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The role of the P2X₇ receptor in infectious diseases

Catherine M Miller1, Nicola R Boulter, Stephen J Fuller

  • 1Institute for the Biotechnology of Infectious Diseases, University of Technology, Sydney, Broadway, New South Wales, Australia.

Plos Pathogens
|November 22, 2011
PubMed

Insights

Adenosine triphosphate (ATP) signals through the P2X₇ receptor, a key player in immune responses and infectious diseases. Genetic variations in this receptor impact susceptibility to pathogens, highlighting its critical role in host defense.

Area of Science:

  • Immunology
  • Cell Biology
  • Pathogen-Host Interactions

Background:

  • Extracellular adenosine triphosphate (ATP) serves as a crucial danger signal for the immune system, especially during inflammation.
  • The P2X₇ receptor is a primary sensor for extracellular ATP, with its expression elevated by pro-inflammatory cytokines.
  • The P2X₇ receptor plays a significant role in initiating host defense mechanisms against pathogens, particularly those infecting macrophages.

Purpose of the Study:

  • To elucidate the multifaceted roles of the P2X₇ receptor in immune signaling and host defense against infectious agents.
  • To explore how P2X₇ receptor activation influences various intracellular pathways, including inflammasome activation, apoptosis, and reactive intermediate generation.
  • To investigate the genetic basis of infectious disease susceptibility and resistance linked to P2X₇ receptor polymorphisms.

Main Methods:

  • Analysis of P2X₇ receptor signaling pathways, including inflammasome activation, stress-activated protein kinase, mitogen-activated protein kinase, and phospholipase D.
  • Investigation of P2X₇ receptor's role in macrophage-mediated pathogen clearance.
  • Review of genetic studies linking P2X₇ receptor polymorphisms to infectious disease outcomes.

Main Results:

  • P2X₇ receptor activation triggers cation channel opening, altering cellular ionic environments and activating key inflammatory and cell death pathways.
  • Activated pathways include inflammasome (IL-1β, IL-18 production), SAPK (apoptosis), MAPK (ROS/RNS generation), and phospholipase D (phagosome-lysosome fusion).
  • Genetic studies reveal significant associations between P2X₇ receptor variants and susceptibility/resistance to parasitic and bacterial infections.

Conclusions:

  • The P2X₇ receptor is a critical mediator of immune responses to extracellular ATP, influencing host defense and pathogen interactions.
  • Pathogens can exploit the P2X₇ receptor to manipulate host responses.
  • P2X₇ receptor polymorphisms are important determinants of infectious disease susceptibility, underscoring its clinical relevance.

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