Research Article: Protective Enterotoxigenic Escherichia coli Antigens in a Murine Intranasal Challenge Model

Date Published: August 5, 2015

Publisher: Public Library of Science

Author(s): Amit Kumar, Mike Hays, Francis Lim, Leonard J. Foster, Mingxu Zhou, Guoqiang Zhu, Tracy Miesner, Philip R. Hardwidge, Joseph M. Vinetz.

Abstract: Enterotoxigenic Escherichia coli (ETEC) is an endemic health threat in underdeveloped nations. Despite the significant effort extended to vaccine trials using ETEC colonization factors, these approaches have generally not been especially effective in mediating cross-protective immunity. We used quantitative proteomics to identify 24 proteins that differed in abundance in membrane protein preparations derived from wild-type vs. a type II secretion system mutant of ETEC. We expressed and purified a subset of these proteins and identified nine antigens that generated significant immune responses in mice. Sera from mice immunized with either the MltA-interacting protein MipA, the periplasmic chaperone seventeen kilodalton protein, Skp, or a long-chain fatty acid outer membrane transporter, ETEC_2479, reduced the adherence of multiple ETEC strains differing in colonization factor expression to human intestinal epithelial cells. In intranasal challenge assays of mice, immunization with ETEC_2479 protected 88% of mice from an otherwise lethal challenge with ETEC H10407. Immunization with either Skp or MipA provided an intermediate degree of protection, 68 and 64%, respectively. Protection was significantly correlated with the induction of a secretory immunoglobulin A response. This study has identified several proteins that are conserved among heterologous ETEC strains and may thus potentially improve cross-protective efficacy if incorporated into future vaccine designs.

Partial Text: Enterotoxigenic Escherichia coli (ETEC) is a significant cause of human morbidity due to infectious diarrhea and resultant malnutrition [1]. A recent Global Enteric Multicenter study conducted over a 3-year period to identify the etiology of pediatric diarrheal diseases in sub-Saharan Africa and South Asia found that ETEC infection led to moderate to severe diarrhea in 60–70% of ETEC infected patients and found that ETEC was present at all study sites [2].

Bacterial surface proteins mediate adhesion and invasion to host cells and are often important vaccine candidates. The T2SS is considered important to ETEC virulence, as it is involved in secretion of proteins to the bacterial surface [50, 32]. We compared the difference in abundance between membrane protein preparations from ETEC H10407 strains possessing or lacking a functional T2SS system. In vitro adherence studies using the antisera produced in mice refined our study towards three antigens that showed a protective effect against bacterial adhesion to host cells. Similar approaches could be used to identify ETEC OMPs that are secreted by pathways other than the T2SS.



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