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Determinants of Streptococcus pyogenes fitness in the female primate genital tract: A genome-wide analysis

雌性灵长类生殖道中化脓性链球菌适应性的决定因素：全基因组分析

基本信息

批准号：
9805040
负责人：
James MALLORY Musser
金额：
$ 20.19万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9805040
关键词：
Address Anatomy Animals Bacterial Genes Basic Science Binding Biology Blood Candidate Disease Gene Clinical Complement Data Diagnosis Disease Environment Epidemic Epithelium Event Female Future Gene Silencing Genes Genome Goals Gold Human In Vitro Individual Infection Knowledge Libraries Macaca Medicine Methods Modeling Molecular Monitor Morbidity - disease rate Motivation Mouse Strains Mucous Membrane Mutagenesis Myositis Necrotizing fasciitis Neonatal Organism Pathogenesis Pharyngitis Phase Phylogenetic Analysis Primates Process Puerperal Infection Puerperal pyrexia Recording of previous events Reporting Research Research Activity Role Saliva Sepsis Septicemia Serotyping Severities Site Streptococcus pyogenes Surface Targeted Research Technology Time Translational Research Vaccines Vagina Virulence Virulence Factors Work base design experience fitness gene product genome sequencing genome wide screen genome-wide genome-wide analysis human disease human pathogen in vivo innovation interest knockout gene mortality mouse model mucosal site mutant neonatal sepsis nonhuman primate novel pathogen pathogenic bacteria prevent reproductive tract subcutaneous success tool transcriptome transcriptome sequencing translational approach vaccine candidate

项目摘要

PROJECT SUMMARY The human bacterial pathogen Streptococcus pyogenes (group A streptococcus, GAS) causes more than 700 million human infections annually worldwide. The proposed research seeks to discover, on a genome- wide scale, GAS genes required for, or contributing to fitness in the female genital tract, an infection site for which very little basic understanding is known. We will use a serotype M28 GAS strain because for reasons that aren’t understood, these organisms are non-randomly associated with female genital tract disease, including puerperal sepsis (childbed fever) and neonatal invasive infections. The pathogen genes and fundamental molecular pathogenesis processes contributing to two phases of genital tract interaction will be studied: (i) colonization and proliferation and (ii) persistence. This basic science knowledge deficit has severely limited the ability to create new clinical tools such as a successful GAS vaccine. Thus, the studies are designed to address this critical knowledge deficit. We will combine our very recent success in applying transposon-directed insertion site sequencing (TraDIS) technology to GAS with our 18 years of productive experience with cynomolgus macaque models of GAS infection, currently the gold standard experimental animal to study this human pathogen. We will use TraDIS to conduct an in vivo genome-wide screen that will systematically identify GAS genes required for colonization and proliferation, and persistence in the genital tract of female cynomolgus macaques. The goal of the proposed studies is to identify new molecular mechanisms used by GAS to enhance fitness in this anatomic niche. The results of our studies may ultimately help in formulating novel translational strategies to prevent or treat GAS infections. To achieve our goals, the following two specific aims are proposed: Specific Aim 1: Exploit TraDIS for genome-wide identification of GAS genes required for (i) colonization and proliferation, and (ii) persistence (i.e., fitness) in the genital tract of female cynomolgus macaques. Specific Aim 2: Use isogenic gene-knockout mutant strains to validate the importance of four selected candidate genes to GAS colonization and proliferation, and persistence identified by the genome-wide screen. The proposed line of research will exploit our innovative and successful application of TraDIS to GAS, including infections in cynomolgus macaques. It will be the first use of TraDIS in the genital tract of female non-human primates and the first study to investigate determinants of GAS colonization and proliferation, and persistence, on a mucosal surface using genome-wide transposon mutagenesis.

项目总结