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.

项目摘要：该项目的目标是建立小鼠 A 组链球菌 (GAS) 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 引起常见咽部和皮肤感染的人类病原体。 GAS 偶尔也会导致严重的 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。鼠类和 非人类灵长类动物感染模型对于理解 GAS 发病机制很有价值；然而，这些 模型涉及高 GAS 接种，不能用于研究咽部 GAS 感染的发病情况。 因此，在免疫保护和 GAS 发病机制方面存在显着的知识差距。 急性咽部 GAS 感染发作。另一个知识差距是缺乏对基础的理解 男性和女性对传染性呼吸道疾病的易感性存在差异。我们最近 发现野生型 M1T1 GAS 在小鼠气管内肺炎感染中被有效地从肺部清除 模型，但不是来自皮下感染的皮肤，并且气体从肺部的清除需要 gp91Phox (Nox2) 基因，编码 NADPH 氧化酶催化亚基的 β 链。这些 研究结果启发我们测试 gp91phox 敲除 (KO) 幼鼠是否会在体内发生急性 GAS 感染 鼻咽和口咽与在鼻孔中接种了疫苗的供体小鼠混合后的鼻咽和口咽 气体。初步测试表明，雄性而非雌性 gp91phox KO 受体小鼠在体内获得了急性感染。 混合后6天内的上呼吸道粘膜上皮。基于这些令人兴奋和 令人惊讶的初步结果，我们建议建立一个男性 A 组链球菌传播模型 gp91phox KO 受体小鼠上呼吸道粘膜上皮的偏向急性感染（Aim 1) 确定粘膜急性A族链球菌感染性别偏倚的依据 上呼吸道上皮细胞（目标 2）。该项目的成功实施将为 GAS 传播模型对于先天免疫保护和 GAS 的研究具有不可估量的价值 咽部 GAS 感染发作期间的发病机制。该项目还有可能提供 解释呼吸道感染易感性性别差异的新范式。