JAK inhibitors and COVID-19

Abstract

During SARS-CoV-2 infection, the innate immune response can be inhibited or delayed, and the subsequent persistent viral replication can induce emergency signals that may culminate in a cytokine storm contributing to the severe evolution of COVID-19. Cytokines are key regulators of the immune response and virus clearance, and, as such, are linked to the-possibly altered-response to the SARS-CoV-2. They act via a family of more than 40 transmembrane receptors that are coupled to one or several of the 4 Janus kinases (JAKs) coded by the human genome, namely JAK1, JAK2, JAK3, and TYK2. Once activated, JAKs act on pathways for either survival, proliferation, differentiation, immune regulation or, in the case of type I interferons, antiviral and antiproliferative effects. Studies of graft-versus-host and systemic rheumatic diseases indicated that JAK inhibitors (JAKi) exert immunosuppressive effects that are non-redundant with those of corticotherapy. Therefore, they hold the potential to cut-off pathological reactions in COVID-19. Significant clinical experience already exists with several JAKi in COVID-19, such as baricitinib, ruxolitinib, tofacitinib, and nezulcitinib, which were suggested by a meta-analysis (Patoulias et al.) to exert a benefit in terms of risk reduction concerning major outcomes when added to standard of care in patients with COVID-19. Yet, only baricitinib is recommended in first line for severe COVID-19 treatment by the WHO, as it is the only JAKi that has proven efficient to reduce mortality in individual randomized clinical trials (RCT), especially the Adaptive COVID-19 Treatment Trial (ACTT-2) and COV-BARRIER phase 3 trials. As for secondary effects of JAKi treatment, the main caution with baricitinib consists in the induced immunosuppression as long-term side effects should not be an issue in patients treated for COVID-19.We discuss whether a class effect of JAKi may be emerging in COVID-19 treatment, although at the moment the convincing data are for baricitinib only. Given the key role of JAK1 in both type I IFN action and signaling by cytokines involved in pathogenic effects, establishing the precise timing of treatment will be very important in future trials, along with the control of viral replication by associating antiviral molecules.

Keywords: COVID-19; autoimmunity; cytokines; hematologic neoplasms; therapies, investigational.

Figure 1

JAK-dependent cytokine receptors signaling involved in response to SARS-CoV-2 infection and potentially in COVID-19 immunopathology. EC, extracellular; IC, intracellular; IFN, interferon; JAK, Janus kinase.

Figure 2

Homodimeric cytokine receptor signaling via JAK2. (A) Homodimeric cytokine receptors and conformational changes on activation by ligands. JAK2 binds to boxes 1 and 2 motifs of the cytosolic domains of receptors, via the FERM and SH2 domains, respectively. The region separating the end of the transmembrane domain and the Box 1 is denoted ‘switch region’ and is required for ligand-activation of receptors and JAK2. (B) JAK2 domain structure and the activating mutations in myeloproliferative neoplasms (V617F and insertions and deletions mutating K539) shown as red stars. FERM, SH2, pseudokinase and kinase domains are shown from the NH2- to the COOH-terminus. kinase inhibitors currently in use act on the ATP-binding pocket of the kinase domain and inhibit both mutated and wild type forms of JAK2. EC, extracellular; IC, intracellular; IFN, interferon; JAK, Janus kinase.

Figure 3

Signaling by heterodimeric type I interferon (IFN) receptor and changes of conformation on activation of the IFN receptor by its ligands. JAK1 binds to boxes 1 and 2 motifs of the cytosolic domain of ifnar2 respectively via the FERM and SH2 domains. Tyk2 binds to the cytosolic domain of IFNAR1. EC, extracellular; IC, intracellular; IFN, interferon; IL, intereukin; JAK, Janus kinase.