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Aging and Innate Immune Mechanisms in Pulmonary Infection

肺部感染的衰老和先天免疫机制

基本信息

批准号：
8967869
负责人：
RICHARD J BUCALA
金额：
$ 41.63万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8967869
关键词：
Age Aging Agonist Alleles Alveolar Bacterial Infections Bacterial Pneumonia Cell Aging Cell Cycle Cell surface Clinical Clinical Markers Communities Complement Data Disease Exhibits Frequencies Gene Frequency Genetic Genetic Markers Genetic Polymorphism Genetic study Health Host Defense Human Genetics Hypoxia Inducible Factor Immune Immune response Impairment In Vitro Individual Infection Inflammation Mediators Inflammatory Response Influenza Interferon Type I Lung Measures Migration Inhibitory Factor Minor Modeling Molecular Morbidity - disease rate Mus Mutant Strains Mice Natural Immunity Outcome Pathway interactions Pneumonia Predisposition Prevalence Production Publishing Recurrence Relative (related person)Respiratory Tract Infections Respiratory physiology Role Sentinel Sepsis Severities Signal Pathway Streptococcus pneumoniae TLR4 gene Testing Toll-like receptors Transgenic Mice Up-Regulation Viral Virus Diseases Wild Type Mouse age related aged base cell age clinically relevant cytokine improved inflammatory marker influenzavirus insight interferon regulatory factor-7 mortality mouse model novel overexpression pathogen phenylpyruvate tautomerase prognostic protective effect public health relevance respiratory response secondary infection senescence transcription factor

项目摘要

DESCRIPTION (provided by applicant): Older people suffer from a higher morbidity and mortality from influenza viral lung infections and secondary bacterial pneumonia than younger people. Yet the mechanisms by which aging impairs host defense to respiratory infections are not well understood. Recent human genetic studies have shown that high expression of macrophage migration inhibitory factor (MIF) alleles confer a 50% survival benefit in older individuals with community-acquired pneumonia. In support of this, our preliminary data indicate that aging is associated with reduced MIF within the aging lung in mice. Furthermore, we show that in the lungs, aging and MIF deficiency share several features: increased senescence prior to lung infection, and increased lung damage, and impaired viral clearance after influenza viral lung infection. Importantly, MIF deficiency also worsens outcomes after influenza viral infection followed by S. pneumonia bacterial infection. Here, we will investigate the mechanisms underlying MIF's effects during infectious exacerbations of the aging lung by studying genetically-defined mice infected with two clinically-relevant respiratory models: primary influenza virus, and influenza viral infection followed by S. pneumonia bacterial infection. Aim 1 will investigate mechanisms by which aging and MIF deficiency impair clearance of influenza virus with increased lung damage, with a focus on type I interferon production, an inflammatory mediator that is critical to host defense against viral infection. Aim 2 will investigate the role f MIF in host defense after secondary bacterial infection with aging. Both Aims will test the role of MIF by employing novel MIF transgenic mice and new pharmacological MIF modulators. Therefore, this proposal will yield novel information concerning how the aging lung responds to respiratory pathogens, which could provide novel information to improve therapies for older people who succumb to respiratory infections.