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Interactions between Pseudomonas aeruginosa and Streptococcus salivarius and effects on the host immune response

铜绿假单胞菌和唾液链球菌之间的相互作用及其对宿主免疫反应的影响

基本信息

批准号：
10388005
负责人：
Sara N Stoner
金额：
$ 3.8万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10388005
关键词：
Adult Affinity Alginates Anti-Inflammatory Agents Bacteria Bacterial Infections Binding Binding Proteins Biological Assay Calorimetry Carbon Caucasians Cells Chronic Coculture Techniques Colony-forming units Communities Confocal Microscopy Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Deterioration Development Disease Outcome Drosophila melanogaster Enzyme-Linked Immunosorbent Assay Epithelial Cells Genetic Diseases Growth Histopathology Hour Human IL8 gene Immune Immune Evasion Immune response In Vitro Infection Infiltration Inflammation Inflammatory Inflammatory Response Interleukin-1 Interleukin-1 alpha Interleukin-1 beta Interleukin-6 Kinetics Laser Microscopy Learning Lectin Literature Lung Lung infections Measures Mediating Metabolism Microbial Biofilms Modeling Mucociliary Clearance Mucous body substance Multi-Drug Resistance Mutation NF-kappa B Neutrophil Infiltration Pathogenesis Pathway interactions Persons Play Production Pseudomonas aeruginosa Pseudomonas aeruginosa infection Pulmonary Cystic Fibrosis Pulmonary Inflammation Rattus Regulator Genes Research Role SECTM1 gene Source Stains Streptococcus Streptococcus salivarius TNF gene Techniques Testing Thick Tissues Titrations Virulence Work antimicrobial base bronchial epithelium chronic infection co-infection commensal bacteria cystic fibrosis patients cytokine drug resistant pathogen experience histological stains improved in vivo lung colonization lung injury lung microbiota male maltose-binding protein microbial mortality multi-drug resistant pathogen novel oral commensal oral streptococci overexpression pathogen pulmonary function recruit respiratory respiratory colonization respiratory pathogen response

项目摘要

PROJECT SUMMARY Pseudomonas aeruginosa is a multi-drug resistant pathogen which causes chronic lung infections and is a leading cause of mortality in cystic fibrosis (CF) patients. P. aeruginosa produces a biofilm matrix which protects the bacterium from antimicrobials and aids in host immune evasion. The main component of this biofilm matrix are three exopolysaccharides- Pel, Psl, and alginate. Additionally, P. aeruginosa contributes to inflammation and lung damage by activating the pro-inflammatory NF-κB pathway in host cells, leading to the production of inflammatory cytokines and recruitment of inflammatory immune cells to the lungs, causing subsequent tissue damage. NF-κB activation is naturally elevated in the lungs of CF patients, which is further exacerbated by P. aeruginosa infection. Although P. aeruginosa is generally studied as an isolated infection, other species colonize the lungs of CF patients and could potentially modulate P. aeruginosa virulence. Colonization of oral streptococci in the lungs has recently been associated with CF lung stability. Of these oral streptococci, Streptococcus salivarius, was found to be the most prevalent streptococcal species in the lungs of CF patients. S. salivarius has been shown to inhibit growth of multiple respiratory pathogens, as well as inhibit activation of the NF-κB pathway in human bronchial epithelial cells. Although S. salivarius has been correlated with stable lung function in CF patients, no studies have examined interactions between S. salivarius and P. aeruginosa and their impact on the host response. To characterize the interactions between the two species, we first measured changes in biofilm formation of the two species when co-cultured. Our preliminary results demonstrated that S. salivarius biofilm formation is significantly increased in the presence of the exopolysaccharide Psl, which is produced by the non-mucoid P. aeruginosa strain PAO1. Additionally, the S. salivarius maltose-binding protein MalE was overexpressed in the presence of P. aeruginosa. Aim 1 will test the hypothesis that MalE interacts with Psl to promote biofilm formation of S. salivarius. Whole-cell ELISA and isothermal titration calorimetry will be used to characterize the binding affinity of the two targets. Our preliminary data also demonstrated that Drosophila melanogaster were protected from P. aeruginosa-mediated killing in the presence of S. salivarius, highlighting the need to further examine the impact of S. salivarius on P. aeruginosa pathogenesis. Aim 2 will test the hypothesis that the presence of S. salivarius in the CF lung improves lung function by downregulating pro- inflammatory cytokines downstream of NF-κB produced in response to P. aeruginosa infection. We will develop a CF rat model of co-infection in which we measure specific pro-inflammatory cytokines, neutrophil recruitment, and lung histopathology during P. aeruginosa infection in the presence or absence of S. salivarius. Data generated from this proposal will promote our understanding of how S. salivarius incorporates into the P. aeruginosa biofilm and modulates the host response to a P. aeruginosa infection.

项目总结