Protective Enterotoxigenic Escherichia coli Antigens in a Murine Intranasal Challenge Model.
Protective Enterotoxigenic Escherichia coli Antigens in a Murine Intranasal Challenge Model.
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DOI：
10.1371/journal.pntd.0003924
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发表时间：
2015
影响因子：
3.8
通讯作者：
Hardwidge PR
中科院分区：
文献类型：
--
作者：
Kumar A;Hays M;Lim F;Foster LJ;Zhou M;Zhu G;Miesner T;Hardwidge PR
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. Diarrheal disease is an endemic health threat in underdeveloped nations. One of the major causative agents of diarrheal disease is a group of bacteria collectively known as enterotoxigenic Escherichia coli (ETEC). These organisms can cause disease symptoms ranging from mild diarrhea to a more severe, cholera-like form. We were interested in characterizing ETEC proteins that can generate a protective immune response as the first step in identifying potential new vaccine candidates. We used proteomics to identify a subset of ETEC proteins and then characterized this subset for their ability to inhibit ETEC binding to cultured intestinal epithelial cells. We then vaccinated mice with the most promising antigen candidates and were able to identify three proteins that protected mice from clinical signs of disease normally caused by ETEC infection. We suggest that future characterization of these proteins may potentially improve our collective efforts to create safe, effective, and broadly protective ETEC vaccines.
