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

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 has implicated us to re-look into its signaling cascades drawing attention towards the JAK/STAT pathway. Considered as a major signaling mediator of cytokines and chemokines, the JAK/STAT pathway has significantly contributed to the worsening of COVID-19. 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 infection triggers the inflammation via the JAK/STAT pathway mainly through its structural and non-structural proteins leading towards the development of cytokine storms. This produces various inflammatory markers in the host that determine the disease severity. Therefore, inhibiting JAK/STAT signaling with JAK/STAT inhibitors like Ruxolitinib, Baricitinib, Tofacitinib could hamper the inflammatory cascade and reduce inflammation. 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 to be speculative for which further investigations are required.

Epithelial response to IFN‐γ promotes SARS‐CoV‐2 infection

“…While IFN‐γ is likely important in the context of the host immune response to SARS‐CoV‐2 infection, its effects on epithelial differentiation and ACE2 expression may explain why it is inefficient in limiting infection in some patients. Several clinical trials are currently investigating the outcome of SARS‐CoV‐2 infection as a function of activation of IFN signaling as well as suppression of this pathway via Jak‐Stat inhibitors (Satarker et al , 2020). These studies will reveal whether, in a clinical setting, this signaling pathway induces immunity and is beneficial, or whether the virus highjacks IFN signaling through the mechanisms described here.…”

The contributory role of lymphocyte subsets, pathophysiology of lymphopenia and its implication as prognostic and therapeutic opportunity in COVID-19

“…The JAK/STAT pathway is one of the common signaling axes that is recruiting by both SARS-CoV-2 host cells and immune cells to transmit their desired messages to the nucleus [135] . Given this, it seems if this pathway is inhibited, an order of unnecessary cytokine production would be interrupted.…”

Nanotechnology to the Rescue: Treatment Perspective for the Immune Dysregulation Observed in COVID-19

“…SARS-CoV-2-mediated hyperinflammation is primarily brought about via the JAK/STAT signaling cascade that can be triggered both by the SARS-CoV-2 structural and non-structural proteins that eventually results in elevated cytokine levels. The escalating cytokine levels (IL-6, IL-1β, and IFNγ) further stimulate the activation of the JAK/STAT signaling pathway in patients, which results in a degenerative feedback loop being established (Battagello et al, 2020;Luo W. et al, 2020;Satarker et al, 2020). SARS-CoV-2 inhibits STAT1 phosphorylation which results in blocking ISGs transcription in monocyte-derived dendritic cells and macrophages, thus contributing to the impairment of interferon responses.…”