin- serotonin, which in turn stimulates the release of
coated vesicles or the so-called Arf6 endocytic vasointestinal peptide from local enteric neurons,
pathway.58 The A subunit is then cleaved into two also producing diarrhea.59
peptides; A1 and A2. The A1 peptide has enzy-
matic ADP-ribosylating activity, and stimulates Enterotoxigenic E. coli
the ribosylation of Gs, the stimulatory subunit of ETEC infection causes a noninflammatory
heterotrimeric G protein, leading to irreversible toxin-mediated diarrhea that is similar to, but
activation of adenylate cyclase.55 The resultant less severe than, cholera. As with V. cholerae,
ncpgh_2007_261f1.eps
november 2008 vol 5 no 11 Navaneethan and Giannella nature clinical practice GASTROENTEROLOGY & HEPATOLOGY 641
review
www.nature.com/clinicalpractice/gasthep
ETEC initially adhere to the surface of small damaging the small intestine. This malabsorption
intestinal enterocytes through ligandreceptor can occur through the broadening and blunting
interactions via protein antigens on the surface of villi, and by the diminished activity of intes-
of fimbriae, known as adherence antigens or tinal disaccharidases, similar to the mechanisms
colonization factor antigens.60 used by rotavirus to cause diarrhea.8
After colonization, ETEC can secrete two
types of plasmid-encoded enterotoxinheat- Cryptosporidium parvum
labile enterotoxin and heat-stable enterotoxin. C. parvum infection is traditionally classified as
The heat-labile enterotoxin is closely related causing noninflammatory diarrhea, but it has
to cholera toxin, both biologically and anti- also been known to cause inflammatory diar-
genically; it also acts on intestinal epithelia and rhea in children. Indeed, diarrhea caused by
activates adenylate cyclase through ADP ribo- C.parvum infection in children has been associ-
sylation of Gs.61 Similarly to CTB, the B subunit ated with elevated concentrations of lactoferrin
of heat-labile enterotoxin (LTB) is made up of in stool, a marker of inflammation.8 By con-
five identical subunits. However, in addition to trast, normal levels of lactoferrin are observed
the high affinity of heat-labile enterotoxin for in healthy adults with C. parvum infection.8 Of
GM1, this enterotoxin also has binding affinity note, adults infected with C. parvum usually have
for various receptors in the human intestine, a milder and self-limited illness.
including polylactosaminoglycan-containing C. parvum attaches to a 85kDa surface
receptors or glycoproteins.62 protein on intestinal epithelial cells via its apical
In addition, the heat-stable enterotoxin pro- glycoprotein CSL complex.66 After adhesion,
duced by many ETEC strains causes diarrhea by C.parvum causes fluid secretion through mul-
binding to guanylate cyclase C and triggering tiple mechanisms involving increased local levels
an increase in the intracellular levels of cGMP.8 of prostaglandins, and hence cAMP-mediated
In fact, close to half of clinical isolates of ETEC chloride secretion, inhibition of electroneutral
secrete heat-stable enterotoxin only.63 As men- sodium chloride and decreased water absorp-
tioned above, ETEC diarrhea is usually rela- tion by enterocytes.67,68 Although C. parvum
tively mild, in contrast to the severe dehydration produces secretory diarrhea, villous atrophy and
characteristic of cholera. inflammatory infiltrate in the lamina propria
have been observed, providing an explana-
Rotavirus tion for the inflammatory diarrhea occurring
Rotavirus causes diarrhea by producing an in children.69
enterotoxin and by activation of the enteric
nervous system. Experimental studies in mice Giardia lamblia
have hypothesized that a nonstructural rotavirus G. lamblia trophozoites adhere to the epithelium
protein, NSP4, could be involved in altering epi- of the upper small intestine and damage the
thelial cell function and permeability.64 NSP4 mucosal brush border without invasion.70
has been shown to increase chloride secretory Pathologic changes correlate with the severity
currents through a calcium-dependent chloride of diarrhea and range from normal-appearing
secretory mechanism, and activate the enteric duodenal mucosa to severe villous atrophy with a
nervous system to produce diarrhea.64 NSP4 mononuclear cell infiltrate similar to that seen in
also impairs sodiumsolute symport activities patients with celiac sprue.70,71 The mechanisms
in the gut by blocking the intestinal sodium/ by which G. lamblia causes diarrhea are unclear.
glucose cotransporter 1 (SC5A1), hence contrib-
uting to diarrhea.65 As SC5A1 supports water HIV-1
reabsorption under physiological conditions, the In addition to the opportunistic infections that
inhibition of sodiumsolute symport systems cause diarrhea, HIV-1 can cause severe watery
could also be a cause of rotavirus-induced diarrhea. In vitro models of HIV infection
malabsorptive diarrhea.65 indicate that the transactivating Tat peptide of
HIV-1 might stimulate active fluid secretion in
Norovirus human enterocytes, in a similar way to cholera
The exact mechanisms by which norovirus causes toxin, and could have a role in the pathogenesis
diarrhea are not known. Studies have, however, of diarrhea in patients with AIDS.72 In addition,
shown that norovirus causes malabsorption by Tat protein inhibits sodium ion and glucose
642 nature clinical practice GASTROENTEROLOGY & HEPATOLOGYNavaneethan and Giannella november 2008 vol 5 no 11
review
www.nature.com/clinicalpractice/gasthep
The tcdD gene product upregulates toxin trans the host inflammatory response through toll-
cription, while tcdC probably encodes a toxin like receptor 5,39 and stimulates the release of
gene repressor.75 Toxins A and B are UDP- IL-8, which causes epithelial cell destruction
glucose hydrolases and glucosyltransferases and fluid secretion.21 The role of heat-stable
that contribute to the inflammatory diarrhea; enterotoxin (EAST1) is not clear but it might
however, it is thought that toxin B might be the stimulate secretion.82
major inflammatory toxin.76
Toxins A and B initially attach to non Shigella spp.
proteinaceous disaccharide galactose-14-N- Several Shigella spp. virulence factors, both
acetylglucosamine residues on colonic epithelial chromosomal and plasmid-encoded, are
cells.77 After adhesion, the toxin enters the cell involved in the cellular invasion that leads to the
through receptor-mediated endocytosis and cata- death of an intestinal epithelial cell.22 Shigella
lyzes the transfer of a glucose residue from UDP- spp. contain a large plasmid that encodes the
glucose to guanosine-triphosphate-binding rho principal type III secretion system and other viru
proteins,65 which are the intracellular signaling lence factors that facilitate host invasion.22,83
molecules that regulate cytoskeletal organiza- The plasmid copy number is upregulated on
tion and gene expression. Glucosylation of rho contact with host intestinal cells: IpaB and IpaC
proteins in turn leads to disruption of protein proteins are released and alter the function
synthesis and cell death.75 NF-B and MAP of actin filaments. Shigella spp. also synthesize
kinases are also activated, leading to the release an actin-nucleating protein (IcsA) that helps the
of interleukin (IL)-1, tumor necrosis factor, bacteria move laterally through one cell mem-
and IL8,8 which contributes to the marked brane into an adjacent cell, thereby facilitating
intestinal inflammatory response and secretion the spread of infection by cell-to-cell transfer
that is observed with C. difficile infection. of bacilli.22 Shigella spp. rarely penetrate beyond
the intestinal mucosa, but multiply within the
Enteroaggregative E. coli epithelial cells.83
EAEC infect the intestine and produce diarrhea Apoptosis of infected enterocytes releases
by adhering to the epithelial brush border and infective bacteria along with inflammatory
altering cell function, as discussed in further mediators, such as IL-8, which cause epithelial
detail below. A similar group of organisms, cell destruction.84 In addition to the mechanism
EPEC, cause disease through similar mech described above, S. dysenteriae 1 and certain
anisms. EPEC produce localized adherence strains of S. flexneri and S. sonnei also secrete
whereas EAEC produce a diffuse adherence.78 an enterotoxin that inhibits protein synthesis
Although adherence of EAEC can occur in by irreversible inactivation of the 60S ribosomal
jejunal, ileal and colonic epithelium, the colonic subunit, causing cytotoxicity and cell death.74
epithelium is the principal target. Adherence is This toxin also stimulates intestinal secretion
mediated by the aggregative adherence fimbriae, via upregulation of luminal galanin-1 receptors,
particularly aggregative adherence fimbria II.79 which in turn increases chloride secretion.85
Another protein, dispersin, facilitates the dis-
persal of the EAEC and promotes the develop- Salmonella spp.
ment of new foci of infection.80 Other factors The principal target of Salmonella spp. is the
including membrane associated protein and ileum and, to a lesser extent, the colon.8 As with
aggregative protein 58 might also contribute Shigella infection, both plasmid-encoded and
to adherence.79,80 chromosomal-encoded virulence factors are
EAEC adherence stimulates mucus production important in the pathogenesis of salmonella.
and the production of a mucus biofilm, which The Salmonella spp. plasmid contains genes
might contribute to the development of mal- that encode proteins vital for bacterial spread
nutrition and prolonged diarrhea.81 An acute and invasion, survival within macrophages after
inflammatory response follows after adhesion phagocytosis, and transepithelial signaling to
and is associated with enterocyte damage, cyto- neutrophils, which together trigger cell destruc-
kine release and intestinal secretion. The entero- tion.86 Enterotoxins and the outer-membrane
cyte damage is mediated by several toxins.82 lipopolysaccharide containing the Vi antigen
Plasma encoded toxin produces both enterotoxic contribute to the pathogenesis of Salmonella
and cytotoxic effects.82 EAEC flagellin triggers enterocolitis. Increased intestinal secretion results
644 nature clinical practice GASTROENTEROLOGY & HEPATOLOGYNavaneethan and Giannella november 2008 vol 5 no 11
review
www.nature.com/clinicalpractice/gasthep
november 2008 vol 5 no 11 Navaneethan and Giannella nature clinical practice GASTROENTEROLOGY & HEPATOLOGY 645
review
www.nature.com/clinicalpractice/gasthep
646 nature clinical practice GASTROENTEROLOGY & HEPATOLOGYNavaneethan and Giannella november 2008 vol 5 no 11
review
www.nature.com/clinicalpractice/gasthep
Medicine and Hygiene (ASTMH) 56th Annual Meeting: 70 Hill DR (1990) Giardia lamblia. In: Principles and Competing interests
2007 November 48, Philadelphia, PA Practice of Infectious Diseases 24872493 (Eds The authors declared no
49 Duggal P et al. (2004) Influence of human leukocyte Mandell GL et al.) Philadelphia: Churchill Livingstone competing interests.
antigen class II alleles on susceptibility to Entamoeba 71 Oberhuber G et al. (1997) Giardiasis: a histologic
histolytica infection in Bangladeshi children. J Infect Dis analysis of 567 cases. Scand J Gastroenterol 32: 4851
189: 520526 72 Berni Canani R et al. (2006) Inhibitory effect of HIV-1 Tat
50 Williams-Blangero S et al. (2008) Localization of multiple protein on the sodium-D-glucose symporter of human
quantitative trait loci influencing susceptibility to infection intestinal epithelial cells. AIDS 20: 510
with Ascaris lumbricoides. J Infect Dis 197: 6671 73 Griffin PM et al. (2002) Escherichia coli O157:H7 and
51 Peisong G et al. (2004) An asthma-associated genetic other enterohemorrhagic E. coli. In Infections of the GI
variant of STAT6 predicts low burden of ascaris worm Tract, edn 2 627642 (Eds Blaser M et al.) Philadelphia:
infestation. Genes Immun 5: 5862 Lippincott Williams & Wilkins
52 Oria RB et al. (2007) Role of apolipoprotein E4 in 74 Su C and Brandt LJ (1995) Escherichia coli O157:H7
protecting children against early childhood diarrhea infection in humans. Ann Intern Med 123: 698714
outcomes and implications for later development. Med 75 Warny M and Kelly CP (2003) Pathogenicity of
Hypotheses 68: 10991107 Clostridium difficile toxins. In Microbial Pathogenesis
53 Dhar U et al. (1996) Clinical features, antimicrobial and the Intestinal Epithelial Cell, 503 (Ed. Hecht G)
susceptibility and toxin production in Vibrio cholerae Washington, DC: ASM Press
O139 infection: comparison with V. cholerae O1 76 Riegler M et al. (1995) Clostridium difficile toxin B is
infection. Trans R Soc Trop Med Hyg 90: 402405 more potent than toxin A in damaging human colonic
54 Basu A et al. (2000) Vibrio cholerae 0139 in Calcutta, epithelium in vitro. J Clin Invest 95: 20042011
19921998: incidence, antibiograms, and genotypes. 77 Wilkins TD and Tucker KD (1989) C. difficile toxin A
Emerg Infect Dis 6: 139 uses gal-13gal14GlcNAC as a functional receptor.
55 Sack DA et al. (2004) Cholera. Lancet 363: 223233 Microecol Ther 19: 225231
56 Snchez J and Holmgren J (2005) Virulence factors, 78 Nataro JP and Kaper JB (1998) Diarrheaegenic E. coli.
pathogenesis and vaccine protection in cholera and Clin Microbiol Rev 11: 142201
ETEC diarrhea. Curr Opin Immunol 17: 388398 79 Okeke IN et al. (2000) Heterogeneous virulence of
57 Shogomori H and Futerman AH (2001) Cholera toxin enteroaggregative Escherichia coli strains isolated from
is found in detergent insoluble rafts/domains at the children in Southwest Nigeria. J Infect Dis 181: 252260
cell surface of hippocampal neurons but is internalized 80 Sheikh J et al. (2002) A novel dispersin protein in
via a raft-independent mechanism. J Biol Chem 276: enteroaggregative Escherichia coli. J Clin Invest 110:
91829188 13291337
58 Massol RH et al. (2004) Cholera toxin toxicity does 81 Vial PA et al. (1988) Characterization of enteroadherent-
not require functional Arf6- and dynamin-dependent aggregative Escherichia coli, a putative agent of
endocytic pathways. Mol Biol Cell 15: 36313641 diarrheal disease. J Infect Dis 158: 7079
59 Mourad FH et al. (1995) Role of 5-hydroxytryptamine 82 Weintraub A (2007) Enteroaggregative E. coli:
type 3 receptors in rat intestinal fluid and electrolyte epidemiology, virulence, and detection. J Med
secretion induced by cholera and Escherichia coli Microbiol 56: 48
enterotoxins. Gut 37: 340345 83 Phalipon A and Sansonetti PJ (2003) Shigellosis:
60 Evans DG et al. (1975) Plasmid-controlled colonization innate mechanisms of inflammatory destruction of the
factor associated with virulence in Escherichia coli intestinal epithelium, adaptive immune response, and
enterotoxigenic for humans. Infect Immun 12: 656667 vaccine development. Crit Rev Immunol 23: 371401
61 Moss J and Richardson SH (1978) Activation of 84 Fleckenstein JM and Kopecko DJ (2001) Breaching the
adenylate cyclase by heat-labile E. coli enterotoxin. mucosal barrier by stealth: an emerging pathogenic
JClin Invest 62: 281285 mechanism for enteroadherent bacterial pathogens.
62 Karlsson KA et al. (1996) Unexpected carbohydrate JClin Invest 107: 2730
cross-binding by Escherichia coli heat-labile 85 Matkowskyj KA et al. (2000) Galanin-1 receptor up-
enterotoxin. Recognition of human and rabbit target regulation mediates the excess colonic fluid production
cell glycoconjugates in comparison with cholera toxin. caused by infection with enteric pathogens. Nat Med 6:
Bioorg Med Chem 4: 19191928 10481051
63 Wolf MK (1997) Occurrence, distribution, and 86 Grassl GA and Finlay BB (2008) Pathogenesis of enteric
associations of O and H serogroups, colonization factor Salmonella infections. Curr Opin Gastroenterol 24:
antigens, and toxins of enterotoxigenic Escherichia coli. 2226
Clin Microbiol Rev 10: 569584 87 Oelschlaeger TA et al. (1993) Unusual microtubule-
64 Lundgren O and Svensson L (2001) Pathogenesis of dependent endocytosis mechanisms triggered by
Rotavirus diarrhea. Microbes Infect 3: 11451156 Campylobacter jejuni and Citrobacter freundii. Proc
65 Halaihel N et al. (2000) Rotavirus infection impairs Natl Acad Sci USA 90: 68846888
intestinal brush-border membrane Na (+) solute co 88 Hu L and Kopecko DJ (2000) Interactions of
transport activities in young rabbits. Am J Physiol Campylobacter with eukaryotic cells: gut luminal
Gastrointest Liver Physiol 279: G587G596 colonization and mucosal invasion mechanisms. In
66 Langer RC et al. (2001) Characterization of an Campylobacter, edn 2 191205 (Eds Nachamkin I and
intestinal epithelial cell receptor recognized by the Blaser MJ) Washington, DC: ASM Press
Cryptosporidium parvum sporozoite ligand CSL. Infect 89 Hickey TE et al. (2000) Campylobacter jejuni cytolethal
Immun 69: 16611670 distending toxin mediates release of interleukin-8 from
67 Simon D et al. (1994) Studies on the pathogenesis intestinal epithelial cells. Infect Immun 68: 65356541
of cryptosporidia-incuced diarrhea in HIV-infected 90 Ravdin JI and Guerrant RL (1981) Role of adherence in
individuals. Am J Gastroenterol 89: 22772278 cytopathogenic mechanisms of Entamoeba histolytica:
68 Guarino A et al. (1995). Human intestinal study with mammalian tissue culture cells and human
cryptosporidiosis: secretory diarrhea and enterotoxic erythrocytes. J Clin Invest 68: 13051313
activity in Caco-2 cells. J Infect Dis 171: 976983 91 Moncada D et al. (2003) Entamoeba histolytica cysteine
69 Genta RM et al. (1993) Duodenal morphology and proteinases disrupt the polymeric structure of colonic
intensity of infection in AIDS-related intestinal mucin and alter its protective function. Infect Immun 71:
cryptosporidiosis. Gastroenterology 105: 17691775 838844
november 2008 vol 5 no 11 Navaneethan and Giannella nature clinical practice GASTROENTEROLOGY & HEPATOLOGY 647