Janus kinase signaling as risk factor and therapeutic target for severe SARS-CoV-2 infection

Abstract

Cytokine signaling, especially interferon (IFN) signaling is closely linked to several aspects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. During initial SARS-CoV-2 infection, symptomatic patients present with impaired type I/III IFN-mediated antiviral responses. Interestingly, IFNs regulate the cellular entry receptor for SARS-CoV-2 on epithelial and endothelial cells. As reported recently, critically ill COVID-19 patients show genetic polymorphisms in one IFN receptor gene (IFNRA2) and in a gene locus near the Janus kinase (JAK) TYK2, which is key for IFN, interleukin (IL)-12 and IL-23 signaling, and T helper (Th) 1/Th17 cell-mediated antiviral immune responses. In the advanced stage of the disease, critically ill COVID-19 patients develop a cytokine storm where many inflammatory mediators using the JAK/STAT signaling pathway such as IL-6, IFN-γ, the granulocyte colony-stimulating factor (G-CSF) or IL-2, and chemokines result in an influx of macrophages and neutrophils damaging the lung tissue. The knowledge on the cytokine and JAK/STAT signaling pathways in severe COVID-19 disease explains the promising first results with JAK inhibitors like baricitinib, which not only dampen the inflammation but in the case of baricitinib also affect virus replication and endocytosis in target cells. Here, we summarize the current immunological associations of SARS-CoV-2 infection with cytokine signaling, the JAK/STAT pathway, and the current clinical stage of JAK inhibitors for improving severe COVID-19 disease.

Keywords: JAK inhibitors; Janus kinase; SARS-CoV-2; cytokine storm; severe COVID-19.

Figure 1

Importance of cytokine signaling through Janus kinases (JAK) during SARS‐CoV‐2 lung infection. Viral endocytosis in lung epithelial cells begins through the ACE2 receptor, which is regulated by IFN signaling. The initial antiviral response mediated by type I/III IFNs and downstream JAK/STAT signaling is impaired in severely ill patients. In these patients with progressive disease, SARS‐CoV‐2 infection triggers an excessive immune reaction with release of multiple pro‐inflammatory cytokines such as IL‐2, IL‐6, granulocyte colony stimulating factor (G‐CSF) that signal through the JAK/STAT pathway, and others like TNF. Infiltrating macrophages and neutrophils contribute to lung injury. A genetic susceptibility with polymorphisms in or near the genes for IFNAR2 and TKY2, respectively, and, the development of autoantibodies against IFNs favor the inflammatory profile in severely ill patients. The JAK1/JAK2 inhibitor baricitinib exerts antiviral effects by hampering virus endocytosis and profound anti‐inflammatory effects in severely ill patients by blocking cytokine signaling.