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, 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, Newcastle disease virus, herpes simplex virus 1, and murine leukemia virus. 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 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 the potential as antiviral targets.
Subject(s)
Cyclic AMP/metabolism , Gene Expression/drug effects , Guanine Nucleotide Exchange Factors/metabolism , Interferons/pharmacology , Receptors, Purinergic P2/metabolism , Adenosine Diphosphate/pharmacology , Animals , Cell Line , Cell Survival/drug effects , Guanine Nucleotide Exchange Factors/deficiency , Guanine Nucleotide Exchange Factors/genetics , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, Purinergic P2/deficiency , Receptors, Purinergic P2/genetics , Rhabdoviridae Infections/mortality , Rhabdoviridae Infections/pathology , Rhabdoviridae Infections/prevention & control , Rhabdoviridae Infections/veterinary , Signal Transduction/drug effects , Survival Rate , Vesiculovirus/genetics , Vesiculovirus/pathogenicity , Virus Replication/drug effectsABSTRACT
Accumulating evidence shows that innate immune responses are associated with extracellular nucleotides, particularly ATP. In this article, we demonstrate extensive protection of ATP/P2X7 signaling in a host against viral infection. Interestingly, we observed a significant increase in ATP as a danger signal in vesicular stomatitis virus (VSV)-infected cell supernatant and VSV-infected mice in an exocytosis- and pannexin channel-dependent manner. Furthermore, extracellular ATP reduces the replication of VSV, Newcastle disease virus, murine leukemia virus, and HSV in vivo and in vitro through the P2X7 receptor. Meanwhile, ATP significantly increases IFN-ß expression in a concentration- and time-dependent manner. Mechanistically, ATP facilitates IFN-ß secretion through P38/JNK/ATF-2 signaling pathways, which are crucial in promoting antiviral immunity. Taken together, these results demonstrate the protective role of extracellular ATP and P2X7 in viral infection and suggest a potential therapeutic role for ATP/P2X7 in viral diseases.
