Cholera Caused by Vibrio cholerae O1 Induces T-Cell Responses in the Circulation

Abstract

Considerable effort is being made to understand the acute and memory antibody responses in natural cholera infection, while rather less is known about the roles of cellular immune responses involving T and B lymphocytes. We studied responses in adult patients hospitalized with cholera caused by Vibrio cholerae O1. Peripheral blood mononuclear cells from patients (n ‫؍‬ 15) were analyzed by flow cytometry after stimulation with V. cholerae O1 membrane protein (MP) or toxin-coregulated pilus antigen (TcpA). The gamma interferon (IFN-␥) and interleukin-13 (IL-13) responses in stimulated-lymphocyte supernatants were studied. The responses were compared with those of healthy controls (n ‫؍‬ 10). Vibrio cholerae O1 is a common causative agent of acute watery diarrhea in children and adults in the developing world (1,3,10, 19). After colonizing the proximal small intestine, this bacterium produces cholera toxin, which induces a profuse secretory diarrhea. Cholera remains a key public health problem that results in epidemics in resource-poor settings.It is believed that the immune response to cholera is initiated by antigen presentation in the Peyer's patches of the gastrointestinal mucosa, followed by migration of the stimulated antigen-specific B cells to regional lymph nodes and differentiation of these cells into specific antibody-secreting cells (28). Stimulation of the common mucosal immune system leads to production of both local and systemic antibodies (2, 15, 27) to virulence antigens of V. cholerae (25,28).Natural cholera infection is believed to give rise to long-term protection against subsequent disease. Robust systemic and mucosal antibodies are produced to the V. cholerae lipopolysaccharide, to cholera toxin, and to colonization factors, including the major subunit of the toxin-coregulated pilus, TcpA (2, 24, 25, 28). We have recently shown that there is induction of memory B-cell responses following infection, which may play a role in longer-lasting protection (14). In addition, recent evidence suggests that an innate component of the immune system may also play a role in the host response to cholera (9,22,26). Studies with experimental animals have shown that the mucosal immune response to cholera toxin is T cell dependent and that CD4 T helper cells have an important role (7, 12, 13). However, not much is known about the role of the adaptive cellular immune responses in patients with cholera. The aim of the present study was to decipher the role of T-and B-cellmediated immune responses in natural cholera infection in adults hospitalized with dehydrating illness, who were followed from the acute stage to convalescence. MATERIALS AND METHODSStudy group and recruitment. V. cholerae O1-infected adult male patients (n ϭ 15) who were between 18 and 49 years old were recruited into this study from the hospital of the International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh (ICDDR, B), and the degree of dehydration and clinical severity of the disease in the patients were assessed by a physicia...

Memory T-Cell Responses to Vibrio cholerae O1 Infection

“…Cytokine responses, including an increase in IL-13 secretion by proliferating T cells, have been observed in acute cholera, suggesting a Th2 polarized T-cell response (6). Differences in cytokine levels in the serum and fecal extracts of parasite coinfected cholera patients compared to parasite-uninfected patients suggest that T-cell responses contribute to differences observed between vaccinee responses in areas where cholera is endemic, where parasitic infection is common, versus areas where it is not endemic (20).…”

“…Previously observed T-cell responses following V. cholerae infection were hypothesized to represent memory T-cell responses because people living in areas of endemicity develop immune responses to V. cholerae as children (6,16,29,30). Memory T cells are a heterogeneous population and, unlike B cells, changes in T cells induced by exposure to antigen may be reversible (4,27).…”

“…We have recently demonstrated that cholera patients mount a primed T-cell response in the mucosa after V. cholerae O1 infection (6). We hypothesize that protection from cholera may be mediated by memory B cells capable of an anamnestic response in the gut mucosa and that these memory B cells may depend on stimulation provided by memory T cells for their development and maintenance.…”

Interleukin-13 (IL-13)/IL-13 Receptor α1 (IL-13Rα1) Signaling Regulates Intestinal Epithelial Cystic Fibrosis Transmembrane Conductance Regulator Channel-dependent Cl− Secretion

“…Notably, the CFTR channel blocker crofelemer stimulates faster symptom resolution in patients with infectious diarrhea such as cholera (69). Furthermore, cryptosporidiosis and cholera infection have been associated with increased T-cell-derived IL-13 (56,70). We speculate that IL-13 regulation of CFTR expression and activity would exacerbate Cl Ϫ and water secretion and diarrhea in cases of infectious diarrhea.…”

Pilot Study of Whole-Blood Gamma Interferon Response to the Vibrio cholerae Toxin B Subunit and Resistance to Enterotoxigenic Escherichia coli -Associated Diarrhea

“…In humans, individuals suffering from acute cholera show increased CD4 ϩ and CD8 ϩ T-cell proliferative responses against V. cholerae during the acute and convalescent stages of infection. Gut-homing CD4 ϩ T cells (␤7 ϩ ), gut-homing CD8 ϩ T cells (␤7 ϩ ), and gut-homing B cells (CD19 ϩ ␤7 ϩ ) also increase during the late convalescent stage of cholera compared to the acute stage of disease (2). This suggests that cellular immunity is important in the response to V. cholerae infection.…”