Possible mechanisms that explain viral persistence and disease severity
(1) Upon viral infection, cells increase the secretion of IL-6, which will paracrinally induce the expression of SOCS-1 via STAT-3 transcription factors [88]. (2) SOCS-1 hampers IFN antiviral signaling, via STAT-1 DE phosphorylation. The inhibition of expression of IFN genes leads to poor antiviral defense, and, as a consequence, reduced T-bet transcription, leading to defective Th1 polarization of CD4+ T cells [86,87,110,253]. (3) Upon viral entry, p38 is phosphorylated and, thereafter, perform downstream phosphorylation of target transcription factors, such as CREB, ATF-1 and AP-1. This effect leads to increased inflammatory gene expression and pro-survival gene expression, which may prolong the viral permanence in the infected cell [136]. (4) Upon recognition of viral particles and LPS from bacteria, TLR4-mediated signaling may lead to increased deleterious inflammation via NF-kB recruitment and p38 phosphorylation [105,106]. TLR4 polymorphism might explain the differential susceptibility to ARDS in COVID-19 patients [106].