Accessory toxin-mediated evasion of innate immunity during V. cholerae infection

描述（由申请人提供）：霍乱弧菌O1是大流行性霍乱的病原体，霍乱是一种严重的腹泻疾病，目前仍在世界范围内流行。1961年开始并持续至今的第七次霍乱大流行的主要病原是产生霍乱毒素的El Tor 01菌株。这些毒株最初被认为具有较低的毒力潜力，因为它们引起的疾病的严重程度低于导致早期大流行的“经典”毒株。然而，据信，El - Tor菌株的毒性较低是其大流行传播的原因之一，因为大多数感染者不会生病，但会被定植并排出传染性生物体。事实上，人们认为导致El Tor菌株出现的一个因素是它们在无症状携带者中平均持续5天的能力，而传统菌株只有1.5天。因此，El - Tor菌株具有经典菌株中不存在的遗传因素，这些遗传因素有助于延长定植。这些遗传因素以前没有被发现。利用一种适合宿主免疫反应研究的新的霍乱动物模型，我们已经证明了副毒素溶血素和RTX是建立霍乱弧菌在小肠隐窝长期定殖的关键因素。这笔拨款将继续通过联合感染研究来研究溶血素、RTX和先天免疫之间的联系，以确定定植缺陷是否可以在细胞外补充。本研究还将调查早期霍乱弧菌感染期间肠道相关淋巴组织募集的细胞类型。最后，本项目将具体确定中性粒细胞和肥大细胞是否是霍乱弧菌先天免疫反应的关键组成部分，以及这些细胞是否在体内被溶血素和RTX毒素破坏。公共卫生相关性：霍乱弧菌O1是大流行性霍乱的病原体，大流行性霍乱是一种严重的腹泻疾病，在世界范围内仍然流行。现代霍乱的流行病学不同于传统疾病，因为流行是由毒性较低的菌株引起的，引起高频率的轻度或无症状感染。这种长时间的弧菌排泄可能有助于疾病的传播。通过一种新的霍乱动物模型，研究人员发现，辅助毒素溶血素和RTX是延长霍乱弧菌肠道定植的关键因素。该项目将研究霍乱弧菌免疫反应的关键组成部分，并确定与先天免疫功能丧失有关的辅助毒素。

DESCRIPTION (provided by applicant): Vibrio cholerae O1 is the causative agent of pandemic cholera, a severe diarrheal disease still prevalent worldwide. The major etiologic agent of the Seventh Cholera Pandemic that began in 1961 and continues today is the cholera toxin producing El Tor O1 strains. These strains were first thought to have low virulence potential as they cause disease of less severity than "classical" strain responsible for earlier pandemics. However, the lowered virulence of El Tor strains is believed to have contributed to their pandemic spread since a majority of infected persons do not become ill but do become colonized and excrete the infectious organisms. Indeed, one factor thought to contribute to the emergence of El Tor strains is their ability to persist an average of 5 days in asymptomatic carriers compared to only 1.5 days for classical strains. Thus, El Tor strains have genetic factor(s) absent in classical strains that contribute to prolonged colonization. These genetic factors had not been previously identified. Using a new animal model of cholera amenable to studies of the host immune response, we have demonstrated that accessory toxins hemolysin and RTX are key factors in establishment of prolonged V. cholerae colonization of the crypts of the small intestine. This grant will continue examining the connection between hemolysin, RTX and innate immunity using coinfection studies to determine if colonization defects can be extracellulary complemented. This study will also investigate the cell types recruited to the gut associated lymphoid tissue during early V. cholerae infection. Finally, this project will specifically determine whether neutrophils and mast cells are key components of the innate immune response to V. cholerae and whether these cells are disabled by hemolysin and RTX toxin both in vivo. PUBLIC HEALTH RELEVANCE: Vibrio cholerae O1 is the causative agent of pandemic cholera, a severe diarrheal disease still prevalent worldwide. The epidemiology of modern cholera is distinct from the Classical disease as epidemics are caused by lower virulence strains that induce a high frequency of mild or asymptomatic infections. This prolonged period of vibrio excretion likely contributes to transmission of disease. Using a new animal model of cholera, accessory toxins hemolysin and RTX are shown to be key factors in prolonging intestinal colonization by V. cholerae. This project will investigate key components of the immune response to V. cholerae and identify is accessory toxins are associated with disabling innate immunity.