Abstract
The induction of interleukin-8 (IL-8) in vitro has been suggested to correlate with the reactogenicity of Vibrio cholerae vaccine candidates. V. cholerae vaccine candidate 638, a hemagglutinin protease/hap-defective strain, was recently reported to be well tolerated in human volunteers, suggesting a role for Hap in reactogenicity. We examined the role of hap in the induction of IL-8 in intestinal epithelial T84 cells. Wild-type V. cholerae strains 3038 and C7258 and a vaccine candidate strain, JBK70, induced levels of IL-8 similar to those of their isogenic hap mutants. Supernatant containing Hap did not stimulate IL-8 production at a variety of concentrations tested, suggesting that Hap itself does not induce IL-8 production. Furthermore, supernatant from CVD115, which had deletions of hap and rtxA (encoding repeats in toxin) and was derived from a reactogenic strain, CVD110, induced IL-8 production in T84 cells in a dose-dependent manner. The IL-8-stimulating activity of CVD115 culture supernatants was growth phase dependent and was strongest in stationary phase cultures. This IL-8 stimulator(s) was resistant to heat treatment but sensitive to proteinase. Protease activity in vitro did not correlate with the reactogenicity of V. cholerae vaccine candidates. Our data suggest that Hap is not an IL-8 inducer in T84 cells and that the IL-8 stimulator in the supernatant of V. cholerae culture may play a role in reactogenicity.
Highlights
The acute diarrheal disease cholera remains a significant public health problem, causing more than five million cases and 200,000 deaths annually in the world [47]
It was reported that reactogenic V. cholerae strains induced higher levels of IL-8 in vitro than nonreactogenic strains such as 638 and CVD103-HgR
These data suggest that the nonreactogenicity of these strains may be due to their diminished ability to induce IL-8 production in intestinal epithelial cells [38]
Summary
The acute diarrheal disease cholera remains a significant public health problem, causing more than five million cases and 200,000 deaths annually in the world [47]. The etiologic agent of cholera, is transmitted by contaminated water and food. It colonizes the surface of the small intestine, where it secretes cholera toxin (CT), which is largely responsible for the acute diarrhea characteristic of cholera. High levels of lactoferrin were found in stool samples of volunteers who received the El Tor vaccine candidate CVD110, strongly suggesting intestinal inflammation [41]. The levels of fecal lactoferrin found with CVD110 were nearly as high as those found in stool samples from volunteers who ingested Shigella, the classic etiologic agent of inflammatory diarrhea [41].
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