The Potential of Purinergic Signaling to Thwart Viruses Including SARS-CoV-2

Abstract

A long-shared evolutionary history is congruent with the multiple roles played by purinergic signaling in viral infection, replication and host responses that can assist or hinder viral functions. An overview of the involvement of purinergic signaling among a range of viruses is compared and contrasted with what is currently understood for SARS-CoV-2. In particular, we focus on the inflammatory and antiviral responses of infected cells mediated by purinergic receptor activation. Although there is considerable variation in a patient's response to SARS-CoV-2 infection, a principle immediate concern in Coronavirus disease (COVID-19) is the possibility of an aberrant inflammatory activation causing diffuse lung oedema and respiratory failure. We discuss the most promising potential interventions modulating purinergic signaling that may attenuate the more serious repercussions of SARS-CoV-2 infection and aspects of their implementation.

Keywords: P1 receptors; P2 receptors; SARS-CoV-2; extracellular ATP; extracellular adenosine; virus.

Figure 1

Viral infection and purinergic signalling. Viruses infecting eucariotic cells induce the release of intracellular nucleotides (ATP, ADP, UTP, UDP) by different ways (connexins, pannexins, membrane stress or damage) activating purinergic P2 (P2X and P2Y) and P1 (A₁, A_2A, A_2B, A₃) receptors and inducing pro- or anti-viral responses depending on virus species, cell type and purinergic receptors expressed. ATP and ADP are hydrolyzed by CD39 and CD73 ecto-nucleotidases generating adenosine (ADO) that is agonist at P1 receptors.

Figure 2

Nucleotide induced defensive responses. (A) ATP and P2X7 dependent immunological response to DENV. Dendritic cells (DC) and Tγδ lymphocytes (Tγδ) major responders against Dengue-2 virus (DENV) infection. Binding of DC P2X7 receptor by extracellular ATP activates Tγδ to produce of interferon-γ (IFN-γ), potentiating the antiviral immune response (59). (B) ADP and P2Y₁₃-dependent antiviral response. Replication of viruses as different as vesicular stomatitis virus (VSV), Newcastle disease virus (NDV), herpes simplex virus 1 (HSV-1) and murine leukemia virus (MLV) is restricted by massive release of ADP from infected cells; (IFN-γ) up-regulates the ADP activated P2Y₁₃ receptor (60). (C) UDP and P2Y₆-mediated response against VSV infection. Murine embryonic fibroblasts (MEF), bone marrow-derived macrophages (BMDM), RAW264.7 or L929 cell lines release UDP upon infection with vesicular stomatitis virus (VSV). The nucleotide activates P2Y₆ receptor and induces interferon-β (IFN-β) secretion (49). Bone marrow-derived macrophages (BMDM), peritoneal macrophages (PEM). (D) ATP and P2X7-mediated response against VSV infection. RAW264.7 or L929 cell lines release ATP upon infection with vesicular stomatitis virus (VSV). The nucleotide activates P2X7 receptor and induces interferon-β (IFN-β) secretion (48).

Figure 3

Schematic representation of purinergic signalling involvement in SARS-Cov-2 infection. Engagement of SARS-Cov-2 virus with ACE2 receptors causes angiotensin II accumulation and production of oxygen radicals (ROS) by NADPH oxidases (NOXes). ROS inhibit 11 beta-hydroxysteroid dehydrogenase (11ßHSD), the enzyme transforming cortisol into cortisone. Cortisol accumulation activates unprotected mineralocorticoid (type I) receptor (MR). Both ROS and MR stimulate ATP release from the cell. Activation of P2X and P2Y receptors by ATP increases intracellular Ca²⁺ concentration [Ca²⁺]_i evoking cell contraction and exocytosis of lysosomes containing ATP from the apical surface of the cell, resulting in a further increase in extracellular ATP concentration and in NALP-3 activation.