Contribution of the Highly Conserved EaeH Surface Protein to Enterotoxigenic Escherichia coli Pathogenesis

Abstract

f Enterotoxigenic Escherichia coli (ETEC) strains are among the most common causes of diarrheal illness worldwide. These pathogens disproportionately afflict children in developing countries, where they cause substantial morbidity and are responsible for hundreds of thousands of deaths each year. Although these organisms are important targets for enteric vaccines, most development efforts to date have centered on a subset of plasmid-encoded fimbrial adhesins known as colonization factors and heatlabile toxin (LT). Emerging data suggest that ETEC undergoes considerable changes in its surface architecture, sequentially deploying a number of putative adhesins during its interactions with the host. We demonstrate here that one putative highly conserved, chromosomally encoded adhesin, EaeH, engages the surfaces of intestinal epithelial cells and contributes to bacterial adhesion, LT delivery, and colonization of the small intestine. Infectious diarrhea continues to cause tremendous suffering in developing countries, resulting in an estimated one to two million deaths each year. Enterotoxigenic Escherichia coli (ETEC) contributes significantly to premature deaths from diarrheal illness in young children (1, 2) and causes substantial morbidity in surviving children and adults (3). ETEC strains are perennially the leading etiology of diarrhea in travelers to areas where ETEC strains are endemic (4).By definition, these organisms secrete heat-labile (LT) and/or heat-stable (ST) enterotoxins that induce host cell production of cyclic nucleotides (cyclic AMP [cAMP] and cGMP, respectively) to activate protein kinases that ultimately result in phosphorylation of the cystic fibrosis transmembrane regulatory channel (CFTR) (5-7) and Na ϩ ion exchangers (8) on the surfaces of intestinal epithelial cells. Ensuing chloride secretion through CFTR, as well as the commensurate loss of salt and water into the intestinal lumen, results in the cholera-like watery diarrhea characteristic of ETEC infections (9).In the current paradigm for ETEC pathogenesis, this organism must effectively colonize the small intestine to deliver LT and/or ST efficiently. The majority of pathogenesis (10-12) and molecular epidemiology (13) studies, as well as subsequent vaccine development efforts (14, 15), have focused primarily on plasmid-encoded fimbrial colonization factors (CFs), which are felt to be critical for colonization of the small intestine.This longstanding but fairly simple view of ETEC pathogenesis in which bacteria adhere via CFs to the small intestine, where these pathogens release their toxin(s), likely underestimates the complexity of these pathogens. More recent investigations have highlighted a number of novel putative virulence factors (16, 17), unique interactions of ETEC with the epithelium (18)(19)(20), and an intricate orchestration of multiple pathogen-host events (21) that culminate in successful toxin delivery to epithelial cell targets (22). Collectively, the emerging data suggest that these sophisticated interactions of ETEC ...

IscR Regulates Synthesis of Colonization Factor Antigen I Fimbriae in Response to Iron Starvation in Enterotoxigenic Escherichia coli

“…The similar expression profiles seen for cexE, aatA, and etpB suggest that these genes may be expressed in tandem with cfa in ETEC to permit early adhesion to epithelial cells upon arrival in the ileum (59). Following initial epithelial cell contact, intimate adhesion events may then be mediated by outer membrane adhesins, such as EaeH, which were not evaluated here (60). In contrast to the known roles of the cfa and etp operons in pathogenesis, the role of cexE remains unknown (49).…”

Animal EnterotoxigenicEscherichia coli

“…Iha is another adhesin usually associated with shigatoxin-producing E. coli that can be detected in some animal ETEC (495, 498). In addition to AIDA and Iha, it is likely that animal ETEC express other virulence factors, including some non-fimbrial adhesins and proteases described for certain human ETEC strains, such as the adhesins and invasins Tia and autotransporter protein TibA (499–502), the autotransporter adhesin TleA (503), the host-activated adhesin EaeH (504, 505), the two partner secreted EtpA adhesin that binds to the flagellar tip and acts as an adhesive bridge (506), the mucin-degrading proteases EatA, an autotransporter serine protease, and YghJ, a secreted metalloprotease (507, 508). Genomic studies and molecular epidemiology will help to evaluate the presence, distribution and frequencies of these or similar virulence factors in animal ETEC strains (509–511), whereas expression and functional investigations will be needed to identify new animal specific factors and potential host-adapted activation dependency (504).…”

Intestinal Enteroids Model Guanylate Cyclase C-Dependent Secretion Induced by Heat-Stable Enterotoxins

“…In vitro models (e.g., human colon cancer cells) may not recapitulate normal tissue architecture, biology, or molecular signaling events (13,16,17,19), while in vivo models, such as suckling mice (20) and ileal loops (21), are labor-intensive and not suited to high-throughput screening. These considerations underscore the need for models of intestinal signaling and secretion which are compatible with high-throughput analyses and recapitulate the pathophysiology of ST-induced diarrhea (2,16,17,22,23).…”