Vibrio cholerae O1 is a noninvasive enteric pathogen and serves as a model for studies of mucosal immunity. Although symptomatic V. cholerae infection induces durable protection against subsequent disease, vaccination with oral killed whole-cell V. cholerae stimulates less long-lasting protection against cholera. In this study, we demonstrated that cholera induces an early proinflammatory cellular immune response that results in priming of Th1-and Th17-type cytokine responses to ex vivo antigenic stimulation and an increase in the ratio of Th1 to Th2 CD4 ؉ T-cell responses. Comparable priming of Th1 and Th17 responses, with an increased ratio of Th1 to Th2 CD4 ؉ T-cell responses, was not observed in subjects who received two doses of the oral cholera vaccine Dukoral (a whole-cell cholera toxin B subunit containing [WC-CTB] vaccine). These findings suggest that natural V. cholerae infection induces an early, proinflammatory cellular immune response, despite the apparent lack of clinical signs of inflammation. The failure of the WC-CTB vaccine to activate equivalent, CD4؉ T-cell responses is a potential explanation for the shorter duration of protection following immunization with this vaccine. Additional studies are needed to determine whether these early T-cell-mediated events predict the subsequent duration of immunologic memory.Vibrio cholerae causes 3 million to 5 million cases of diarrhea and over 100,000 deaths annually (2). Organisms colonize the epithelial surface of the small intestine and elaborate cholera toxin (CT), an essential virulence factor for all pandemic strains of V. cholerae (30). Because V. cholerae is a prototypical noninvasive pathogen, it serves as a model for the study of mucosal immunity (17).Natural infection with V. cholerae provides greater than 90% protection against subsequent disease for at least 3 years in U.S. volunteer studies (the maximum period studied) and an average of 3 to 8 years on the basis of epidemiological studies in areas of endemicity (5,19,21). The mechanism(s) of protective immunity against cholera is not well understood but has been hypothesized to depend on anamnestic responses of memory B cells (16,25,35). Consistent with this, our group previously demonstrated that V. cholerae protein antigen-specific memory B cells remain detectable in the circulation for over a year following cholera, after circulating antibody levels have returned to baseline levels. In contrast, memory B-cell responses to lipopolysaccharide, a T-cell-independent antigen, were found to decrease more rapidly after infection (16). Such long-lasting memory B cells against V. cholerae protein antigens could play a role in mediating anamnestic responses and protection against subsequent infection.In contrast, a currently licensed cholera vaccine, Dukoral (a whole-cell CT B subunit [WC-CTB] vaccine), consists of killed V. cholerae O1 supplemented with recombinant cholera toxin B subunit (rCTB) and provides over 60% protection. However, protection wanes by 3 years after vaccination, and the vacc...

Tether complexes play important roles in endocytic and exocytic trafficking of lipids and proteins. In yeast, the multisubunit transport protein particle (TRAPP) tether regulates endoplasmic reticulum (ER)-to-Golgi and intra-Golgi transport and is also implicated in autophagy. In addition, the TRAPP complex acts as a guanine nucleotide exchange factor (GEF) for Ypt1, which is homologous to human Rab1a and Rab1b. Here, we show that human TRAPPC13 and other TRAPP subunits are critically involved in the survival response to several Golgi-disrupting agents. Loss of TRAPPC13 partially preserves the secretory pathway and viability in response to brefeldin A, in a manner that is dependent on ARF1 and the large GEF GBF1, and concomitant with reduced caspase activation and ER stress marker induction. TRAPPC13 depletion reduces Rab1a and Rab1b activity, impairs autophagy and leads to increased infectivity to the pathogenic bacterium in response to brefeldin A. Thus, our results lend support for the existence of a mammalian TRAPPIII complex containing TRAPPC13, which is important for autophagic flux under certain stress conditions.

Understanding the cellular populations and mechanisms responsible for overcoming immune compartmentalization is valuable for designing vaccination strategies targeting distal mucosae. In this study we show that the human pathogen, Chlamydia trachomatis, infects the murine respiratory and genital mucosa and that T cells, but not antibodies, elicited through intranasal immunization can protect against a subsequent transcervical challenge. Unlike the genital infection where CD8+ T cells are primed, yet fail to confer protection, we found that intranasal priming engages both CD4+ and CD8+ T cells, allowing for protection against genital infection with C. trachomatis. The protection is largely dependent on IFNγ secretion by T cells. Moreover, different chemokine receptors are critical for C. trachomatis-specific CD4+ T cells to home to the lung, rather than the CXCR3 and CCR5-dependent migration observed during genital infection. Overall, this study demonstrates that the cross-mucosa protective immunity against genital C. trachomatis infection following intranasal immunization is not dependent on antibody response but is mediated by not only CD4+ T cells but also CD8+ T cells. This study provides insights for the development of vaccines against mucosal pathogens that threaten reproductive health worldwide.

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