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The role of PMNs and CD73 in host-resistance against S. pneumoniae / influenza A virus co-infection

PMNs和CD73在宿主抵抗肺炎链球菌/甲型流感病毒混合感染中的作用

基本信息

批准号：
10652758
负责人：
Elsa Bou Ghanem
金额：
$ 22.96万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
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：
2023-02-24 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10652758
关键词：
Accounting Adenosine Adoptive Transfer Age Aging Animal Model Anti-Bacterial Agents Antibacterial Response Bacteria Bacterial Infections Bacterial Pneumonia Cells Cessation of life Clinical Disease Drug Targeting Economic Burden Elderly Environment Enzymes Epithelium Etiology Evolution Goals Healthcare Host resistance Human Immune Immune response Impairment Individual Infection Inflammation Influenza Influenza A virus Knockout Mice Lower respiratory tract structure Lung Lung diseases Mediating Microbial Biofilms Modeling Mus Nasal cavity Nasopharynx Outcome Pathway interactions Pharmaceutical Preparations Physiological Play Pneumococcal Infections Pneumococcal Pneumonia Predisposition Production Resistance Resistance to infection Respiratory Tract Infections Risk Role Secondary to Signal Transduction Streptococcus pneumoniae Testing Time Tissues Virus Diseases Vulnerable Populations Work age effect aged antimicrobial cell injury co-infection combat design extracellular human disease human old age (65+)improved influenza infection innovation lung injury mouse model neutrophil novel novel strategies novel therapeutics pandemic disease pathogen pharmacologic receptor recruit response synergism time use

项目摘要

ABSTRACT Following influenza A virus (IAV) infection, the risk for subsequent pneumococcal pneumonia caused by Streptococcus pneumoniae is enhanced 100-fold. Host aging is associated with more severe outcomes, thus novel approaches that boost resistance to infections are needed. Our goal is to elucidate how IAV infection alters the responses of polymorphonuclear leukocytes (PMN) and the extracellular adenosine (EAD) pathway across host age, during pneumococcal pneumonia. Background: Following primary S. pneumoniae infection, PMNs, which are innate immune cells whose function declines with age, are required for controlling bacterial numbers. EAD, which is produced from breakdown of ATP leaking from injured cells by CD73, controls PMN responses during infection. We found that CD73 was crucial for host resistance and PMN pulmonary influx as well as anti-microbial function during primary pneumococcal pneumonia. Importantly, old mice had significant changes in expression of EAD enzymes and receptors and targeting this pathway reversed the age-driven susceptibility to primary pneumococcal infection. In humans, pneumococcal carriage in the nasopharynx is a prerequisite to invasive diseases. Further, IAV infection of the respiratory tract where it triggers epithelial damage and impairs host antibacterial responses is key for the lethal synergy of co-infection. However, animal models incorporating the evolution of S. pneumoniae from colonizer to pathogen during IAV co-infection while mimicking the severe disease seen in humans, are lacking. Therefore, we established an optimized model where mice are intra-nasally colonized with pneumococci followed by IAV infection of the nasopharynx and lungs. This model resulted in obvious signs of illness and lethality in half of the young mice and importantly, reproduced the susceptibility of aging, where significantly more old mice displayed severe clinical signs and succumbed to lethality compared to young controls. Using this model, we strikingly found that the role of CD73 was reversed, where CD73 became detrimental to resistance of young hosts to co-infection. This highlighted that IAV infection triggers profound changes in the interaction of the host with pneumococci. However, the effect of polymicrobial infections on host responses and the mechanisms behind that remain a gap in the field. Here we will use our improved model to test the Hypothesis that IAV infection alters CD73-mediated control of PMN responses to pneumococcal infection across host age using two specific Aims: 1) Test the effect of age and IAV infection on PMN responses during secondary pneumococcal pneumonia; 2) Test the role of CD73 in PMN responses and host resistance to S. pneumoniae/IAV co-infection. Significance/innovation/ relevance: Using this physiologically relevant model that mimics aspects of human disease to elucidate how PMN responses change in mono vs polymicrobial infections across host age and the role of CD73 in that, has the potential to uncover novel pathways that drive host susceptibly to infection. This work can lead to highly innovative approaches incorporating adenosine-based drugs to combat this serious lung disease.

摘要