DNA damage contributes to age-associated differences in SARS-CoV-2 infection

Abstract

Coronavirus disease 2019 (COVID-19), caused by coronavirus SARS-CoV-2, is known to disproportionately affect older individuals. Age is the most important determinant of disease severity and mortality. How aging processes affect the disease progression remains largely unknown. Here we found that DNA damage, a common denominator and major cause of aging, promoted susceptibility to SARS-CoV-2 infection in cells and intestinal organoids. SARS-CoV-2 entry was facilitated by DNA damage caused by either telomere attrition or extrinsic genotoxic stress and hampered by inhibition of DNA damage response. Mechanistic analysis revealed that the DNA damage response increased expression of ACE2, the receptor of SARS-CoV-2, by activation of transcription factor c-Jun in vitro and in vivo. Knockdown of c-Jun significantly reduced cell susceptibility to SARS-CoV-2. To explore the clinical clues of contribution of DNA damage in SARS-CoV-2 infection, we analyzed the expression of ACE2, γH2Ax and p-c-Jun in old and young human and mouse tissues. Expression of ACE2 was elevated in older human and mouse tissues and positively correlated with γH2Ax and p-c-Jun. Finally, targeting DNA damage by increasing the DNA repair capacity, alleviated cell susceptibility to SARS-CoV-2. Our data provide insight into the age-associated differences in SARS-CoV-2 infection and a novel target for anti-viral intervention.