IFN-stimulated P2Y13 protects mice from viral infection by suppressing the cAMP/EPAC1 signaling pathway

Abstract

Among the most important sensors of extracellular danger signals, purinergic receptors have been demonstrated to play crucial roles in host defense against infection. However, the function of P2 receptors in viral infection has been little explored. Here we demonstrated that P2Y13 and its ligand ADP play an important role in protecting hosts from viral infections. First, we demonstrate that P2Y13, as a typical interferon-stimulated gene (ISG), is induced together with extracellular ADP during viral infection. Most importantly, extracellular ADP restricts the replication of different kinds of viruses, including vesicular stomatitis virus (VSV), Newcastle disease virus (NDV), herpes simplex virus 1 (HSV-1), and murine leukemia virus (MLV). This kind of protection is dependent on P2Y13 but not P2Y1 or P2Y12, which are also considered as receptors for ADP. Furthermore, cyclic adenosine monophosphate (cAMP) and EPAC1 are downregulated by extracellular ADP through the P2Y13-coupled Gi alpha subunit. Accordingly, inhibition or deletion of EPAC1 significantly eliminates ADP/P2Y13-mediated antiviral activities. Taken together, our results show that P2Y13 and ADP play pivotal roles in the clearance of invaded virus and have potential as antiviral targets.

The P2X7 Receptor 489C>T Gain of Function Polymorphism Favors HHV-6A Infection and Associates With Female Idiopathic Infertility

“…Purinergic signaling is known to participate in viral infection and replication, and in anti-viral inflammatory responses and, consequently, purinergic receptors have been proposed as targets for antiviral therapy (Ferrari et al, 2018;Savio et al, 2018;Zhang et al, 2019). Among P2 purinergic receptors, the P2X7R is one of the best candidates for such intervention as its activity in promoting or inhibiting viral infection, or alternatively its ability to support antiviral responses was widely demonstrated.…”

The roles of microglia in viral encephalitis: from sensome to therapeutic targeting

“…In vitro studies with bone marrow-derived macrophages showed that P2RY13, but not P2RY12, may be an interferon-stimulated gene (ISG), as P2RY13 expression is enhanced after TLR3 stimulation or interferon (IFN) treatment. 67 Interestingly, it has been shown that P2RY12 expression is decreased in microglia during the development of viral encephalitis 32 and other pathologies. 68 Since microglia express both P2RY12 and P2RY13 under homeostatic conditions, 56 we propose a model in which P2RY12 signaling on microglia allows their recruitment to infected/injured cells during the early events after viral infection of CNS cells.…”

Metabolite-Sensing G Protein Coupled Receptor TGR5 Protects Host From Viral Infection Through Amplifying Type I Interferon Responses

“…For example, CXC-chemokine receptor-4 (CXCR4) and CC-chemokine receptor-5 (CCR5) are cell fusion co-receptors for HIV infection ( 10 ). Meanwhile, our previous studies have demonstrated that P2Y 6 ( 11 ), P2Y 13 ( 12 ), GPR146 ( 13 ), LGR4 ( 14 ), and GPR54 ( 15 ) are all related to viral infection in distinctive manners. Thus, identification of additional GPCRs in viral infection and related immune responses may be clinically important in the prevention and control of viral infectious diseases.…”