Abstract
Enteric infections induced by pathogens like Vibrio cholerae and enterotoxigenic Escherichia coli (ETEC) remain a massive burden in developing countries with increasing morbidity and mortality rates. Previously, we showed that the immunization with genetically detoxified outer membrane vesicles (OMVs) derived from V. cholerae elicits a protective immune response based on the generation of O antigen antibodies, which effectively block the motility by binding to the sheathed flagellum. In this study, we investigated the potential of lipopolysaccharide (LPS)-modified and toxin negative OMVs isolated from V. cholerae and ETEC as a combined OMV vaccine candidate. Our results indicate that the immunization with V. cholerae or ETEC OMVs induced a species-specific immune response, whereas the combination of both OMV species resulted in a high-titer, protective immune response against both pathogens. Interestingly, the immunization with V. cholerae OMVs alone resulted in a so far uncharacterized and cholera toxin B-subunit (CTB) independent protection mechanism against an ETEC colonization. Furthermore, we investigated the potential use of V. cholerae OMVs as delivery vehicles for the heterologously expression of the ETEC surface antigens, CFA/I, and FliC. Although we induced a detectable immune response against both heterologously expressed antigens, none of these approaches resulted in an improved protection compared to a simple combination of V. cholerae and ETEC OMVs. Finally, we expanded the current protection model from V. cholerae to ETEC by demonstrating that the inhibition of motility via anti-FliC antibodies represents a relevant protection mechanism of an OMV-based ETEC vaccine candidate in vivo.
Highlights
Enteric infections associated with diarrhea remain a leading global health problem
Characterization of Detoxified and Enterotoxin Negative Mutants in V. cholerae and enterotoxigenic Escherichia coli (ETEC) We recently demonstrated that outer membrane vesicles (OMVs) derived from V. cholerae lacking one functional secondary lipid A acyltransferase, MsbB, exhibit 50% less endotoxicity and retain their potential to induce a high-titer, protective immune response (Leitner et al, 2013)
Encouraged by the promising results, we describe the first combined vaccine approach based on OMVs derived from different OMV donor species namely V. cholerae and ETEC
Summary
Enteric infections associated with diarrhea remain a leading global health problem. They have been recognized as the first leading cause of neonatal diarrhea and the second major cause of infant mortality in developing countries (Rao et al, 2003; Bryce et al, 2005; Levine, 2006). In general the pathophysiology of both pathogens is quite similar They enter the human host via contaminated food or water, passage through the stomach and reach the intestinal tract representing the primary colonization site. Both pathogens attach to the mucosal surface via surface-associated structures, i.e., the toxincoregulated pilus in case of V. cholerae or various fimbrial colonization factors (CFs) in case of ETEC. The secretory diarrhea is mainly caused by closely related AB-toxins known as cholera toxin (CT) or heat-labile enterotoxin (LT) for V. cholerae or ETEC, respectively (Faruque et al, 1998; Sánchez and Holmgren, 2005; Fleckenstein et al, 2014)
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