IMMUNE RESPONSES TO V. CHOLERAE INFECTION IN BANGLADESH

描述（改编自应用摘要）：霍乱弧菌引起 严重的，脱水的，偶尔致命的人类腹泻。有一 据估计，全世界有500万至700万例霍乱病例， 死亡霍乱的大部分影响发生在世界上的发展中地区， 特别是在南亚和东南亚，如孟加拉国和印度。 霍乱弧菌感染诱导持久的保护性免疫， 随后的霍乱，虽然免疫反应介导的保护， 完全理解许多以前的实地研究免疫反应的V。 霍乱感染是在20世纪70年代，在更现代的到来之前， 用于测量粘膜免疫应答的技术，例如使用 抗体分泌细胞测定。关于霍乱弧菌感染的最新研究 在正常的志愿者中，许多人在美国完成， 关于这种病原体感染的免疫反应的信息，但这些 反应可能与流行地区患者的反应大不相同， 特别是关于年龄、发病率、营养不良和 之前接触过相关抗原最近做了很多工作， 开发有效的口服减毒活霍乱弧菌疫苗， 预防临床霍乱并作为表达异源的载体 抗原以保护粘膜表面免受其他感染。这 该提案将建立科学家之间的长期合作， 美国和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 在一个地方性的人群中。该项目的长期目标是更好地 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 这些反应可以解释患者之间观察到的差异， 流行区和正常人类志愿者。提案的具体目标 1）确定免疫应答的全部范围，特别是粘膜免疫应答。 孟加拉国霍乱患者的抗体反应， 杀弧菌和粘膜抗体应答，并通过以下方法对这些应答进行分层： 患者和微生物特征。我们将测试假设， 血清杀弧菌反应代表粘膜炎的替代标志物， 对相关抗原或实际上具有保护性的抗原的应答：2） 将粘膜抗-V霍乱抗体水平与暴露于微生物相关 防止随后的临床霍乱。我们会研究 假设预先存在对LPS分泌免疫。CtxB、MSHA和/或TcpA 在霍乱弧菌定殖时， 疾病：3）评估远处（非肠道）对CtxB免疫应答 临床霍乱后的粘膜部位，作为免疫应答的模型， 霍乱弧菌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.