Vaccine Potential of Type IV Pilin from Clostridium difficle

描述(申请人提供)：艰难梭菌是一种新出现的病原体，会导致严重的结肠炎，有时甚至是致命的。流行病学证据表明，艰难梭菌相关性疾病(CDAD)的严重程度和发病率都在以惊人的速度增长。可用的治疗方法不足，而且没有获得许可的疫苗。IV型菌毛(T4P)是一种表面附属物，在各种细菌病原体引起的感染中发挥重要作用，已被用于疫苗开发。最近在产气荚膜梭菌中发现了T4Ps，艰难梭菌中也发现了T4Ps基因。我们的总体假设是，对主要菌毛素的免疫反应将保护机体免受侵袭和CDAD。为了验证这一假设，我们将首先确定艰难梭菌T4P的主要结构亚基编码的菌毛蛋白基因，然后在小鼠模型中研究纯化的菌毛蛋白免疫在预防艰难梭菌定植和疾病方面的效果。这项拟议的研究具有很高的创新性，因为它将检查一种新的抗原的潜力，这种新型抗原通常与革兰氏阴性菌一起识别，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预防和治疗梭状芽胞杆菌感染的研究和战略产生深远影响。研究人员在马里兰大学研究T4P并使用疾病和环境的动物模型的生产率方面有既定的记录，巴尔的摩大学是拟议中的研究的理想选择。鉴于T4P在其他感染中不可或缺的作用，毛孔蛋白的免疫原性，以及其他T4P疫苗的成功，我们预计艰难梭菌毛孔疫苗(单独或与毒素疫苗结合使用)将对这种潜在的致命感染产生强大的保护性免疫反应。在高度相关的动物模型中展示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.