Innate immune mechanisms underlying sex differences in COVID-19

Abstract

Abstract COVID-19 exhibits a sex-bias with males showing signs of more severe disease and hospitalizations compared to females. The mechanisms are not clear but differential immune responses, particularly the initial innate immune response, between sexes may be playing a role. The early innate immune responses to SARS-CoV2 have not been studied because of the gap in timing between the patient getting infected, showing symptoms, and getting the treatment. The primary objective of the present study was to compare the response of DCs and monocytes from males and females to SARS-CoV2 24h after infection. To investigated this, PBMCs from healthy young individuals were stimulated in vitro with the virus. Our results indicate that DCs and monocytes from females displayed increased activation compared to males. In addition, females secreted significantly higher levels of IFN-α and IL-29 early while the secretion of IFN-α was delayed and prolonged in males. Further investigations revealed that the secretion of CXCL-10, a chemokine associated with lung complications, was higher in males than females. The PBMCs from females also displayed increased induction of CTLs. Bulk RNA-seq analysis indicates that IFN related pathways may be upregulated in females at baseline. Altogether, our results suggest that decreased activation of pDCs, mDCs and monocytes, the delayed and prolonged IFN-α secretion along with increased CXCL-10 secretion may be responsible for the severity of COVID-19 in males. The study is supported by grants R00RG2352 and R01RG3735 to AA from University of California office of the President (UCOP).