O-Specific Polysaccharide Responses and Cholera

描述(申请人提供)：霍乱是一种由霍乱弧菌引起的严重脱水疾病。对霍乱的保护是血清组特异性的，而血清组特异性是由霍乱弧菌脂多糖(LPS)的O型特异性多糖(OSP)成分定义的。我们最近发现，针对霍乱弧菌内毒素的记忆B细胞反应与孟加拉国霍乱指数患者的家庭接触者对霍乱的保护相关，并且以前曾将霍乱患者的家庭接触者对霍乱的保护与基线的血浆和粪便抗内毒素IgA反应以及杀弧性反应(后者主要由抗内毒素IgM反应组成)相关联。我们最近还表明，野生型霍乱患者可以针对霍乱弧菌脂多糖产生强大的记忆B细胞反应，但目前可用的口服灭活霍乱疫苗的接受者不会。后一种观察结果可能在很大程度上解释了为什么目前可用的霍乱疫苗没有在霍乱幸存者身上产生高水平和长期的保护作用。尽管有这些观察，霍乱和霍乱疫苗接种后的抗OSP免疫反应从未被描述过。因此，在这个项目中，我们建议利用我们最近获得的作为独立抗原和结合形式纯化霍乱弧菌OSP的能力，继续与NIDDK碳水化合物科科长Paul Kovac建立合作，并与正在孟加拉国达卡进行的由NIAID赞助的霍乱免疫研究协同进行，该研究涉及达卡国际腹泻疾病研究中心(ICDDR，B)和波士顿马萨诸塞州总医院-哈佛大学的研究人员。在这项应用中，我们建议表征孟加拉国儿童和成人霍乱患者以及口服灭活霍乱疫苗接受者的OSP反应，包括评估记忆和粘膜免疫反应(在霍乱患者的十二指肠活检标本中)。我们还建议评估达卡霍乱指数患者的家庭接触者中抗OSP免疫与预防霍乱之间的关联，以及评估OSP结合物在小鼠中诱导与预防人类霍乱相关的抗OSP反应的能力。通过这项计划获得的知识将大大增强我们对免疫反应的了解，免疫反应是预防霍乱的最有可能的决定因素，即抗OSP反应，并将为开发改进的霍乱疫苗或免疫战略提供关键信息。

DESCRIPTION (provided by applicant): Cholera is a severe dehydrating disease caused by Vibrio cholerae. Protection against cholera is serogroup specific, and serogroup specificity is defined by the O-specific polysaccharide (OSP) component of V. cholerae lipopolysaccharide (LPS). We have recently shown that memory B cell responses that target V. cholerae LPS are associated with protection from cholera among household contacts of cholera index patients in Bangladesh, and have previously correlated protection from cholera in household contacts of cholera patients with baseline plasma and stool anti-LPS IgA responses, as well as vibriocidal responses (the latter largely being comprised of anti-LPS IgM responses). We have also recently shown that patients with wild type cholera develop robust memory B cell responses targeting V. cholerae LPS, but that recipients of currently available oral killed cholera vaccines do not. The latter observation may in large measure explain why currently available cholera vaccines do not induce the high-level and long-term protection seen in patients who survive cholera. Despite these observations, the anti-OSP immune responses following cholera and cholera vaccination have never been characterized. In this program, we therefore propose to take advantage of our recently acquired ability to purify V. cholerae OSP, both as an independent antigen as well as in conjugate form, continuing an established collaboration with Paul Kovac, Chief-Carbohydrate Section, NIDDK, and to synergize with an ongoing NIAID-sponsored cholera immune study in Dhaka, Bangladesh that involves researchers at the International Centre for Diarrhoeal Disease Research in Dhaka (ICDDR,B) and the Massachusetts General Hospital-Harvard University in Boston. In this application, we propose to characterize OSP-responses in child and adult cholera patients in Bangladesh, as well as in recipients of oral killed cholera vaccines, including assessing memory and mucosal immune responses (in duodenal biopsy specimens of cholera patients). We also propose to assess the association of anti-OSP immunity with protection from cholera among household contacts of cholera index patients in Dhaka, as well as to assess the ability of an OSP-conjugate to induce in mice anti-OSP responses that correlate with protection from cholera in humans. The knowledge gained through this program would significantly enhance our knowledge of the immune response that is the most likely determinant of protection against cholera, the anti-OSP response, and would critically inform efforts to develop an improved cholera vaccine or immunization strategy.