Contribution of STAT3 to the pathogenesis of COVID-19

Abstract

Hyper-inflammatory responses, lymphopenia, unbalanced immune responses, cytokine storm, large viral replication and massive cell death play fundamental roles in the pathogenesis of COVID-19. Extreme production of many kinds of pro-inflammatory cytokines and chemokines occur in severe COVID-19 that called cytokine storm. Signal transducer and activator of transcription-3 (STAT-3) present in the cytoplasm in an inactive form and can be stimulated by a vast range of cytokines, chemokines and growth factors. Thus, STAT-3 can participate in the induction of inflammatory responses during coronavirus infections. STAT-3 can also suppress anti-virus interferon response and induce unbalanced anti-virus adaptive immune response, through influencing Th17-, Th1-, Treg-, and B cell-mediated functions. Furthermore, STAT-3 can contribute to the M2 macrophage polarization, lung fibrosis and thrombosis. Moreover, STAT-3 may be directly targeted by some virus-derived protein and operate as a pro-viral or anti-viral element in a virus-specific process. Here, the possible contribution of STAT-3 to the pathogenesis of COVID-19 was explained, while providing potential approaches to target this transcription factor in an attempt for COVID-19 treatment.

Keywords: COVID-19; Immune response; Inflammation; Pathogenesis; SARS-CoV-2; STAT3; Treatment.

Fig. 1

Activation of STAT-3: Binding of numerous cytokines or growth factors to their specific receptors induces phosphorylation of the receptor-associated JAK1 and then STAT3 is phosphorylated by JAK1. Phosphorylated STAT3 is dimerized and translocated to the nucleus, which causes the expression of target genes contributing to the immunosuppression, inflammation, angiogenesis, proliferation and survival.

Fig. 2

Contribution of STAT-3-mediated pathways to COVID-19 pathogenesis. Activated STAT-3 can down-regulate lymphopoiesis, E-cadherin expression by vascular endothelial cells, Treg cell activity and anti-viral immune responses (including type I IFN-mediated signaling, NK cells activity, Th1 cell responses and CD8⁺ CTLs) supporting the lymphopenia, the vascular leak, hyper-inflammation and virus persistence, respectively. Activated STAT-3 can up-regulate the formation of the extracellular matrix, the expression of plasminogen activator inhibitor-1, the polarization and activation of Th17 cells and the polarization of M2 macrophages promoting lung fibrosis, thrombosis, hyper-inflammation/cytokine storm, and virus persistence/lung fibrosis, respectively.