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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.

项目总结