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：该项目的目的是建立一个鼠组A链球菌（气）传输 导致在受体小鼠上呼吸道粘膜中导致急性感染的模型。气是主要的 引起常见咽部和皮肤感染的人类病原体。气体偶尔也会导致严重 侵入性感染，例如肺炎，坏死性筋膜炎，细菌和有毒休克综合征。鼠和 非人类灵长类动物感染模型对于理解气体发病机理很有价值。但是，这些 模型涉及高气体接种物，不能用于研究咽气体感染的发作。 因此，关于免疫保护和气体发病机理存在很大的知识差距 急性咽气体感染的发作。另一个知识差距是对基础缺乏理解 对于男性和女性之间感染性呼吸道疾病的敏感性差异。我们最近 发现野生型M1T1气体在鼠内气管内肺炎感染中有效清除 模型，但不能来自皮下感染的皮肤，肺部的气体清除需要 GP91Phox（NOX2）基因编码NADPH氧化物的催化亚基的β链。这些 调查结果激发了我们测试GP91Phox敲除（KO）幼稚小鼠是否在 鼻咽和口咽与供体小鼠接种的供体小鼠后 气体。试验测试表明，男性但不是女性GP91Phox KO受体小鼠在该中获得了急性感染 上呼吸道的粘膜上皮在降临后6天内。基于这些令人兴奋的 令人惊讶 GP91Phox KO受体小鼠的上呼吸道粘膜上皮中的急性急性感染（AIM 1）并确定急性组A链球菌感染中性别偏差的基础 上呼吸道上皮（AIM 2）。该项目的成功执行将提供小说 天然气传输模型对于投资先天免疫保护和天然气是无价的 咽气体感染发作期间的发病机理。该项目还有可能提供 新的范式来解释呼吸道感染敏感性的性别差异。