Figure 4

Summary of the molecular processes during COVID-19 infections that are affected in DS. The figure recapitulates the pathways affected in DS, and how they contribute to Sars-Cov-2 infection and the severity of COVID-19. Mechanisms contributing to viral entry: viral entry could be facilitated in DS thanks to TMPRSS2 triplication that leads to increased activation of the viral S-protein and also thanks to tight junctions’ downregulation, since tight junctions hamper virus’ endocytosis. Another protease able to prime the S-protein is FURIN, which can be inhibited by EGCG, a polyphenol that has been used in DS individuals. Mechanisms involved in inflammation and viral replication: triplication of IFNAR1/2 results in activation of the interferon (IFN) I response and subsequently of the JAK/STAT/OAS pathway, that in turn, leads both to increased inflammation but also to activation of the RNAseL that could degrade the viral RNA. We detected upregulation in DS of the interferon-induced antiviral proteins IFI27, BST2, IFITM1, that inhibit viral genome release. ER stress, the unfolded protein response, and the IFN signaling lead to upregulation of EIF2AK2 that phosphorylate/inactivated EIF2α leading to the block of protein synthesis. The virus inhibits EIF2AK2 to allow viral replication, while in DS upregulation of EIF2AK2 together with downregulation of the phosphatase PPP1CA might block protein synthesis. However, the downregulation of nucleoporins in DS might instead favor viral replication. The viral protein M inhibits AST1 leading to apoptosis which could be counteracted in DS by AKT1 upregulation. Mechanisms involved in the severity of COVID-19: the IFN signaling also leads to increased bradykinin signaling (via ACE2 upregulation), that together with higher levels of CPA3 and ADAMTS1 can lead to lung fibrosis. The IFN signaling eventually downregulates the NLRP3 inflammasome (that is normally activated by the viral orf3a) which is downregulated in DS, leading to higher susceptibility to secondary bacterial infections. Finally, the cytokine storm could be potentiated in DS as a result of increased levels of the chemokine CXCL10 and IL10 that leads to increased fibrocytes and M2 macrophages activation leading to lung fibrosis. Upper red arrows indicate that the given gene is upregulated, blue down arrow, downregulated.