The Role of Purinergic Signaling in Human Cytomegalovirus Infection

Abstract

Human cytomegalovirus (HCMV) is highly prevalent and easily transmissible. Though typically asymptomatic in healthy individuals, the virus can cause lifethreatening disease in immunocompromised patients, debilitating birth defects in newborns, and has been increasingly associated with a wide range of chronic conditions. Such broad clinical implications result from the modulation of multiple host cell processes that occurs during viral infection. In this study, we investigate the biological role that infection-related manipulation of cellular purinergic signaling plays in the HCMV life cycle. Preliminary data from RNA sequencing show that purinergic receptors P2Y2 and P2X5, as well as ectonucleotidases ENPP4 and ENTPD2 are overexpressed in HCMV-infected fibroblast cells. An analysis of the kinetics of purinergic receptor expression shows that P2Y2 and P2X5 transcript levels are elevated in HCMV-infected cells at 24hpi compared to mock-infected controls and remain so for the rest of the infection. Viral binding is not sufficient to induce the upregulation of P2Y2 transcripts. Inhibiting the expression or activity of P2Y2 and P2X5 receptors reduces the transcript levels of various classes of viral genes and alters the release of infectious progeny, but does not affect viral entry. It is proposed that the P2Y2 receptor may be an important regulator of calcium homeostasis and viral DNA synthesis. P2X5 may be involved in cell cycle regulation. Future studies should work to elucidate the exact mechanisms by which purinergic inhibition influences viral gene expression and progeny release. Based on the results presented here, we speculate that blocking P2Y2 receptor activity has the potential to become an attractive novel treatment option for HCMV infection.