A Murine Group A Streptococcus Transmission Model for Male-Biased Acute Infection in the Mucosa of the Upper Respiratory Tract

上呼吸道粘膜男性偏向急性感染的小鼠 A 组链球菌传播模型

• 批准号: 10040605
• 负责人: BENFANG LEI
• 金额: $ 21.6万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10040605
• 关键词: Acute; Address; Anterior nares; Autophagocytosis; Bacteremia; Catalytic Domain; Colony-forming units; Data; Epithelial; Epithelial Cells; Epithelium; Female; Gender; Genes; Goals; Immune; Infection; Infectious Skin Diseases; Interleukin-6; Invaded; Investigation; Knock-out; Knockout Mice; Knowledge; Lung; Lung diseases; Mediating; Medical; Modeling; Monitor; Mucous Membrane; Mus; NADPH Oxidase; Nasopharynx; Necrotizing fasciitis; Oropharyngeal; Pathogenesis; Pharyngitis; Play; Pneumonia; Predisposition; Respiratory Tract Infections; Role; Sex Bias; Skin; Streptococcal Infections; Streptococcus pyogenes; Structure of mucous membrane of nose; Study models; TLR7 gene; TNF gene; Testing; Time; Toxic Shock Syndrome; Upper respiratory tract; Virulence Factors; acute infection; base; cytokine; gender difference; human pathogen; male; mutant; neutrophil; nonhuman primate; novel; prevent; response; subcutaneous; transmission process

Project Summary: The goal of this project is to establish a murine Group A Streptococcus (GAS) transmission model that leads to acute infection in the mucosa of the upper respiratory tract in recipient mice. GAS is a major human pathogen that causes common pharyngeal and skin infections. GAS also occasionally causes severe invasive infections such as pneumonia, necrotizing fasciitis, bacteremia, and toxic shock syndrome. Murine and nonhuman primate infection models have been valuable for understanding GAS pathogenesis; however, these models involve high GAS inocula and cannot be used to investigate the onset of pharyngeal GAS infections. Consequently, there is a significant knowledge gap regarding immune protection and GAS pathogenesis during the onset of acute pharyngeal GAS infection. Another knowledge gap is the lack of understanding of the basis for the differential susceptibility to infectious respiratory diseases between males and females. We recently found that wild-type M1T1 GAS is effectively cleared from the lung in a murine intratracheal pneumonia infection model but not from the skin with subcutaneous infection and that the clearance of GAS from the lung requires the gp91Phox (Nox2) gene, which encodes the β chain of the catalytic subunit of the NADPH oxidase. These findings inspired us to test whether gp91phox knockout (KO) naïve mice develop acute GAS infection in the nasopharynx and oropharynx after they are comingled with donor mice that were inoculated in the nostrils with GAS. Pilot tests showed that male but not female gp91phox KO recipient mice acquired acute infection in the mucosal epithelium of the upper respiratory tract within 6 days after comingling. Based on these exciting and surprising preliminary results, we propose to establish a Group A Streptococcus transmission model for male- biased acute infection in the mucosal epithelium of the upper respiratory tract in gp91phox KO recipient mice (Aim 1) and determine the basis for the gender bias in acute Group A Streptococcus infection in the mucosal epithelium of the upper respiratory tract (Aim 2). The successful execution of this project would provide a novel GAS transmission model that will be invaluable for investigation of innate immune protection and GAS pathogenesis during the onset of pharyngeal GAS infections. This project also has the potential to provide a new paradigm to explain the gender differences in susceptibility to respiratory infections.

项目概述：本项目的目标是建立一个小鼠A组链球菌（GAS）的传播 导致受体小鼠上呼吸道粘膜急性感染的模型。GAS是一个主要的 引起普通咽部和皮肤感染的人类病原体。偶尔也会引起严重的 侵袭性感染如肺炎、坏死性筋膜炎、菌血症和中毒性休克综合征。鼠和 非人灵长类动物感染模型对于理解GAS发病机制是有价值的;然而，这些模型 模型涉及高GAS接种，不能用于研究咽部GAS感染的发作。 因此，在免疫保护和GAS发病机制方面存在重大的知识缺口， 急性咽部GAS感染的发作。另一个知识差距是对基础的认识不足 男性和女性对传染性呼吸道疾病的易感性不同。我们最近 发现野生型M1 T1 GAS在小鼠肺炎感染中有效地从肺中清除 模型，但不是从皮下感染的皮肤，从肺部清除GAS需要 gp 91 Phox（Nox 2）基因，其编码NADPH氧化酶的催化亚基的β链。这些 这些发现启发我们测试gp 91 phox敲除（KO）的未处理小鼠是否会发生急性GAS感染。 在它们与供体小鼠混合后， 气体初步试验表明，雄性而非雌性gp 91 phox KO受体小鼠在体内获得急性感染。 混合后6天内上呼吸道粘膜上皮。基于这些令人兴奋和 初步结果令人惊讶，我们建议建立一个A组链球菌传播模型的男性- gp 91 phox KO受体小鼠上呼吸道粘膜上皮中的偏性急性感染（Aim 1)并确定急性A组链球菌感染粘膜中性别偏倚的基础 上呼吸道上皮（目的2）。该项目的成功执行将提供一部小说 GAS传递模型，这将是非常宝贵的研究先天免疫保护和GAS 咽部GAS感染发作期间的发病机制。该项目也有可能提供一个 解释呼吸道感染易感性的性别差异的新范式。