Vaccine Potential of Type IV Pilin from Clostridium difficle

描述（由申请人提供）：艰难梭菌是一种新兴的病原体，可引起严重的，有时是致命的结肠炎。流行病学证据表明，C。难治性疾病（CDAD）正在以惊人的速度增长。现有的治疗不足，也没有获得许可的疫苗。IV型皮利（T4 Ps）是在由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，在C.产气荚膜梭菌和T4Ps基因存在于C.很难我们的总体假设表明，针对主要菌毛蛋白的免疫应答将保护免受定植和CDAD。为了验证这一假设，我们将首先确定哪一个菌毛蛋白基因编码C。目的探讨纯化菌毛蛋白免疫对艰难梭菌T4P的预防作用。艰难梭菌定殖和疾病。拟议的研究是高度创新的，因为它将研究一种通常与革兰氏阴性细菌鉴定的新型抗原的潜力，以防止革兰氏阳性厌氧菌的定植。表明保护作用的结果将对梭菌感染的预防和治疗的研究和策略产生深远的影响。研究人员已经建立了研究T4 P的生产率记录，并使用马里兰州巴尔的摩大学的疾病和环境动物模型，这是拟议研究的理想选择。鉴于T4Ps在其他感染中不可或缺的作用，菌毛蛋白的免疫原性，以及其他T4P疫苗的成功，我们预计C.艰难梭菌菌毛蛋白疫苗（单独或与类毒素疫苗组合）将产生针对这种潜在致命感染的有效保护性免疫应答。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。 公共卫生相关性：艰难梭菌是一种细菌，导致严重的，有时是致命的大肠感染。C.艰难 相关疾病（CDAD）正在以惊人的速度增长。现有的治疗不足，也没有获得许可的疫苗。IV型皮利（T4 Ps）是由许多引起疾病的重要细菌产生的表面纤维。T4Ps在感染中发挥重要作用，并已成功用作疫苗。我们试图确定是否与最近发现的C. difficile将保护免受殖民化和CDAD。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，并可能导致预防这种致死性感染的新武器。

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. PUBLIC HEALTH RELEVANCE: Clostridium difficile is a bacterium that causes severe and sometimes deadly infections of the large intestine. 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) are surface fibers made by many important bacteria that cause disease. T4Ps play important roles in infection and have been used successfully as vaccines. We seek to determine whether vaccination with the protein that makes up the recently discovered T4P of C. difficile will protect against colonization and CDAD. Demonstration of protection in a highly relevant animal model will pave the road to further preclinical and clinical testing and potentially lead to a new weapon to prevent this letha infection.