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Review
. 2021 Jun;133(5):489-507.
doi: 10.1080/00325481.2020.1855921. Epub 2020 Dec 16.

JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy

Sairaj Satarker  1 , Antriya Annie Tom  2 , Roshitha Ann Shaji  2 , Aaja Alosious  2 , Mariya Luvis  2 , Madhavan Nampoothiri  1
Affiliations
Review

JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy

Sairaj Satarker et al. Postgrad Med. 2021 Jun.

Abstract

As the incidence of COVID-19 increases with time, more and more efforts are made to pave a way out for the therapeutic strategies to deal with the disease progression. Inflammation being a significant influencer in COVID-19 patients, it drives our focus onto the signaling cascades of the JAK/STAT pathway. JAK phosphorylation mediated by cytokine receptor activation leads to phosphorylation of STATs that translocate into the nucleus to translate for inflammatory mediators. The SARS-CoV-2 structural proteins like spike, nucleocapsid, membrane and envelope proteins along with the non- structural proteins 1-16 including proteases like 3CL pro and PLpro promote its entry and survival in hosts. The SARS-CoV-2 infection triggers inflammation via the JAK/STAT pathway leading to recruitment of pneumocytes, endothelial cells, macrophages, monocytes, lymphocytes, natural killer cells and dendritic cells progressing towards cytokine storm. This produces various inflammatory markers in the host that determine the disease severity. The JAK/STAT signaling also mediates immune responses via B cell and T cell differentiation.With an attempt to reduce excessive inflammation, JAK/STAT inhibitors like Ruxolitinib, Baricitinib, Tofacitinib have been employed that mediate its actions via suppressors of cytokine signaling, cytokine inducible SH2 containing protein, Protein inhibitor of activated STAT and protein tyrosine phosphatases. Even though they are implicated with multiple adverse effects, the regulatory authorities have supported its use, and numerous clinical trials are in progress to prove their safety and efficacy. On the contrary, the exact mechanism of JAK/STAT inhibition at molecular levels remains speculative for which further investigations are required.

Keywords: COVID-19; Janus kinase; SARS-CoV-2; STAT; cytokine storm; inflammation; inhibitors.

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Conflict of interest statement

No potential conflict of interest was reported by the authors.

Figures

Figure 1.
Figure 1.
The cascade of the JAK/STAT pathway initiated upon the binding of cytokines produced by the SARS-CoV-2 infection onto their corresponding cytokine receptors
Figure 2.
Figure 2.
Various stakeholders involved in inflammation induced by cytokine storm upon SARS-CoV-2 infection in alveolar cells
Figure 3.
Figure 3.
Interaction of SARS-CoV-2 proteins with JAK/STAT signaling
Figure 4.
Figure 4.
The effect of inhibitory proteins on the functioning of the JAK/STAT pathway
Figure 5.
Figure 5.
Some of the JAK/STAT inhibitors used in COVID-19
See this image and copyright information in PMC

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