Purinergic Signalling (2007) 3:83–90 DOI 10.1007/s11302-006-9039-6 REVIEW The role of P2 receptors in controlling infections by intracellular pathogens Robson Coutinho-Silva & Cristiane Monteiro da Cruz & Pedro M. Persechini & David M. Ojcius Received: 28 December 2005 / Accepted: 13 January 2006 / Published online: 12 January 2007 # Springer Science + Business Media B.V. 2007 Abstract A growing number of studies have demonstrated the importance of ATPe-signalling via P2 receptors as an important component of the inflammatory response to infection. More recent studies have shown that ATPe can also have a direct effect on infection by intracellular pathogens, by modulating membrane trafficking in cells that contain vacuoles that harbour intracellular pathogens, such as mycobacteria and chlamydiae. A conserved mechanism appears to be involved in controlling infection by both of these pathogens, as a role for phospholipase D in inducing fusion between lysosomes and the vacuoles has been demonstrated. Other P2-dependent mechanisms are most likely operative in the cases of pathogens, such as Leishmania, which survive in an acidic phagolysosomal- like compartment. ATPe may function as a “danger signal” that alerts the immune system to the presence of intracel- lular pathogens that damage the host cell, while different intracellular pathogens have evolved enzymes or other mechanisms to inhibit ATPe-mediated signalling, which should, thus, be viewed as virulence factors for these pathogens. Key words apoptosis . ATP . infection . inflammation . necrosis . purinergic receptors R. Coutinho-Silva (*) : C. Monteiro da Cruz : P. M. Persechini Programa de Imunobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ), Bloco G do CCS, Cidade Universitária, Ilha do Fundão, Rio de Janeiro 21941-590, Brazil e-mail: rcsilva@biof.ufrj.br C. Monteiro da Cruz : D. M. Ojcius School of Natural Sciences, University of California, Merced, CA, USA Abbreviations ATPe Extracellular ATP IL-1β Interleukin-1β IFN-+ Interferon-+ LPS Lipopolysaccharide PGE2 Prostaglandin E2 PLD Phospholipase D ROI Reactive oxygen intermediates RNI Reactive nitrogen intermediates TNF-! Tumour necrosis factor-! Introduction Intracellular pathogens invade, survive and replicate in mammalian cells, modulating host-cell membrane traffick- ing and cytoskeletal dynamics in order to establish persistent infection in the mammalian host [1–3]. Macro- phages are a frequent target of microbial infections, and they respond to microbial invasion by producing factors such as reactive nitrogen and oxygen intermediates (RNIs and ROIs) that have strong microbicidal activity [4]. But many pathogens have evolved different strategies for avoiding destruction by the macrophage. Some intracellular pathogens, such as Mycobacteria, inhabit a compartment whose endocytic maturation is delayed, while Chlamydiae survive within a membrane-bound vacuole that avoids fusion with lysosomes and maintains a neutral pH [5, 6]. Unlike Mycobacteria and Chlamydia, the protozoan para- site Leishmania thrives in a parasitophorous vacuole that has an acidic pH and high hydrolytic activity, and Trypanosoma cruzi actively induces its uptake into lyso- some-like host-cell vacuoles, from which, the parasite rapidly escapes into the cytosol [7–10].