P2RX7 at the Host-Pathogen Interface of Infectious Diseases

Abstract

The P2X7 receptor (P2RX7) is an important molecule that functions as a danger sensor, detecting extracellular nucleotides from injured cells and thus signaling an inflammatory program to nearby cells. It is expressed in immune cells and plays important roles in pathogen surveillance and cell-mediated responses to infectious organisms. There is an abundance of literature on the role of P2RX7 in inflammatory diseases and the role of these receptors in host-pathogen interactions. Here, we describe the current knowledge of the role of P2RX7 in the host response to a variety of pathogens, including viruses, bacteria, fungi, protozoa, and helminths. We describe in vitro and in vivo evidence for the critical role these receptors play in mediating and modulating immune responses. Our observations indicate a role for P2X7 signaling in sensing damage-associated molecular patterns released by nearby infected cells to facilitate immunopathology or protection. In this review, we describe how P2RX7 signaling can play critical roles in numerous cells types in response to a diverse array of pathogens in mediating pathogenesis and immunity to infectious agents.

Keywords: P2RX7; infection; inflammasome; inflammatory; purinergic.

FIG 1

P2RX7 structure and function. (A) The P2RX7 monomer is shown with two transmembrane regions and cytoplasmic C and N termini. (B) The P2RX7 homotrimer is shown with three submits in both a side view and a top view. (C) The P2RX7 homotrimer is shown in the cell membrane with ATP binding pockets indicated; when ATP is bound, the P2RX7 can mediate cation flux, including calcium and potassium.

FIG 2

P2RX7 signaling. P2RX7 signaling is dependent upon detection of extracellular ATP, whose export is mediated by Panx1 (pannexin). Multiple signaling can arise from this receptor activation. Calcium update can activate the phagolysosome through RhoA and phospholipase D and through p38, which can lead to assembly of NADPH oxidase with generation of superoxide (O₂⁻) to facilitate transcription of inducible nitric oxide synthase (iNOS), production of nitric oxide (NO), and transcription of NF-κB-dependent inflammatory cytokines in concert with Toll-like receptor (TLR) signaling. Potassium efflux results in reduced intracellular potassium levels that can activate either apoptosis through SAPK/JNK or pyroptosis through the NLRP3 inflammasome, with caspase-1 activation and release of IL-1β and IL-18.

FIG 3

Interaction of various pathogen types and the impact on P2RX7 signaling. Pathogens can interface with host organisms and interfere with P2RX7 signaling through six main mechanisms. E. coli, P. gingivalis, and L. amazonensis are examples of organisms that disrupt membrane integrity through P2RX7 function. Multiple organisms have demonstrated mechanisms of interference with caspase-1 secretion and pyroptosis, including influenza virus, HIV, S. aureus, S. pneumoniae, S. pyogenes, B. anthracis, V. fluvialis, A. actinomycetemcomitans, M. tuberculosis, P. chabaudi, T. gondii, E. histolytica, and Paracoccidioides brasiliensis. Several organisms have demonstrated interferences with NK-kB-dependent cytokine production, including DENV, HIV, S. aureus, C. difficile, T. gondii, Schistosoma, H. polygyrus, and T. spiralis. Both DENV and T. gondii can interfere with ROS and NO production. M. tuberculosis, Chlamydia, and T. gondii interfere with phagosome-lysosome fusion. Finally, several organisms can interfere with apoptotic cell death, including C. perfringens, P. aeruginosa, M. tuberculosis, P. chabaudi, L. amazonensis, and T. cruzi.