COVID-19 and the potential of Janus family kinase (JAK) pathway inhibition: A novel treatment strategy

Abstract

Recent evidence proposed that the severity of the coronavirus disease 2019 (COVID-19) in patients is a consequence of cytokine storm, characterized by increased IL-1β, IL-6, IL-18, TNF-α, and IFN-γ. Hence, managing the cytokine storm by drugs has been suggested for the treatment of patients with severe COVID-19. Several of the proinflammatory cytokines involved in the pathogenesis of COVID-19 infection recruit a distinct intracellular signaling pathway mediated by JAKs. Consequently, JAK inhibitors, including baricitinib, pacritinib, ruxolitinib, and tofacitinib, may represent an effective therapeutic strategy for controlling the JAK to treat COVID-19. This study indicates the mechanism of cytokine storm and JAK/STAT pathway in COVID-19 as well as the medications used for JAK/STAT inhibitors.

Keywords: COVID-19; JAK inhibitors; baricitinib; pacritinib; ruxolitinib; tofacitinib.

Figure 1

Some mechanisms of cytokine storm in COVID-19. (1) NSP9 and NSP 10 of SARS-CoV-2 target NKRF to promote IL-6 production. By engagement of receptor with IL-6, IFN-γ and GM-CSF are secreted by activated T cells; MCP-1, MIP-1, MIP-1, IP-1O, and CCL-5 are secreted by activated monocytes; and neutrophils release pro-inflammatory cytokines such as TNF-α and IL-1. (2) In response to SARS-CoV-2 in epithelial cells, secreted GM-CSF activates CD14+ CD16+ monocytes to produce pro-inflammatory cytokines such as IL-6 and TNF-α. (3) Attachment of SARS-CoV-2 to ACE-2, leads to a reduction in ACE-2 expression and accumulation of AngII in the host cells. The AngII and its receptor (AT1R) complex activate NF-κB, leading to the production of TNF-α and EGFR. (4) In COVID-19, increased levels of IL-1β and IL-18 indicate inflammasome activation and pyroptosis of host infected cells, triggering inflammation by recruiting immune cells and pro-inflammatory cytokine production. (5) Dendritic cells that are triggered by PRRs release TNF-α and IL-1, causing acute inflammatory responses. TNF/TNFR interactions between effector CD4+ T cells and myeloid cells have been suggested to promote IL-1β production. (6) Uncontrolled immune responses and hyperinflammation cause excessive production of pro-inflammatory cytokines, known as cytokine storms which are related to multi-organ failure and even death in COVID-19. NSP, Non-Structural Protein; NKRF, NF-κB repressor; ACE-2, Angiotensin Converting Enzyme-2; AngII, Angiotensin II; AT1R, Angiotensin II Receptor type 1; PRR, Pattern Recognition Receptors Created in Biorender.com.

Figure 2

JAK/STAT signaling induction by type I and II cytokines. (1) In the resting state, the subunits of type I and II cytokine receptors are at a short distance from each other. (2) The engagement of ligand with receptors leads to receptor dimerization and JAK activation. (3) The activated JAKs phosphorylate the tyrosine residue of the receptor which recruits various members of STAT proteins. (4) Phosphorylated and activated STATs make themselves dimmer. (4) STATs complex translocates to the cell nucleus. (5) STATs bind to the promoter and lead to the transcription of cytokine-responsive genes (99).

Figure 3

The Interferon type I and III canonical signaling pathway. (1) Type I and III IFNs (e.g., IFN-α, IFN-β, IFN-λ) released from virus-infected cells bind to their receptors (e.g., IFNA/LR) on neighboring cells, leading to the dimerization of receptors and activation of JAK1 and TYK2. (2) The activated JAK1 and TYK2 phosphorylate the tyrosine residue of the IFN receptor which recruits various members of the STAT family as STAT 1 and STAT2. Also, JAK1 and TYK2 add phosphorus to recruit STATs and activate them. (3) Following separation from the receptor, STAT1/STAT2 dimer interacts with IRF9. (4) The STAT1/STAT2/IRF9 complex moves to the nucleus. (5) Placement of the complex on its promoter on the gene leads to the robust expression of many classical IFN-stimulated genes (ISGs, such as ISG15, MxA, IFITM, etc.), which exert an antiviral role to restrict viral replication and spreading (109). SARS-CoV-2 inhibits IFN production and response through a variety of methods. As a result, target cells close to the original infection fail to receive essential and protective IFN signals, allowing the virus to propagate. The ORF3a can inhibit type III IFN receptors. The structural proteins of SARS-CoV-2, N, and M, and nonstructural proteins such as NSP1, NSP6, NSP13, ORF3a, and ORF7b quench IFN signaling by inhibition of STAT1 phosphorylation. (c) The phosphorylation of STAT2 in COVID-19 is repressed by N, NSP6, NSP13, ORF7a, and ORF7b proteins. (d) The translocation of the STAT1/STAT2/IRF9 into the nucleus is inhibited by N and ORF6 proteins which attenuate the transcription of the interferon-stimulated gene (13, 110, 111). IFN, Interferon; ISG, Interferon Stimulated Gene; STAT, Signal Transducer and activator of Transcription; IRF9, Interferon Regulatory Factor 9; TYK2, Tyrosine Kinase 2; JAK, Janus Kinase; MxA, Myxovirus Resistance Gene A; IFITM, Interferon Induced Transmembrane; OFR, Open Reading Frame; NSP, None Structural Protein.

Figure 4

IL-6 signaling pathways. IL-6 requires two receptors, the IL-6R and the gp130, to begin signaling. IL-6 (classic signaling) binds to either fluid- or membrane-bound IL-6R (SIL-6R, trans-signaling). In two modalities of IL-6R signaling, a hexamer complex with gp130 is formed. The JAK–MAPK route and the JAK–STAT3 pathway are both used by IL-6 to transfer signaling. JAK kinases phosphorylate tyrosine in the cytoplasmic region of gp130, which promotes STAT3 phosphorylation and causes homodimerization, which works as a transcription factor in the nucleus.