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

霍乱弧菌感染期间辅助毒素介导的先天免疫逃避

• 批准号: 8063715
• 负责人: Karla J F Satchell
• 金额: $ 10万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8063715
• 关键词: Accounting; Adoptive Transfer; Animal Model; Antibodies; Bacteria; Cell physiology; Cells; Cholera; Cholera Toxin; Complement; Cytoprotection; Data; Defect; Disabled Persons; Disease; Epidemic; Epidemiology; Excretory function; Fibrinogen; Frequencies; Genetic; Grant; Gut associated lymphoid tissue; Hemolysin; Host Defense; Immune; Immune response; Immune system; Immunity; Individual; Infection; Infectious Agent; Intestines; Mediating; Mesentery; Mus; Natural Immunity; Neutrophil Infiltration; Pathogenesis; Pattern; Persons; Recruitment Activity; Research Design; Role; Severities; Small Intestines; Structure of aggregated lymphoid follicle of small intestine; Time; Toxin; Vibrio; Vibrio cholerae; Vibrio cholerae O1; Virulence; cell type; defined contribution; disease transmission; hemagglutinin-protease; immune clearance; in vivo; innate immune function; lymph nodes; mast cell; mutant; neutrophil; pandemic disease; public health relevance; research study; transmission process

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.

描述(申请人提供)：O1霍乱弧菌是霍乱大流行的病原体，霍乱是一种严重的腹泻疾病，目前仍在世界范围内流行。从1961年开始并持续到今天的第七次霍乱大流行的主要病原体是产生El Tor O1菌株的霍乱毒素。这些菌株最初被认为具有较低的毒力潜力，因为它们引起的疾病没有导致早期大流行的“经典”菌株那么严重。然而，El Tor菌株的毒力降低被认为是导致其大流行传播的原因，因为大多数感染者并没有生病，而是被殖民并排泄了传染病的有机体。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菌株具有经典菌株所不存在的导致长期定植的遗传因素(S)。这些遗传因素此前并未被发现。利用一种新的霍乱动物模型，我们证明了副毒素溶血素和RTX是霍乱弧菌在小肠隐窝长期定植的关键因素。这笔赠款将继续通过联合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。这项研究还将调查在霍乱弧菌感染早期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霍乱弧菌先天免疫反应的关键成分，以及这些细胞是否在体内都被溶血素和RTX毒素所禁用。公共卫生相关性：O1霍乱弧菌是霍乱大流行的病原体，霍乱是一种严重的腹泻疾病，目前仍在全世界流行。现代霍乱的流行病学与经典疾病不同，因为流行是由毒力较低的菌株引起的，这些菌株会导致高频率的轻度或无症状感染。这种长时间的弧菌排泄可能会导致疾病的传播。在一种新的霍乱动物模型上，副毒素溶血素和RTX被证明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成分，并确定副毒素与丧失天然免疫能力有关。