Targeting JAK-STAT Signaling to Control Cytokine Release Syndrome in COVID-19

Abstract

Recent advances in the pathophysiologic understanding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has indicated that patients with severe coronavirus disease 2019 (COVID-19) might experience cytokine release syndrome (CRS), characterized by increased interleukin (IL)-6, IL-2, IL-7, IL-10, etc. Therefore, the treatment of cytokine storm has been proposed as a critical part of rescuing severe COVID-19. Several of the cytokines involved in COVID-19 employ a distinct intracellular signaling pathway mediated by Janus kinases (JAKs). JAK inhibition, therefore, presents an attractive therapeutic strategy for CRS, which is a common cause of adverse clinical outcomes in COVID-19. Below, we review the possibilities and challenges of targeting the pathway in COVID-19.

Keywords: COVID-19; JAK inhibitors; cytokine release syndrome.

Figure I

Schematic Showing the JAK-STAT Signaling Pathway. Abbreviations: JAK, Janus kinase; SOCS, suppressors of cytokine signaling; STAT, signal transducers and activators of transcription.

Figure 1

Key Figure. Schematic Showing JAK-Dependent Cytokines That Are Involved in the Development of COVID-19 and the JAK-Associated Receptors Each Interacts With. The types of cellular responses elicited by these interactions are shown. The FDA-approved (unbroken boxes) and candidate JAK inhibitors in clinical trials (in broken boxes), along with their selectivity, are also shown. Abbreviations: ACE2, angiotensin converting enzyme II; IFN, interferon; IL, interleukin; JAK, Janus kinase; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TYK2, tyrosine kinase 2.

Figure 2

Proposed Mechanism of Action of Baricitinib in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2)-Infected Cells. SARS-CoV-2 enters cells through receptor-mediated endocytosis via interactions with receptors that include angiotensin converting enzyme II (ACE2), a cell surface protein on cells in the kidney, intestine, blood vessels, heart, and, importantly, alveolar epithelial type II cell. Baricitinib, a JAK inhibitor, can inhibit the process of receptor-mediated endocytosis and thus can be a viable therapeutic agent against COVID-19.