Regulation of the Acute Sickness Response by the P2RX7 Receptor

Abstract

Introduction The acute sickness response to infection is a stereotyped set of illness manifestations initiated by pro-inflammatory signals in the periphery, but mediated centrally. P2X7 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. Methods Associations between P2X7 genotype, pore activity, and illness manifestations were examined in a cohort with acute viral and bacterial infections (n=484). Genotyping of 12 P2X7 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 (IL)-1β release. Associations were sought with scores describing the symptom domains, or endophenotypes, derived from principal components analysis. Results Among the 12 SNPs, a four-SNP haplotype block with five 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. Conclusion P2X7 signalling plays a significant role in the acute sickness response to infection, likely acting in both the immune system and the brain.

Predictors of Chronic Fatigue Syndrome and Mood Disturbance After Acute Infection

“…The SNPs positively associated with illness severity included those in: immunological genes including the NLRP3 inflammasome ( 22 ), the pro-inflammatory cytokine genes [interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ] ( 14 , 18 ) and the anti-inflammatory cytokine, IL-10 gene ( 18 ). In addition, functional SNPs in the gene encoding the purinergic P2X7 receptor, which is widely expressed in the immune system and brain, have also been associated with illness severity and duration ( 36 ). Additionally, individual symptom domains or endophenotypes of the illness complex have been differentially associated such as an IFN-γ SNP with fatigue, an IL-6 SNP with mood disturbance, and an IL-10 SNP with neurocognitive difficulties ( 14 ).…”

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“…For example, interferon injection reproducibly triggers a physiologic and behavioral syndrome of fatigue, fever, headache, muscle aches and other symptoms such as social withdrawal that are indistinguishable from authentic viral infections [77]. This set of behaviors is evolutionarily conserved and known as stereotyped sickness behavior [78], which has been shown recently to be initiated by purinergic signaling [79].…”

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