Pegoraro Anna, Bortolotti Daria, Marci Roberto, Caselli Elisabetta, Falzoni Simonetta, De Marchi Elena, Di Virgilio Francesco, Rizzo Roberta, Adinolfi Elena
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
Department of Medical Sciences, University of Ferrara, Ferrara, Italy.
Front Pharmacol. 2020 Feb 21;11:96. doi: 10.3389/fphar.2020.00096. eCollection 2020.
The P2X7 receptor (P2X7R) is an ATP-gated ion channel known for its proinflammatory activity. Despite its participation in host defense against pathogens, the role played in viral infections, notably those caused by herpes viruses, has been seldom studied. Here we investigated the effect of P2X7R expression on human herpes virus 6 A (HHV-6A) infection of P2X7R-expressing HEK293 cells. We show that functional P2X7R increases while its blockade decreases viral load. Interestingly, HHV-6A infection was enhanced in HEK293 cells transfected with P2X7R cDNA bearing the gain of function 489C>T SNP (rs208294, replacing a histidine for tyrosine at position 155). The P2X7R 489C>T polymorphism correlated with HHV-6A infection also in a cohort of 50 women affected with idiopathic infertility, a condition previously shown to correlate with HHV-6A infection. None of the infertile women infected by HHV-6A was homozygote for 489CC genotype, while on the contrary HHV-6A infection significantly associated with the presence of the rs208294 allele. Levels of soluble human leukocyte antigen G (sHLA-G), a factor promoting embryo implant, measured in uterine flushings negatively correlated with the 489TT genotype and HHV-6A infection, while proinflammatory cytokines interleukins 1α (IL-1α), 1β (IL-1β), and 8 (IL-8) positively correlated with both the 489T allele presence and viral infection. Taken together these data point to the P2X7R as a new therapeutic target to prevent HHV-6A infection and the associated infertility.
P2X7受体（P2X7R）是一种以其促炎活性而闻名的ATP门控离子通道。尽管它参与宿主对病原体的防御，但在病毒感染尤其是由疱疹病毒引起的感染中所起的作用却很少被研究。在此，我们研究了P2X7R表达对表达P2X7R的HEK293细胞感染人疱疹病毒6A（HHV-6A）的影响。我们发现功能性P2X7R增加时病毒载量增加，而其被阻断时病毒载量减少。有趣的是，在转染了携带功能获得性489C>T单核苷酸多态性（rs208294，在第155位将组氨酸替换为酪氨酸）的P2X7R cDNA的HEK293细胞中，HHV-6A感染增强。在一组50名患有特发性不孕症的女性中，P2X7R 489C>T多态性也与HHV-6A感染相关，特发性不孕症此前已被证明与HHV-6A感染相关。感染HHV-6A的不孕女性中没有一个是489CC基因型的纯合子，相反，HHV-6A感染与rs208294等位基因的存在显著相关。在子宫冲洗液中测得的可溶性人类白细胞抗原G（sHLA-G）水平，sHLA-G是一种促进胚胎着床的因子，与489TT基因型和HHV-6A感染呈负相关，而促炎细胞因子白细胞介素1α（IL-1α）、1β（IL-1β）和8（IL-8）与489T等位基因的存在和病毒感染均呈正相关。综合这些数据表明，P2X7R是预防HHV-6A感染及相关不孕症的一个新的治疗靶点。
