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.

Public Health Relevance

Progressive age-related impairment in lung function and recurrent pulmonary infections contribute to significant morbidity and mortality in older people but the mechanisms behind these effects remain unclear. Our study will examine the impact of aging on innate immune pathways, specifically MIF and Type I interferon responses, during primary influenza viral lung infection and secondary bacterial pneumonia in mice. Thus, our study may reveal novel potential therapies that could ultimately improve the health of older people infected with respiratory pathogens.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL130669-03
Application #
9300969
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Caler, Elisabet V
Project Start
2015-07-15
Project End
2019-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Goldstein, Daniel R; Jalife, José (2017) Synergistic Research Between the Center of Arrhythmia Research and the Michigan Biology of Cardiovascular Aging at the University of Michigan. Circ Res 121:1221-1223
Wong, Christine K; Smith, Candice A; Sakamoto, Koji et al. (2017) Aging Impairs Alveolar Macrophage Phagocytosis and Increases Influenza-Induced Mortality in Mice. J Immunol 199:1060-1068
Roger, Thierry; Schlapbach, Luregn J; Schneider, Anina et al. (2017) Plasma Levels of Macrophage Migration Inhibitory Factor and d-Dopachrome Tautomerase Show a Highly Specific Profile in Early Life. Front Immunol 8:26
Tynan, Aisling; Mawhinney, Leona; Armstrong, Michelle E et al. (2017) Macrophage migration inhibitory factor enhances Pseudomonas aeruginosa biofilm formation, potentially contributing to cystic fibrosis pathogenesis. FASEB J 31:5102-5110
Colvin, Monica M; Smith, Candice A; Tullius, Stefan G et al. (2017) Aging and the immune response to organ transplantation. J Clin Invest 127:2523-2529
Jane-Wit, Dan; Fang, Caodi; Goldstein, Daniel R (2016) Innate immune mechanisms in transplant allograft vasculopathy. Curr Opin Organ Transplant 21:253-7
Sauler, Maor; Bucala, Richard; Lee, Patty J (2015) Role of macrophage migration inhibitory factor in age-related lung disease. Am J Physiol Lung Cell Mol Physiol 309:L1-10
Weiser, Jeffrey N; Roche, Aoife M; Hergott, Christopher B et al. (2015) Macrophage Migration Inhibitory Factor Is Detrimental in Pneumococcal Pneumonia and a Target for Therapeutic Immunomodulation. J Infect Dis 212:1677-82