STAT3 Roles in Viral Infection: Antiviral or Proviral?

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which can be activated by cytokines, growth factor receptors, and nonreceptor-like tyrosine kinase. An activated STAT3 translocates into the nucleus and combines with DNA to regulate the expression of target genes involved in cell proliferation, differentiation, apoptosis and metastasis. Recent studies have shown that STAT3 plays important roles in viral infection and pathogenesis. STAT3 exhibits a proviral function in several viral infections, including those of HBV, HCV, HSV-1, varicella zoster virus, human CMV and measles virus. However, in some circumstances, STAT3 has an antiviral function in other viral infections, such as enterovirus 71, severe acute respiratory syndrome coronavirus and human metapneumovirus. This review summarizes the roles of STAT3 in viral infection and pathogenesis, and briefly discusses the molecular mechanisms involved in these processes.

Contribution of STAT3 to the pathogenesis of COVID-19

“…In mammalian, the signal transducer and activator of transcription factors (STATs) including STAT-1, -2, -3, -4, -5A, -5B and −6 control the expression of genes regulating cell proliferation, cell differentiation, immune responses, inflammation, apoptosis and oncogenesis [ 9 ]. Six operative domains of STAT-3 molecule include the N-terminal domain, coiled-coil domain, linker domain, DNA binding domain, SH2 domain and C-terminal transcriptional activation domain [ 10 ]. The STAT-3 protein present in the cytoplasm in an inactive form, which is mainly activated by IL-6 upon ligation to its receptor, IL-6Rα.…”

“…The STAT-3 protein present in the cytoplasm in an inactive form, which is mainly activated by IL-6 upon ligation to its receptor, IL-6Rα. Moreover, STAT-3 can be stimulated by numerous types of cytokines such as TNF-α and IFN-γ, IL-5, IL-9, IL-10, IL-11, IL-12, IL-21, IL-22, IL-27, G-CSF, M-CSF, GM-CSF, monocyte chemotactic protein-1 (MCP-1) and CCL5 [ 9 , 10 ], some of them exist in the COVID-19-related cytokine storm [ 6 ].…”

“…Stimulated STAT-3 releases from the receptor to create homodimers or heterodimers with other STATs via its SH2 domain. Homo- or heterodimerized STAT-3 is then transported from the cytoplasmic region to the cell nucleus and finally attach to the promoter regions of target genes to induce gene expression [ 10 ].…”

Quantitative measurement of activity of JAK-STAT signaling pathways in blood samples and immune cells to predict innate and adaptive cellular immune response to viral infection and accelerate vaccine development

“…This suggests that activity of this signaling pathway is more associated with activity of the innate immune response, represented by the monocyte fraction in PBMC samples. Indeed, the JAK-STAT3 pathway is also involved in viral disease, and in addition to a role in generating a host immune response, its activity has been associated with severe inflammatory complications caused by a disbalance between adaptive and innate immune response, such as COVID-19 pneumonia (51), (52), (53), (54).…”

HSV-1 Modulates IL-6 Receptor Expression on Human Dendritic Cells

“…The IL-6 signaling pathway is an important inductor of an anti-viral immune response ( 35 , 36 ) and thus frequently targeted by several viruses, including Enterovirus 71 or influenza A virus ( 37 , 38 ). However, the regulation of the signaling components, i.e., IL6R and STAT3, differs between distinct viruses and infected cell types ( 39 , 40 ).…”