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.

项目概要 B 族链球菌 (GBS) 是一种机会性病原体，无症状地定植于泌尿生殖系统和泌尿生殖系统。大约25-30%的个体的女性生殖道。然而，GBS 可引起严重感染免疫功能低下的个体，包括糖尿病患者。糖尿病伤口感染是一个主要的公众健康负担，大约 25% 的糖尿病患者一生中会出现伤口，其中 25% 伤口无法愈合，28% 需要手术截肢。不良的感染结果与存在多种细菌病原体，GBS 以及金黄色葡萄球菌是最常见的细菌病原体之一。这些伤口中发现的常见细菌。尽管 GBS 很流行，但之前尚未对 GBS 进行研究糖尿病伤口环境中的发病机制。最近，我们开发了2型糖尿病小鼠模型 GBS 糖尿病伤口感染 leprdb 小鼠，并证明 GBS 形成坚固的伤口并持续存在这个环境。进一步观察发现，从糖尿病伤口组织中回收的 GBS 菌落色素沉着过度/溶血，表明在糖尿病感染期间选择毒性更强的 GBS 突变体。这些表型模仿了 covR 突变体的表型，因为 CovR 是 GBS 毒力因子的主要抑制因子，例如如 GBS 溶血素/色素、核酸酶 (NucA) 和表面粘附素纤溶酶原结合蛋白 PbsP。双重的 GBS 和小鼠伤口的 RNA 测序表明，这些相同的 CovR 调节基因高度在糖尿病伤口中上调。此外，GBS感染引发中性粒细胞的募集，中性粒细胞激活，以及感染部位 NET 的形成。最后，我们在小鼠模型中表明金黄色葡萄球菌的存在会促进糖尿病伤口中 GBS 的持续存在。有了这些初步数据，我们有提出的假设解决了GBS在环境中生存和持续存在的多种机制糖尿病伤口环境。这些假设将在以下具体目标中得到解决：目标 1：确定 CovR 调节如何导致糖尿病伤口感染，目标 2：表征 PbsP 对 GBS 糖尿病伤口形成、持续和扩散的贡献，目标 3：检查核酸酶活性在促进 GBS 免疫逃避和伤口持续性方面的贡献。这些研究将增加我们对 GBS 糖尿病伤口感染发病机制的了解，并提供额外研究的平台。