Abstract
Diarrheal illness contributes to malnutrition, stunted growth, impaired cognitive development, and high morbidity rates in children worldwide. Enterotoxigenic Escherichia coli (ETEC) is a major contributor to this diarrheal disease burden. ETEC cause disease in the small intestine by means of colonization factors and by production of a heat-labile enterotoxin (LT) and/or a small non-immunogenic heat-stable enterotoxin (ST). Overall, the majority of ETEC produce both ST and LT. LT induces secretion via an enzymatically active A-subunit (LT-A) and a pentameric, cell-binding B-subunit (LT-B). The importance of anti-LT antibodies has been demonstrated in multiple clinical and epidemiological studies, and a number of potential ETEC vaccine candidates have included LT-B as an important immunogen. However, there is limited information about the potential contribution of LT-A to development of protective immunity. In the current study, we evaluate the immune response against the A-subunit of LT as well as the A-subunit’s potential as a protective antigen when administered alone or in combination with the B-subunit of LT. We evaluated human sera from individuals challenged with a prototypic wild-type ETEC strain as well as sera from individuals living in an ETEC endemic area for the presence of anti-LT, anti-LT-A and anti-LT-B antibodies. In both cases, a significant number of individuals intentionally or endemically infected with ETEC developed antibodies against both LT subunits. In addition, animals immunized with the recombinant proteins developed robust antibody responses that were able to neutralize the enterotoxic and cytotoxic effects of native LT by blocking binding and entry into cells (anti-LT-B) or the intracellular enzymatic activity of the toxin (anti-LT-A). Moreover, antibodies to both LT subunits acted synergistically to neutralize the holotoxin when combined. Taken together, these data support the inclusion of both LT-A and LT-B in prospective vaccines against ETEC.
Highlights
Enterotoxigenic E. coli (ETEC) are a significant cause of diarrheal disease and death, especially in children in developing countries
We first analyzed human immune serum for antibody response to labile enterotoxin (LT) holotoxin or subunits using a pool of sera from individuals challenged 10-days previously with ETEC isolate H10407 (O78:H11:K80 LT+ stable enterotoxin (ST)+), a prototypical strain of enterotoxigenic E. coli which reproducibly elicits diarrhea in human volunteer studies [42]
The ELISA primarily detects antibodies against conformational epitopes and the use of A-subunit contaminated with traces of holotoxin or B-subunit could give a misleading impression of the presence of A-subunit antibodies
Summary
Enterotoxigenic E. coli (ETEC) are a significant cause of diarrheal disease and death, especially in children in developing countries. The importance of anti-LT antibodies in protection from ETEC diarrheal disease has been demonstrated with several ETEC challenge studies in human adults and in a field study monitoring infants naturally receiving breast milk containing anti-LT IgA [23, 24]. These reports have strongly suggested that an anti-LT response provides significant immunity from LT-mediated secretion and possibly ETEC colonization; an LT-related antigen should be an important component of an effective ETEC vaccine
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