Vibrio cholerae infection provides long-lasting protective immunity, while oral, inactivated
cholera vaccines (OCV) result in more-limited protection. To identify characteristics of the innate immune response that may distinguish natural V. cholerae
infection from OCV, we stimulated differentiated, macrophage-like THP-1 cells with live versus heat-inactivated V. cholerae with and without endogenous or exogenous
cholera holotoxin (CT).
Interleukin 23A gene (IL23A) expression was higher in cells exposed to live V. cholerae than in cells exposed to inactivated organisms (mean change, 38-fold; 95% confidence interval [95% CI], 4.0 to 42; P < 0.01).
IL-23 secretion was also higher in cells exposed to live V. cholerae than in cells exposed to inactivated V. cholerae (mean change, 5.6-fold; 95% CI, 4.4 to 11; P < 0.001). This increase in
IL-23 secretion was more marked than for other key innate immune
cytokines (e.g., IL-1β and IL-6) and dependent on exposure to the combination of both live V. cholerae and CT. While
IL-23 secretion was reduced following stimulation with either heat-inactivated wild-type V. cholerae or a live isogenic ctxAB mutant of V. cholerae, the addition of exogenous CT restored
IL-23 secretion in combination with the live isogenic ctxAB mutant V. cholerae, but not when it was paired with stimulation by heat-inactivated V. cholerae The posttranslational regulation of
IL-23 under these conditions was dependent on the activity of the
cysteine protease cathepsin B. In humans,
IL-23 promotes the differentiation of Th17 cells to T follicular helper cells, which maintain and support long-term memory B cell generation after
infection. Based on these findings, the stimulation of
IL-23 production may be a determinant of protective immunity following V. cholerae
infection.IMPORTANCE An episode of
cholera provides better protection against
reinfection than oral
cholera vaccines, and the reasons for this are still under study. To better understand this, we compared the immune responses of human cells exposed to live Vibrio cholerae with those of cells exposed to heat-killed V. cholerae (similar to the contents of oral
cholera vaccines). We also compared the effects of active
cholera toxin and the inactive
cholera toxin B subunit (which is included in some
cholera vaccines). One key immune signaling molecule,
IL-23, was uniquely produced in response to the combination of live bacteria and active
cholera holotoxin. Stimulation with V. cholerae that did not produce the active toxin or was killed did not produce an
IL-23 response. The stimulation of
IL-23 production by
cholera toxin-producing V. cholerae may be important in conferring long-term immunity after
cholera.