IMMUNE RESPONSES TO V. CHOLERAE INFECTION IN BANGLADESH

描述(改编自申请摘要)：霍乱弧菌引起 严重的、脱水的，有时甚至致命的人类腹泻。有一种 全世界估计有500-700万霍乱病例，其中超过10万人 死亡。霍乱的大部分影响发生在世界的发展中地区， 特别是在南亚和东南亚，如孟加拉国和印度。 感染霍乱弧菌可诱导对霍乱弧菌的持久保护性免疫 随后的霍乱，尽管介导保护的免疫反应不是 完全理解。以前对V.V.免疫反应的许多现场研究 霍乱感染是在20世纪70年代进行的，当时更现代的霍乱 测量粘膜免疫反应的技术，例如使用 抗体分泌细胞分析。霍乱弧菌感染的最新研究 在正常的志愿者中，许多人在美国做过，提供了重要的 关于感染这种病原体的免疫反应的信息，但这些 反应可能与流行地区的患者有很大不同， 尤其是与年龄、发病率、营养不良和 以前接触过相关抗原。最近在这方面做了很多工作 霍乱弧菌口服减毒活疫苗的研制 临床霍乱的预防和作为表达异源基因的载体 用来保护粘膜表面免受其他感染的抗原。这 该提案将在科学家之间建立长期的合作关系 美国和#年国际腹泻病研究中心 孟加拉国阐明免疫反应和预防霍乱感染 在地方病流行的人群中。这个项目的长期目标是 了解霍乱弧菌感染后的粘膜免疫反应 疫苗接种，并评估患者和微生物因素对 这些反应可能解释了患者之间观察到的差异 流行区和正常人类志愿者。该提案的具体目的 包括：1)确定各种免疫反应，特别是粘膜免疫反应 孟加拉国霍乱患者的抗体反应，比较 杀弧菌和粘膜抗体反应，并通过以下方式对这些反应进行分层 患者和微生物特征。我们将检验这一假设 血清杀弧菌反应代表粘膜的替代标记物 对实际具有保护性的一个或多个相关抗原的反应：2) 接触有机体时粘膜抗霍乱弧菌抗体水平的相关性 对随后的临床霍乱具有保护作用。我们将研究 假设先前存在对内毒素的分泌性免疫。CtxB、MSHA和/或TCPA 在霍乱弧菌定居时保护 疾病：3)评估远程(非肠道)对CtxB的免疫反应 临床霍乱后粘膜部位作为免疫反应模型的研究 霍乱弧菌口服减毒活疫苗表达的异源抗原 向量。

DESCRIPTION (adapted from 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.