The aging whole blood transcriptome reveals a potential role of FASLG in COVID-19

The risk for severe illness from COVID-19 increases with age as older patients are at the highest risk. Although it is still unclear whether the virus is blood-transmitted, the viral RNA is detected in serum. Identifying how Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) interacts with specific blood components during aging is expected to guide proper therapies. Considering that all human coronavirus require host cellular molecules to promote infection, we investigated the aging whole blood transcriptome from the Genotype-Tissue Expression (GTEx) database to explore differentially expressed genes (DEGs) translated into proteins potentially interacting with viral proteins. From a total of 22 DEGs in aged blood, five genes (FASLG, CTSW, CTSE, VCAM1, andBAG3) changed expression during aging. These age-related genes are involved in immune response, inflammation, cell component and cell adhesion, and platelet activation/aggregation. Both males and females older than 50 overexpressFASLGcompared with younger adults (20-30 years old), possibly inducing a hyper-inflammatory cascade that activates specific immune cells. Furthermore, the expression of cathepsins (CTSWandCTSE) and the anti-apoptotic co-chaperone moleculeBAG3was significantly increased throughout aging in both gender. By exploring publicly available Single-Cell RNA-Sequencing (scRNA-Seq) data on peripheral blood of SARS-CoV-2-infected patients, we foundFASLGandCTSWexpressed mainly in natural killer (NK) cells and CD8+ (cytotoxic) T lymphocytes whereasBAG3was expressed in CD4+ T cells, naive T cells, and CD14+ monocytes. The increased expression ofFASLGin blood during aging may explain why older patients are more prone to severe acute viral infection complications. These results indicateFASLGas a prognostic candidate and potential therapeutic target for more aggressive clinical manifestation of COVID-19.