Role of extracellular nucleotides in the immune response against intracellular bacteria and protozoan parasites

Abstract

Extracellular nucleotides are danger signals involved in recognition and control of intracellular pathogens. They are an important component of the innate immune response against intracellular pathogens, inducing the recruitment of inflammatory cells, stimulating secretion of cytokines, and producing inflammatory mediators such as reactive oxygen species (ROS) and nitric oxide (NO). In the case of extracellular ATP, some of the immune responses are mediated through activation of the NLRP3 inflammasome and secretion of the cytokine, interleukin-1β (IL-1β), through a mechanism dependent on ligation of the P2X7 receptor. Here we review the role of extracellular nucleotides as sensors of intracellular bacteria and protozoan parasites, and discuss how these pathogens manipulate purinergic signaling to diminish the immune response against infection.

Fig. 1

Schematic overview of intracellular parasite elimination following ATP ligation of P2X7. (1) The presence of the parasite triggers a signaling cascade by members of the Toll-like receptor (TLR) family, (2) dephosphorylation of IκB allows NFκB translocation to the nucleous, (3) and expression of genes such as pro-IL-1β. (4) Ligation of P2X7 by extracellular ATP induces ROS production, (5) which can either directly stimulate parasite elimination or activate the NLRP3 inflammasome. (6) Activated caspase-1 cleaves pro-IL-1β, (7) generating the biologically active IL-1β, (8) which acts on its receptor and (9) contributes to the elimination of the parasites. (10) Additionally, PAMPs from parasites can enter the cell through the pannexin pores activated by extracellular ATP, (11) which in turn can also activate the NLRP3 inflammasome.

Fig. 2

Purinergic signaling cascade due to nucleotide activation of P2Y2 and P2Y4 during Leishmania amazonensis infection. A) There is little signaling through P2Y receptors in uninfected cells. B) In infected cells, enhanced PLC activation and NO and ROS production leads to intracellular calcium mobilization, NO and ROS production, and caspase-3-dependent host cell apoptosis. Taken together, these mechanisms eliminate the parasites or help to contain the infection.