Human Mucosal IgA Immune Responses against Enterotoxigenic Escherichia coli

Abstract

Infection with enterotoxigenic Escherichia coli (ETEC) is a major contributor to diarrheal illness in children in low- and middle-income countries and travelers to these areas. There is an ongoing effort to develop vaccines against ETEC, and the most reliable immune correlate of protection against ETEC is considered to be the small intestinal secretory IgA response that targets ETEC-specific virulence factors. Since isolating IgA from small intestinal mucosa is technically and ethically challenging, requiring the use of invasive medical procedures, several other indirect methods are used as a proxy for gauging the small intestinal IgA responses. In this review, we summarize the literature reporting on anti-ETEC human IgA responses observed in blood, activated lymphocyte assayss, intestinal lavage/duodenal aspirates, and saliva from human volunteers being experimentally infected with ETEC. We describe the IgA response kinetics and responder ratios against classical and noncanonical ETEC antigens in the different sample types and discuss the implications that the results may have on vaccine development and testing.

Keywords: ETEC; IgA; SIgA; experimental infection; immunity; mucosal.

Figure 1

Production and secretion of secretory IgA. (a) IgA is secreted from mucosal plasma cells in the lamina propria (i.e., effector sites) after infection. Two IgA monomers combine with a J chain peptide to form IgA dimers before binding to the polymeric immunoglobulin receptor (pIgR) that is expressed on the basolateral surface of epithelial cells and responsible for transport across the epithelium in a process known as transcytosis. (b) The pIgR-bound dimeric IgA is transferred to the mucosal surface where most of the pIgR is cleaved off and dimeric IgA is released. The part of pIgR that remains is known as the secretory component (SC), and a dimeric IgA that has SC attached is known as a secretory IgA (SIgA) [35]. (c) Example of how SIgA may neutralize virulence factors. The figure shows the adhesion of one ETEC colonization factor fimbria anchored to the intestinal cell surface. SIgAs that recognize these fimbrial proteins block the binding of two other fimbriae. (d) Schematic diagram showing SIgA, a dimeric IgA antibody with J chain and secretory component. (e) Cleavage of pIgR at the apical surface of epithelial cells leads to the release of the secretory component that remains attached to SIgA.

Figure 2

ETEC antigens. (a) Illustrates the cell wall of ETEC with the inner and outer membrane, LPS, and fimbriae. (b) Demonstrates attachment of fimbria on the tip of microvillus and subsequent release of virulence factors. Mucus is degraded by the action of mucinases YghJ and EatA. This action enables ETEC to penetrate the mucosal layer and enabling the tip adhesin to adhere to the microvillus and allow access for LT and ST. (c) Flagellum with an EtpA adhesin bound at its tip attaches to the N-acetyl-galactosamine receptor on the microvillus of epithelial cells. In addition, the binding of CFA/I fimbrial tip adhesin CfaE to asialo GM1 on the microvillus is also shown. (d) Attachment of ST to guanylyl cyclase receptor and LT to ganglioside GM1 receptor induces secretion of ions into the intestinal lumen, causing diarrhea.