Since our competitive renewal was funded last year, a global pandemic of a novel coronavirus has emerged that has resulted in higher number of deaths than prior coronavirus outbreaks (e.g., SARS, MERS). In particular, older patients (i.e., > 60 years old) exhibit markedly increased mortality from COVID-19 (SARS-CoV 2) infections. Hence, we urgently need to understand why older people exhibit worse outcomes during COVID- 19 infection. Based upon our preliminary data in mice employed in the parent R01, we hypothesize that during COVID-19 infection with aging, senescent alveolar epithelial cells (AEC) secrete neutrophil-attracting chemokines to induce neutrophil recruitment into the lung as well as PGE2, a pleiotropic lipid mediator, which suppresses alveolar macrophage proliferation and function. As alveolar macrophages are key in clearing debris and resolving inflammation, we postulate that impairments in alveolar macrophages with aging inhibit inflammation resolution during influenza infection.
In Aim 1, we will leverage the human AEC culture described in the parent R01, to understand how aging impacts the inflammatory response to SARS-CoV2 infection in AEC and how this impacts neutrophil and alveolar macrophage.
In Aim 2, we will leverage, through our collaborators, ongoing screens of repurposed FDA agents and novel anti-microbial peptides to identify novel therapeutics to mitigate the effects of SARS-CoV2 infection in AECs with aging. This administrative supplement is a natural extension of our funded NIA project on aging and the innate immune response to influenza, and could provide urgently needed insights to the mechanisms by which aging promotes mortality to COVID-19 and potential therapeutics to reduce the suffering and death of older people with COVID 19.
Emerging evidence during the current pandemic indicates that older people exhibit increased morbidity to COVID-19. Our proposal will examine whether the mechanism behind the increased mortality to viral infection with aging is due to dysregulated inflammation in lung alveolar epithelial cells. We also will employ lung alveolar epithelial cell culture to test potential promising novel therapeutic agents to mitigate against COVID-19 infection in lung alveolar epithelial cells particularly with aging.
| 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 |
| 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 |
| Du, Wei; Wong, Christine; Song, Yang et al. (2016) Age-associated vascular inflammation promotes monocytosis during atherogenesis. Aging Cell 15:766-77 |
| Mori, Daniel N; Shen, Hua; Galan, Anjela et al. (2016) Aged B cells alter immune regulation of allografts in mice. Eur J Immunol 46:2650-2658 |
| Braza, Faouzi; Brouard, Sophie; Chadban, Steve et al. (2016) Role of TLRs and DAMPs in allograft inflammation and transplant outcomes. Nat Rev Nephrol 12:281-90 |
| Spahn, Jessica H; Li, Wenjun; Bribriesco, Alejandro C et al. (2015) DAP12 expression in lung macrophages mediates ischemia/reperfusion injury by promoting neutrophil extravasation. J Immunol 194:4039-48 |
| Shen, Hua; Heuzey, Elizabeth; Mori, Daniel N et al. (2015) Haptoglobin enhances cardiac transplant rejection. Circ Res 116:1670-9 |
| Mori, Daniel N; Kreisel, Daniel; Fullerton, James N et al. (2014) Inflammatory triggers of acute rejection of organ allografts. Immunol Rev 258:132-44 |
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