Protective role of cross-reactive anti-enteric antibody

描述(由申请人提供)：我们假设本土菌群启动适应性免疫反应，这种反应可以在初次感染病原体时被招募，这些病原体与共生体具有共同或相似的细胞表面抗原。我们使用小鼠的一种粘膜病原体--轮状柠檬酸杆菌来研究这些反应的性质和募集。我们小组先前的研究已经证实，早期依赖T细胞的血清抗体反应对于在感染的急性期存活至关重要，而预先存在的分泌型IgA似乎影响定植的早期事件，从而影响随后的感染严重程度。这项提案概述了一系列实验，以定义来自正常菌群的抗原，这些抗原可以诱导免疫球蛋白对轮状柠檬酸杆菌的免疫球蛋白反应，轮状柠檬酸杆菌是一种附着和消除病原体，类似于EPEC和其他B类生物恐怖主义制剂。我们将确定针对这些共同抗原的血清和粘膜抗体的作用，目的如下：(1)识别轮状芽胞杆菌和共生物种之间的共同抗原，对未受感染的小鼠产生抗体反应，(2)开发针对这些抗原的单克隆粘膜(IgA)和血清(Ig G或Ig M)抗体，并评估注射免疫球蛋白影响定植和症状性感染发展的能力(3)通过使用交叉反应抗原的系统接种策略，确定对野生型和免疫缺陷小鼠的保护作用。这些实验的结果将为了解本土菌群的免疫保护功能提供分子基础，并有助于开发更好的疫苗和疗法，以提供对许多对人类和兽医具有重要意义的肠道病原体的广泛保护。

DESCRIPTION (provided by applicant): We hypothesize that the indigenous flora primes adaptive immune responses that can be recruited during primary infection with pathogens that share common or similar cell surface antigens with commensals. We use Citrobacter rodentium, a mucosal pathogen of mice, to study the nature and recruitment of these responses. Prior studies by our group have identified that an early T cell-dependent serum antibody response is critical for surviving the acute phase of infection while pre-existing secretory IgA appears to impact early events in colonization, which influence the subsequent severity of infection. This proposal outlines a series of experiments to define antigens from normal flora that elicit immunoglobulin responses against Citrobacter rodentium, an attaching and effacing pathogen similar to the EPEC and other class B bioterrorism agents. We will determine the role of serum and mucosal antibody against these shared antigens with the following aims:(1) identify antigens shared between C. rodentium and commensal species to which mice naive to infection generate an antibody response, (2) develop monoclonal mucosal (IgA) and serum (IgG or IgM) antibodies against these antigens and assess the ability of administered immunoglobulin to impact colonization and the development of symptomatic infection (3) ascertain protection conferred in wild-type and immunodeficient mice by systemic vaccination strategies using cross-reactive antigens. The results from these experiments will provide a molecular basis for understanding the immunoprotective functions of the indigenous flora, and can assist in the development of better vaccines and therapeutics to provide broad protection against many enteric pathogens of human and veterinary importance.