Vaccine Potential of Type IV Pilin from Clostridium difficle

描述（由申请人提供）：艰难梭菌是一种新出现的病原体，可引起严重甚至致命的结肠炎。流行病学证据表明，艰难梭菌相关疾病（CDAD）的严重程度和发病率都在以惊人的速度增加。现有的治疗方法不足，也没有获得许可的疫苗。IV型菌毛（T4Ps）是在多种细菌病原体引起的感染中起重要作用的表面附属物，已被用于疫苗开发。最近，产气荚膜梭菌中发现了T4Ps，艰难梭菌中也存在T4Ps基因。我们的总体假设是，针对主要蛋白的免疫反应将防止定植和CDAD。为了验证这一假设，我们将首先确定哪个pilin基因编码艰难梭菌T4P的主要结构亚基，然后在小鼠模型中研究纯化的pilin免疫预防艰难梭菌定植和疾病的效果。这项提议的研究是高度创新的，因为它将检验一种通常与革兰氏阴性细菌鉴定的新抗原的潜力，以防止革兰氏阳性厌氧菌的定植。这一结果将对梭状芽孢杆菌感染的研究和防治策略产生深远的影响。研究人员在研究T4P方面已经有了良好的记录，并且在马里兰大学巴尔的摩分校使用疾病和环境的动物模型是拟议研究的理想选择。考虑到T4Ps在其他感染中不可或缺的作用、匹林蛋白的免疫原性以及其他T4P疫苗的成功，我们预计艰难梭菌匹林疫苗（单独或与类毒素疫苗联合）将对这种潜在的致命感染产生有效的保护性免疫反应。在高度相关的动物模型中证明保护作用将为进一步的临床前和临床试验铺平道路。

DESCRIPTION (provided by applicant): Clostridium difficile is an emerging pathogen that causes severe and sometimes deadly colitis. Epidemiological evidence indicates that both the severity and incidence of C. difficile-associated disease (CDAD) are increasing at an alarming rate. Available treatment is inadequate and there are no licensed vaccines. Type IV pili (T4Ps), surface appendages that play important roles in infections caused by diverse bacterial pathogens, have been exploited for vaccine development. Recently, T4Ps were discovered in C. perfringens and the genes for T4Ps are present in C. difficile. Our overall hypothesis states that an immune response against the major pilin will protect against colonization and CDAD. To test this hypothesis we will first determine which pilin gene encodes the major structural subunit of the C. difficile T4P and then investigate the efficacy of immunization with purified pilin in prevention of C. difficile colonization and disease in a murine model. The proposed research is highly innovative because it will examine the potential of a novel antigen usually identified with Gram-negative bacteria to protect against colonization by a Gram-positive anaerobe. A result indicating a protective effect will have a profound effect on research and strategies for prevention and therapy for clostridial infections. The investigators have an established record of productivity studying T4P and using animal models of disease and the environment at the University of Maryland Baltimore is ideal for the proposed research. Given the indispensible role of T4Ps for other infections, the immunogenicity of pilin proteins, and the success of other T4P vaccines, we expect that a C. difficile pilin vaccine (alone or in combination with a toxoid vaccine) will generate a potent protective immune response against this potentially lethal infection. Demonstration of protection in a highly relevant animal model will pave the road to further preclinical and clinical testing.