application abstract): Vibrio cholerae causes a severe, dehydrating, and occasionally fatal diarrhea in humans. There are an estimated 5-7 million cases worldwide of cholera, with more than 100,000 deaths. Much of the impact of cholera occurs in developing areas of the world, particularly in South and Southeast Asia such as Bangladesh and India. Infection with V. cholerae induces long-lasting protective immunity to subsequent cholera, although the immune responses mediating protection are not fully understood. Many of the previous field studies of immune responses to V. cholerae infection were done in the 1970s, prior to the advent of more modern techniques for measuring mucosal immune responses, such as the use of antibody-secreting cell assays. More recent studies of V. cholerae infection in normal volunteers, many done in the United States, have provided important information on immune responses to infection with this pathogen, but these responses may differ substantially than those in patients in endemic areas, particularly as relates to the influence of age, morbidity, malnutrition and prior exposure to related antigens. Much work has been done recently on development of effective live, oral, attenuated V. cholerae vaccines, both for prevention of clinical cholera and as vectors for expressing heterologous antigens to protect against other infections at mucosal surfaces. This proposal would establish a long-term collaboration between scientists in the US and at the International Centre for Diarrhoeal Disease Research in Bangladesh to elucidate immune responses and protection from cholera infection in an endemic population. The Long-Term Goals of this project are to better understand mucosal immune responses after V. cholerae infection and vaccination, and to assess the effect of patient and microbial factors on these responses that may explain differences observed between patients from endemic areas and normal human volunteers.
The Specific Aims of the proposal are: 1) determine the full range of immune responses, particularly mucosal antibody responses, in patients with cholera in Bangladesh, comparing vibriocidal and mucosal antibody responses and stratifying these responses by patient and microbial characteristics. We will test the hypothesis that the serum vibriocidal response represents a surrogate marker for a mucosal response to a relevant antigen or antigens that is actually protective: 2) correlate mucosal anti-V cholerae antibody levels on exposure to the organism with protection from subsequent clinical cholera. We will examine the hypothesis that pre-existing secretory immunity to LPS. CtxB, MSHA and/or TcpA at the time of colonization of V. cholerae protects against subsequent illness: 3) assess immune responses to CtxB at distant (non-intestinal) mucosal sites after clinical cholera, as a model for immune responses to heterologous antigens expressed by live, oral, attenuated V. cholerae vaccine vectors.
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