Viral Immunology Systems Program, Kirby Institute, University of New South Wales, Sydney, Australia.
Department of Human Behaviour, School of Psychiatry, University of New South Wales, Sydney, Australia.
J Infect Dis. 2021 Sep 1;224(5):914-920. doi: 10.1093/infdis/jiab027.
The acute sickness response to infection is a stereotyped set of illness manifestations initiated by proinflammatory signals in the periphery but mediated centrally. P2RX7 is a highly polymorphic gene encoding an ATP-gated cationic pore, widely expressed on immune cells and the brain, and regulating the NLRP3 inflammasome, as well as diverse neural functions.
Associations between P2RX7 genotype, pore activity, and illness manifestations were examined in a cohort with acute viral and bacterial infections (n = 484). Genotyping of 12 P2RX7 function-modifying single-nucleotide polymorphisms (SNPs) was used to identify haplotypes and diplotypes. Leucocyte pore activity was measured by uptake of the fluorescent dye, YO-PRO-1, and by ATP-induced interleukin-1β (IL-1β) release. Associations were sought with scores describing the symptom domains, or endophenotypes, derived from principal components analysis.
Among the 12 SNPs, a 4-SNP haplotype block with 5 variants was found in 99.5% of the subjects. These haplotypes and diplotypes were closely associated with variations in pore activity and IL-1β production. Homozygous diplotypes were associated with overall illness severity as well as fatigue, pain, and mood disturbances.
P2RX7 signaling plays a significant role in the acute sickness response to infection, likely acting in both the immune system and the brain.
感染引起的急性疾病反应是一种由外周炎症信号引发的刻板的疾病表现，但其介导中心位于中枢。P2RX7 是一个高度多态性的基因，编码一种 ATP 门控阳离子通道，广泛表达于免疫细胞和大脑，调节 NLRP3 炎症小体以及各种神经功能。
在急性病毒和细菌感染患者队列（n=484）中，研究了 P2RX7 基因型、孔活性与疾病表现之间的关系。通过对 12 个 P2RX7 功能改变单核苷酸多态性（SNP）的基因分型，鉴定了单倍型和二倍型。通过荧光染料 YO-PRO-1 的摄取和 ATP 诱导的白细胞介素 1β（IL-1β）释放来测量白细胞孔活性。通过主成分分析得到的症状域或表型相关分数，研究了与这些分数之间的关联。
在 12 个 SNP 中，发现了一个由 5 个变异体组成的 4-SNP 单倍型块，在 99.5%的研究对象中存在。这些单倍型和二倍型与孔活性和 IL-1β产生的变化密切相关。纯合二倍型与整体疾病严重程度以及疲劳、疼痛和情绪障碍有关。
P2RX7 信号在感染引起的急性疾病反应中起着重要作用，可能在免疫系统和大脑中都发挥作用。
