Molecular mechanism of V. vulnificus MARTX toxin in pathogenesis and food safety

描述（由申请人提供）：创伤弧菌是沿海沃茨的自然居民，包括美国海湾。这种细菌在食用受污染的海鲜（特别是生牡蛎）后会导致快速败血症，主要发生在肝功能障碍的人身上。在食物来源的病原体中，创伤弧菌以其高住院率和死亡率而闻名。事实上，V. vulnificus占食物源性疾病死亡人数的1%，尽管仅引起0.003%的疾病。虽然感染是罕见的，但近年来严重感染的数量一直在增加，这可能是由于全球变暖导致沿海沃茨适合创伤弧菌生长的天数增加。FDA试图通过实施收获后处理规定来保护消费者，但遭到贝类收获行业的强烈抵制，迫使FDA审查其政策。因此，研究创伤弧菌的发病机制已成为食品安全和公共政策的优先事项。最近的研究表明，创伤弧菌的细胞毒性主要与一种大的多功能自处理RTX毒素（MARTXVv）有关。在这项研究中，我们证明，这种毒素是直接联系到发病机制的胃内途径的感染，虽然它的目标在体内和分子作用机制仍然未知。我们建议使用体内、细胞培养和生化系统研究MARTXVv毒素在发病机制中的作用。该提案的重点将是直接影响因食用受污染食品而引起的疾病的机制，以及与细胞裂解和毒性潜力增加有关的毒素特定区域的鉴定和表征。

DESCRIPTION (provided by applicant): Vibrio vulnificus is a natural inhabitant of coastal waters, including the US Gulf. The bacterium causes rapid septicemia after consumption of contaminated seafood (especially raw oysters), predominantly in persons with liver dysfunction. Among food-bourne pathogens, V. vulnificus is most notable for its high rates of hospitalization and death. Indeed, V. vulnificus accounts for 1% of deaths from food-bourne illness despite causing only 0.003% of illnesses. Although infections are rare, the number of serious infections has been increasing in recent years, possibly due to global warming that has caused a rise in the number of days amenable to growth of V. vulnificus in coastal waters. Attempts by the FDA to protect consumers by implementation of post-harvest processing mandates met with significant resistance from the shellfish harvesting industry forcing the FDA to review its policies. Thus, the study of V. vulnificus pathogenesis has become a food safety and public policy priority. Recent studies establish that cytotoxicity of V. vulnificus is predominantly associated with a large Multifunctional-Autoprocessing RTX toxin (MARTXVv). In this study, we demonstrate that this toxin is directly linked to pathogenesis by the intragastric route of infection, although its targets in vivo and molecular mechanism of action remain unknown. We propose to study the role of the MARTXVv toxin in pathogenesis using in vivo, cell culture, and biochemical systems. The focus of the proposal will be mechanisms directly impacting disease due to consumption of contaminated food and identification and characterization of specific regions of the toxin linked to cell lysis and increased virulence potential.