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，大流行性霍乱是一种严重的霍乱疾病，仍在世界范围内流行。第七次霍乱大流行始于1961年，至今仍在继续，其主要病原体是产生霍乱毒素的El Tor O1菌株。这些菌株最初被认为具有低毒力潜力，因为它们引起的疾病的严重性低于导致早期大流行的“经典”菌株。然而，据信El Tor菌株的毒性降低导致了它们的大流行性传播，因为大多数感染者不会生病，但会定植并排出传染性生物体。事实上，被认为有助于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，而经典菌株仅为1.5天。因此，El Tor菌株具有经典菌株中不存在的遗传因子，其有助于延长定殖。这些遗传因素以前没有被发现。使用一种新的霍乱动物模型，适用于宿主免疫反应的研究，我们已经证明，辅助毒素溶血素和RTX是建立长期的V. cholesterol定植的小肠隐窝的关键因素。这项资助将继续使用共感染研究来检查溶血素，RTX和先天免疫之间的联系，以确定是否可以在细胞外补充定植缺陷。本研究还将研究在早期霍乱弧菌感染期间招募到肠道相关淋巴组织的细胞类型。最后，该项目将专门确定中性粒细胞和肥大细胞是否是对霍乱弧菌的先天免疫反应的关键组成部分，以及这些细胞是否被溶血素和RTX毒素在体内禁用。 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霍乱疾病，仍然在世界范围内流行。现代霍乱的流行病学与经典疾病不同，因为流行病是由低毒力菌株引起的，这些菌株引起高频率的轻度或无症状感染。这种弧菌排泄时间的延长可能有助于疾病的传播。使用一种新的霍乱动物模型，辅助毒素溶血素和RTX被证明是延长肠道定植的关键因素。该项目将研究对霍乱弧菌免疫反应的关键组成部分，并确定与先天免疫能力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.