Purinergic signaling pathway in severe COVID-19

Abstract

Substantial efforts have been made to understand the immune response during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, in order to identify and characterize risk factors, immune mechanisms responsible for the induction of tissue injury and potential therapeutic targets. Purinergic signaling pathway has shown to modulate the inflammatory processes in the course of several infectious diseases, but its role in the coronavirus disease 2019 (COVID-19) has not been clearly defined. Inflammation is usually associated to the release of ATP from different cell types, starting a cascade of events through the activation of a set of different purinergic receptors. This review summarizes the evidence showing the involvement of the purinergic system in the inflammatory condition that characterizes severe COVID-19.

Figure 1

Pro-inflammatory pathways related with purinergic signaling during severe COVID-19. SARS-CoV-2 infection of respiratory epithelial cells promote cell stress and cell damage inducing ATP release to the extracellular space through different mechanisms, including the transient opening of PANX1. Injury of different cell types in the course of severe COVID-19, such as tissue damage mediated by neutrophils, also contributes to the enhancement in the extracellular concentration of ATP (not shown in the Figure). Severe COVID-19 is associated to an increased expression of CD39 and a decreased expression of CD73. This result in an increased ATP/ADP: adenosine ratio that promotes the activation of immune cells and platelets through the P2X7R and P2Y12R, respectively, and the development of inflammatory and thrombotic events. Abbreviations: PANX1, pannexin 1; Ado, adenosine; P2X7R, P2X7 receptor; NLPR3, NLR family pyrin domain containing 3; NETs, Neutrophil Extracellular Traps; ROS; Reactive Oxygen Species; P2Y12R; P2Y12 receptor. The figure was drawn by using pictures from Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 Unported License.