Clostridium difficile Immunity: Role of IGA and GALT

描述(由申请人提供)：本提案的目的是阐明IgA和胃肠道淋巴组织(GALT)在艰难梭菌(CD)免疫中的作用。CD是一种胃肠道病原体，是一种主要的且不断增加的卫生保健负担，每年给美国造成的损失估计为30亿美元，每年约有7,752-20,000人死于CD感染和疾病(CDI)。感染CDI的危险因素包括抗生素治疗、年龄(65岁)、住院治疗以及未能对CD毒素产生或维持足够的抗体反应。最重要的是需要安全有效的疫苗，以诱导针对CD毒素的中和抗体，并减少CDI负担。Cd毒素产生于结肠，胃肠道淋巴组织(GalT)主要产生IgA，这是肠道抵御病原体和毒素的主要防御机制。在GALT中也能诱导抗原特异性的免疫球蛋白反应，这可能对血清免疫球蛋白池有贡献。目前还没有研究确定CDI的保护需要IgA还是GALT。大多数候选CD疫苗是非肠道疫苗，它们诱导CD毒素特异性血清免疫球蛋白G，但不诱导肠道免疫球蛋白A，这可能是获得对CDI的强大保护所必需的。以维生素A代谢物全反式维甲酸(RA)为佐剂的非CD肠外疫苗可诱导IgA抗体分泌细胞的肠靶向归巢，并产生抗原特异性IgA。这项应用的目的是确定在CDI期间诱导的保护性免疫途径。我们假设GALT和IgA对于CDI的保护性免疫至关重要，将RA与肠外注射的CD疫苗一起使用将通过增强粘膜IgA显著增强保护性免疫。这一假设将通过回答以下问题来解决。目的1：确定IgA是否在CDI保护性免疫中起关键作用。预防CDI感染需要免疫球蛋白A吗？RA是否诱导结肠毒素特异性IgA并增强CDI保护性免疫？目的2：确定结肠免疫反应在CDI保护性免疫中是否起重要作用。对镉毒素的免疫球蛋白A和免疫球蛋白抗体反应都是在高尔基体启动的吗？高尔的缺失是否会削弱对CDI的保护？拟议的研究具有创新性，因为它们挑战了流行的CDI保护性免疫模式的关键方面，在他们的结论中，我们将首次确定粘膜IgA和GALT在CDI保护性免疫中的作用，并确定通过RA等佐剂诱导肠道IgA来增强非肠道疫苗诱导的保护的新方法。我们提出的研究有望为CD免疫提供与CDI治疗和靶向疫苗设计相关的新的和重要的见解。

DESCRIPTION (provided by applicant): The goal of this proposal is to elucidate the role of IgA and gastrointestinal lymphoid tissues (GALT) in Clostridium difficile (CD) immunity. CD is a gastrointestinal pathogen that is a major and increasing health care burden costing the United States an estimated 3 billion dollars/year and an estimated 7,752-20,000 deaths occurring annually from CD infection and disease (CDI). Risk factors for acquiring CDI include antibiotic therapy, age (>65 years), hospitalization, and failure to mount or maintain an adequate antibody response to the CD toxins. The need for safe and effective vaccines that induce neutralizing antibody to the CD toxins and reduce CDI burden is paramount. The CD toxins are produced in the colon where gastrointestinal lymphoid tissues (GALT) predominantly produce IgA, which is the major defense mechanism of the gut from pathogens and toxins. Antigen-specific IgG responses are also induced in the GALT that may contribute to serum IgG pools. No studies have identified whether IgA or GALT is required for CDI protection. The majority of candidate CD vaccines are parenteral vaccines that induce CD toxin-specific serum IgG but do not induce intestinal IgA, which may be required to obtain robust protection against CDI. Non-CD parenteral vaccines adjuvanted with the vitamin A metabolite all trans retinoic acid (RA) induce gut targeted homing of IgA antibody secreting cells and production of antigen-specific IgA. The objective of this application is to define protective immunological pathways that are induced during CDI. We hypothesize that the GALT and IgA are critical for protective immunity to CDI and that inclusion of RA with parenterally administered CD vaccines will significantly enhance protective immunity through the enhancement of mucosal IgA. This hypothesis will be addressed by answering the following questions. Aim 1: Determine whether IgA is critical to CDI protective immunity. Is IgA required for protection against CDI infection? Does RA induce colonic toxin-specific IgA and enhance CDI protective immunity? Aim 2: Determine whether colonic immune responses are important in protective immunity to CDI. Are both IgA and IgG antibody responses to CD toxins initiated in GALT? Does the absence of GALT ablate protection from CDI? The proposed studies are innovative as they challenge key facets of the prevailing model of protective immunity to CDI and at their conclusion, we will have defined for the first time the role of mucosal IgA and GALT in protective immunity to CDI and identified new approaches to enhance protection induced by parenteral vaccines through induction of intestinal IgA by adjuvants like RA. Our proposed studies promise to yield novel and important insights to CD immunity relevant to CDI therapy and targeted vaccine design.