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: 10171774
• 负责人: BENFANG LEI
• 金额: $ 18万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10171774
• 关键词: Acute; Address; Anterior nares; Autophagocytosis; Bacteremia; Catalytic Domain; Colony-forming units; Data; Epithelial; Epithelial Cells; 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.

项目简介：该项目的目标是建立一种小鼠A组链球菌(GAS)传播 导致受体小鼠上呼吸道黏膜急性感染的模型。天然气是一个主要的 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。小鼠和 非人灵长类动物感染模型对于理解GAS的发病机制很有价值；然而，这些 模型涉及大量气体接种，不能用于调查咽部气体感染的发病情况。 因此，在免疫保护和GAS发病机制方面存在着显著的知识差距。 急性咽气感染的发病。另一个知识鸿沟是缺乏对基础的理解 由于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M1T1气体在小鼠气管内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，从肺部清除气体需要 Gp91Phox(NOX2)基因，编码NADPH氧化酶催化亚基的β链。这些 这些发现启发我们测试gp91Phox基因敲除(KO)幼稚小鼠是否会在 鼻咽和口咽与供体小鼠接触后，经鼻孔接种 汽油。初步试验表明，雄性而不是雌性gp91Phox KO受体小鼠在 发病后6天内有上呼吸道粘膜上皮细胞。基于这些令人兴奋的和 令人惊讶的初步结果，我们建议建立A组链球菌在男性- Gp91Phox KO受体小鼠上呼吸道黏膜上皮偏向性急性感染(目的) 1)和确定急性A组粘膜链球菌感染的性别偏见的基础 上呼吸道上皮(目标2)。该项目的成功实施将提供一种新颖的 气体传输模型对研究先天免疫保护和GAS具有重要价值 发病时发生咽气感染。该项目还有可能提供一种 解释呼吸道感染易感性性别差异的新范式。

项目成果

Slipped-strand mispairing within a polycytidine tract in transcriptional regulator mga leads to M protein phase variation and Mga length polymorphism in Group A Streptococcus.

• DOI: 10.3389/fmicb.2023.1212149
• 发表时间: 2023
• 期刊: Frontiers in microbiology
• 影响因子: 5.2

Host-to-Host Group A Streptococcus Transmission Causes Infection of the Lamina Propria but Not Epithelium of the Upper Respiratory Tract in MyD88-Deficient Mice.

在 MyD88 缺陷小鼠中，宿主间 A 组链球菌传播会导致固有层感染，但不会导致上呼吸道上皮感染。

• DOI: 10.1128/iai.00423-21
• 发表时间: 2022
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Minor,Dylan;Cavon,Jacob;Johnson,Thea;Ontiveros,Savannah;Gao,Daniel;Quinn,MarkT;Lei,Benfang
• 通讯作者: Lei,Benfang