Defining inflammaging and monocyte dysfunction in COVID-19 disease

Abstract: People over 65 are disproportionately burdened by coronavirus disease 2019 (COVID-19). Oder adults (i.e.,65 years old and older), more often men, experience higher disease severity and increased mortality comparedto younger individuals and women (1, 2). Notably, aging is associated with chronic low-grade inflammation(i.e., inflammaging) that can exacerbate many diseases and has been associated with reduced vaccineresponse to respiratory infections, such as influenza A virus (IAV) (4, 5). COVID-19 severity has beenobserved (6) to resemble a "cytokine storm" - a term first described in relation to severe IAV infection (7, 8).Because respiratory viral infections often result in the recruitment of monocytes where they can amplifyinflammatory response, a better knowledge of monocyte dysfunction would inform the development of effectivetherapeutics to reduce inflammation and improve vaccine responsiveness. A critical age-related dysregulationobserved in response to IAV infection (that we speculate may be relevant to SARS-CoV2 infection) is theprofound dysregulation in monocyte response. Notably, peripheral blood monocytes isolated from olderindividuals when compared to monocytes from younger individuals have an amplified inflammatory response(e.g., upregulated NF-kB pathway) and a profound deficit in antiviral interferon response (e.g., type I and IIinterferons, interferon stimulated genes).We have access to a unique cohort through collaborative linkage with Italian investigators at the University ofModena and Emilio Reggio and the Modena COVID-19 working group that includes samples from 167 SARS-CoV2 infected men and women that were hospitalized with COVID-19. The age range of the men and womenis 30-90 years old. We hypothesize that a focus on interferon, proinflammatory, metabolic and senescencepathways will provide proteomic signatures that distinguish disease outcomes. Our primary objective in thissupplement is to characterize inflammatory signatures in serum and primary monocytes in COVID-19disease, controlling for age and biological sex. We will characterize serum circulating proteomes andprimary monocyte proteomes using banked serum and primary monocytes from uninfected (n=20), SARS-CoV2 positive adults hospitalized then discharged (n=20) and SARS-CoV2 positive adults that are deceased(n=20). Serum and cellular proteomic signatures will be used to evaluate type I-III interferons, pro/anti-inflammatory pathway, metabolic pathways and immunosenescence (e.g., senescence associated secretoryphenotype: SASP).