Bruton's Tyrosine Kinase: A Promising Target for the Treatment of COVID-19

Coronavirus Disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 in China and quickly spread throughout the world. By June 24, 2020, the World Health Organization (WHO) reported the total number of 8,993,659 laboratory-confirmed cases leading to 469,587 deaths worldwide (1). COVID-19 has a range of clinical manifestations from asymptomatic cases to severe and life-threatening illnesses (2). The most severe form of the disease is the rapidly progressing failure of the respiratory system, presenting by severe dyspnea and profound hypoxemia, and may lead to acute respiratory distress syndrome (ARDS)(3) . The pathophysiology of COVID-19 is under investigation and has not yet certainly defined. Like other severe forms of coronavirus diseases, the hyperactivation of the immune system resulting in hyper inflammation and cytokine storm syndrome has been postulated (4) . Most of the patients with the severe form of COVID-19 have higher serum levels of various inflammatory cytokines and chemokines, including interleukin-1β (IL-1β), IL-6, granulocyte colony-stimulating factor (G-CSF), granulocyte/macrophage colony-stimulating factor (GM-CSF), interferon-γ (IFN-γ), tumor necrosis factor (TNF), and macrophage inflammatory protein-1α (MIP1α)(5, 6) . Although more than 350 ongoing clinical trials concerning potentiality effective therapeutic agents are underway, unfortunately, no treatment has been proved to treat COVID-19 cases (7). Due to some similarities between COVID-19 and macrophage activation syndrome, targeting the innate immune system may be an effective strategy to control the disease (8). Bruton’s tyrosine kinase (BTK) is a non-receptor intracellular tyrosine kinase, important in the development of various stages of B lymphocytes. Historically, its mutation initially was described in X-linked agammaglobulinemia (XLA) (8). However, the expression of BTK is not limited to B cells and is expressed by all cells of the hematopoietic lineage except T cells, natural killer (NK) cells, and plasma cells (9, 10). BTK is an essential agent active in innate immunity (11) and has an important role in multiple signaling pathways. In neutrophils, it mediates signaling via Toll-like receptor 4 (TLR-4) (12) and in human macrophages and dendritic cells, BTK is involved in the recognition of pathogens via multiple TLRs (11). In macrophages, TLRs recognize RNA from respiratory viruses, like SARS-CoV-2, and initiate signaling through BTKdependent activation of nuclear factor ƙB (NF-ƙB). BTK regulates transcription factors, such as NF-ƙB and IFN-regulatory factors, which are important for macrophage M1 polarization leading to the production of multiple inflammatory chemokines, cytokines, and phagocytosis (Figure 1) (8, 13).