Mechanisms of Group B Streptococcal Pathogenesis in the Diabetic Wound

糖尿病伤口中 B 族链球菌的发病机制

基本信息

批准号：
10676441
负责人：
Rebecca Keogh
金额：
$ 6.95万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10676441
关键词：
Address Adherence Adult Amputation Attenuated Bacteria Bacterial Adhesins Binding Binding Proteins Chromogenic Substrates Communities Complement Complex Coupled Data Diabetes Mellitus Disease Environment Exhibits Extracellular Matrix Female Genes Genetic Transcription Genitourinary system Goals Hemolysis Hyperpigmentation Immune Evasion Immune response Immune system Immunocompromised Host Incidence Individual Infection Lower Extremity Modeling Mus Mutation Neutrophil Activation Neutrophil Infiltration Operative Surgical Procedures Operon Outcome Pathogenesis Patient-Focused Outcomes Phenotype Pigments Plasminogen Population Prevalence Proteins Public Health Regulation Reproductive Health Site Skin Skin colonization Staphylococcus aureus Streptococcal Infections Streptococcus Group B Surface Transcript Type 2 diabetic Virulence Virulence Factors Virulent Work Wound Infection capsule clinically relevant co-infection diabetic diabetic patient diabetic ulcer extracellular in vitro Model in vivo in vivo Model keratinocyte mouse model mutant neonate neutrophil novel therapeutics nuclease opportunistic pathogen pathogen pathogenic bacteria prevent reproductive tract response restoration streptococcal group B hemolysin transcriptome sequencing wound wound care wound environment wound healing

项目摘要

PROJECT SUMMARY Group B Streptococcus (GBS), is an opportunistic pathogen that asymptomatically colonizes the urogenital and female reproductive tract of approximately 25-30% of individuals. However, GBS can cause serious infections in immunocompromised individuals including those with diabetes. Diabetic wound infections are a major public health burden, with approximately 25% of diabetic individuals developing a wound in their lifetime, 25% of these wounds not healing and 28% requiring surgical amputation. Poor infection outcomes are correlated with the presence of numerous bacterial pathogens, and GBS, along with Staphylococcus aureus, is one of the most common bacteria found in these wounds. Despite its prevalence, no prior work has been done on GBS pathogenesis in the diabetic wound environment. Recently, we developed a Type 2 diabetic murine model of GBS diabetic wound infection in leprdb mice, and demonstrated that GBS forms a robust wound and persists in this environment. Further observations found that GBS colonies recovered from diabetic wound tissue were hyper-pigmented/hemolytic, suggesting selection of more virulent GBS mutants during diabetic infection. These phenotypes mimic those of a covR mutant, as CovR is a major repressor of GBS virulence factors such as the GBS hemolysin/pigment, nuclease (NucA), and surface adhesin plasminogen binding protein PbsP. Dual RNA-sequencing of GBS and the murine wound revealed that these same CovR regulated genes were highly upregulated in the diabetic wound. In addition, GBS infection triggered the recruitment of neutrophils, neutrophil activation, and NET formation at the site of infection. Finally, we have shown in our murine model that the presence of S. aureus promotes GBS persistence in the diabetic wound. With these preliminary data, we have formulated hypotheses which address multiple mechanisms by which GBS may survive and persist in the diabetic wound environment. These hypotheses will be addressed in the following specific aims: Aim 1: Determine how CovR regulation contributes to diabetic wound infection, Aim 2: Characterize the contribution of PbsP to GBS diabetic wound formation, persistence, and dissemination, Aim 3: Examine the contribution of nuclease activity in promoting GBS immune evasion and wound persistence. These studies will increase our understanding of the pathogenesis of GBS diabetic wound infection and will provide a platform for additional studies.

项目摘要 B组链球菌（GBS）是一种机会性的病原体，无疑地将泌尿生殖器和大约25-30％个体的女性生殖道。但是，GB会引起严重的感染在包括糖尿病患者在内的免疫功能低下的个体中。糖尿病伤口感染是主要的公众健康负担，大约25％伤口无法愈合，需要手术截肢的28％。感染不良的结局与存在众多细菌病原体，GBS以及金黄色葡萄球菌是最多的细菌病原体在这些伤口中发现的常见细菌。尽管率很高，但在GBS上尚未做过以前的工作糖尿病伤口的发病机理。最近，我们开发了一种2型糖尿病鼠模型 LEPRDB小鼠中的GBS糖尿病伤口感染，并证明GBS形成了强大的伤口，并持续存在这个环境。进一步的观察发现，从糖尿病伤口组织中回收的GBS菌落是糖尿病感染期间选择了更毒的GBS突变体。这些表型模仿了COVR突变体的表型，因为COVR是GBS毒力因子的主要阻遏物作为GBS血解素/色素，核酸酶（Nuca）和表面粘附质纤溶蛋白原结合蛋白PBSP的作为GBS。双重的 GBS和鼠伤口的RNA测序表明，这些相同的COVR调节基因高度高糖尿病伤口上调。此外，GBS感染触发了嗜中性粒细胞的募集感染部位的激活和净形成。最后，我们在鼠模型中表明金黄色葡萄球菌的存在促进了糖尿病伤口中的GBS持久性。有了这些初步数据，我们有提出的假设，这些假设涉及多种机制，通过这些机制，GB可以生存并持续存在糖尿病伤口环境。这些假设将在以下具体目的中解决：目标1：确定COVR调节如何导致糖尿病伤口感染，目标2：表征 PBS对GBS糖尿病伤口形成，持久性和传播的贡献，目标3：检查核酸酶活性在促进GBS免疫逃避和伤口持久性方面的贡献。这些研究将增加我们对GBS糖尿病伤口感染的发病机理的理解，并将提供额外研究的平台。