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 compared to 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 vaccine response to respiratory infections, such as influenza A virus (IAV) (4, 5). COVID-19 severity has been observed (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 amplify inflammatory response, a better knowledge of monocyte dysfunction would inform the development of effective therapeutics to reduce inflammation and improve vaccine responsiveness. A critical age-related dysregulation observed in response to IAV infection (that we speculate may be relevant to SARS-CoV2 infection) is the profound dysregulation in monocyte response. Notably, peripheral blood monocytes isolated from older individuals 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 II interferons, interferon stimulated genes). We have access to a unique cohort through collaborative linkage with Italian investigators at the University of Modena 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 women is 30-90 years old. We hypothesize that a focus on interferon, proinflammatory, metabolic and senescence pathways will provide proteomic signatures that distinguish disease outcomes. Our primary objective in this supplement is to characterize inflammatory signatures in serum and primary monocytes in COVID-19 disease, controlling for age and biological sex. We will characterize serum circulating proteomes and primary 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 secretory phenotype: SASP).
There is a knowledge gap in our understanding of COVID-19 inflammatory profiles in relation to older age and biological sex. This proposal will leverage the use of banked specimens from COVID-19 patients in Italy to identify proteomic signatures of infection and disease outcome. A deeper knowledge of age-related inflammatory biomarkers would support development of effective therapeutics and vaccine responsiveness.
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