The Many Faces of JAKs and STATs Within the COVID-19 Storm

Abstract

The positive-sense single stranded RNA virus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), resulted in a global pandemic with horrendous health and economic consequences not seen in a century. At a finer scale, immunologically, many of these devastating effects by SARS-CoV-2 can be traced to a “cytokine storm” resulting in the simultaneous activation of Janus Kinases (JAKs) and Signal Transducers and Activators of Transcription (STAT) proteins downstream of the many cytokine receptor families triggered by elevated cytokines found in Coronavirus Disease 2019 (COVID-19). In this report, cytokines found in the storm are discussed in relation to the JAK-STAT pathway in response to SARS-CoV-2 and the lessons learned from RNA viruses and previous Coronaviruses (CoVs). Therapeutic strategies to counteract the SARS-CoV-2 mediated storm are discussed with an emphasis on cell signaling and JAK inhibition.

Co-Regulation of Protein Coding Genes by Transcription Factor and Long Non-Coding RNA in SARS-CoV-2 Infected Cells: An In Silico Analysis

“…Various TF especially IRFs (IRF1-IRF9) and Transducers and Activators of Transcription (STAT1-STAT6) play important roles in viral infection including SARS-CoV-2 infection through the regulation of IFN production and potentiate the expression of antiviral genes including inflammatory cytokine genes [71][72][73]. IRFs are also involved in diverse cellular functions including innate immunity, cell cycle progression, apoptosis, and tumor suppression [74].…”

“…Hospitalized COVID-19 patients showed increased levels of various cytokines that in turn activate multiple cytokine receptor families and downstream Janus Kinases (JAKs) and STAT proteins to eradicate the SARS-CoV-2 pathogen and restore immune homeostasis. Cytokines utilizing IFN-I, IFN-II, and G-Protein Coupled Receptors propagate direct signals through JAKs and STATs and many have been linked to COVID-19 disease severity [71]. ISGF3, a tripartite transcription factor formed by high levels of IRF9, STAT1, and STAT2, induces the expression of hundreds of ISGs.…”

Coagulopathies after Vaccination against SARS-CoV-2 May Be Derived from a Combined Effect of SARS-CoV-2 Spike Protein and Adenovirus Vector-Triggered Signaling Pathways

“…These processes are triggered in a broad variety of cell types that express the respective receptors, including epithelial cells (e.g., in the lung), macrophages (including alveolar macrophages), and endothelial cells, found in all organs [ 77 , 78 , 79 , 80 ]. Activations of additional signal transduction pathways, such as JAK/STAT3 pathway, are activated by the NF-κB triggered release of IL-6, colony stimulating factors, and various G-protein binding chemokines [ 83 , 88 , 89 , 90 , 91 ].…”

“…Parallel to the activation of the NF-κB pathway (or probably also as a result of the NF-κB-induced cytokines/chemokines), there is also a prominent activation of Janus kinases/signal transducer and activator of transcription 3 (JAK/STAT3) pathway following SARS-CoV-2 infection. Cytokines which bind to type I (e.g., IL-6, G-CSF) and type II (e.g., IL-10) receptors, as well as multiple chemokines binding to G-protein coupled receptors, directly trigger the activation of JAK/STAT3 pathway, characterized by Tyr phosphorylation [ 88 , 89 ].…”

“…Various other cytokines, such as G-SCF or GM-CSF, and a variety of chemokines such as IL-8, MCP-1, MIP1α, and MIP1β found to be elevated in acute COVID-19 patients [ 18 ] are also known to activate the JAK/SAT3 pathway [ 88 , 92 ]. The enhanced transcription of JAK/STAT3 activators, such as IL-6 and multiple chemokines (including IL-8, MCP-1, MIP1α, and MIP1β), found during acute respiratory viral infections, including also SARS-CoV-2, is largely triggered also by NF-κB pathway activation [ 38 , 93 , 94 ].…”