Mechanisms of dysregulated immunity with aging

PROJECT SUMMARY/ABSTRACTSince our competitive renewal was funded last year, a global pandemic of a novel coronavirus has emergedthat has resulted in higher number of deaths than prior coronavirus outbreaks (e.g., SARS, MERS). Inparticular, older patients (i.e., > 60 years old) exhibit markedly increased mortality from COVID-19 (SARS-CoV2) 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 duringCOVID-19 infection with aging, senescent alveolar epithelial cells (AEC) secrete neutrophil-attractingchemokines to induce neutrophil recruitment into the lung as well as PGE2, a pleiotropic lipid mediator, whichsuppresses alveolar macrophage proliferation and function. As alveolar macrophages are key in clearingdebris and resolving inflammation, we postulate that impairments in alveolar macrophages with aging inhibitinflammation resolution during influenza infection. In Aim 1, we will leverage the human AEC culture describedin the parent R01, to understand how aging impacts the inflammatory response to SARS-CoV2 infection inAEC and how this impacts neutrophil and alveolar macrophage. In Aim 2, we will leverage, through ourcollaborators, ongoing screens of repurposed FDA agents and novel anti-microbial peptides to identify noveltherapeutics to mitigate the effects of SARS-CoV2 infection in AECs with aging. This administrativesupplement is a natural extension of our funded NIA project on aging and the innate immune response toinfluenza, and could provide urgently needed insights to the mechanisms by which aging promotes mortality toCOVID-19 and potential therapeutics to reduce the suffering and death of older people with COVID 19.