Lysophosphatidylcholine: A Novel Modulator of Trypanosoma cruzi Transmission

Hindawi Publishing Corporation Journal of Parasitology Research Volume 2012, Article ID 625838, 8 pages doi:10.1155/2012/625838 Review Article Lysophosphatidylcholine: A Novel Modulator of Trypanosoma cruzi Transmission Mário A. C. Silva-Neto,1, 2 Alan B. Carneiro,1, 2 Livia Silva-Cardoso,1, 2 and Georgia C. Atella1, 2 1 Instituto de Bioquı́mica Médica at Universidade Federal do Rio de Janeiro (UFRJ), 21940-590 Rio de Janeiro, RJ, Brazil 2 Instituto Nacional de Ciência e Tecnologia em Entomologia Molecular (INCT), 21940-902 Rio de janeiro, RJ, Brazil Correspondence should be addressed to Mário A. C. Silva-Neto, Received 29 April 2011; Revised 29 July 2011; Accepted 12 September 2011 Academic Editor: Dario Zamboni Copyright © 2012 Mário A. C. Silva-Neto et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Lysophosphatidylcholine is a bioactive lipid that regulates a large number of cellular processes and is especially present during the deposition and infiltration of inflammatory cells and deposition of atheromatous plaque. Such molecule is also present in saliva and feces of the hematophagous organism Rhodnius prolixus, a triatominae bug vector of Chagas disease. We have recently demonstrated that LPC is a modulator of Trypanosoma cruzi transmission. It acts as a powerful chemoattractant for inflammatory cells at the site of the insect bite, which will provide a concentrated population of cells available for parasite infection. Also, LPC increases macrophage intracellular calcium concentrations that ultimately enhance parasite invasion. Finally, LPC inhibits NO production by macrophages stimulated by live T. cruzi, and thus interferes with the immune system of the vertebrate host. In the present paper, we discuss the main signaling mechanisms that are likely used by such molecule and their eventual use as targets to block parasite transmission and the pathogenesis of Chagas disease. 1. Immune Response to Trypanosoma cruzi Infection in the Vertebrate Host T. cruzi infects the vertebrate host through bite wounds produced in skin by a feeding bug or through the interaction of the parasite with conjunctival mucosa. Such interaction sometimes produces visible signs called Romaña’s sign or chagoma inoculation. The histology of this initial site of infection is defined by an elevated number of mononuclear cells [1]. This first sign of infection suggests that T. cruzi can stimulate skin cells to produce mediators that trigger a local inflammatory response. Despite controversies about the mechanism of the pathogenesis of Chagas disease [2–5], until recently, some authors believed that the disease was limited to an acute phase, followed by a chronic phase that was considered an autoimmune disease, where the parasites would be physically linked to sites of inflammation in the heart and esophagus [6–8]. However, nowadays, the disease is considered multifactorial, with multiple and continuous interactions between pathogen and host [9]. After the incubation period of 2 to 3 weeks, infection with T. cruzi is manifested by the presence of a large number of parasites in the blood and tissues. Acute infection is accompanied by an excessive activation of the immune system that includes the production of high levels of cytokines, intense activation of T and B cells, lymphadenopathy, splenomegaly, and intense inflammation associated with tissue infection niches. The acute phase induces the development of an effective acquired immunity leading to the control of parasitemia. The chronic phase is considered lifelong and is associated with only a few parasites in the host. The beginning of chronic infection with T. cruzi is asymptomatic in most patients. However, with the advance of the disease, clinical manifestations become variable, ranging from no symptoms to the involvement of cardiovascular and/or gastrointestinal symptoms [10, 11]. Before the acquired immunity is established, the innate immune system appears to be essential for at least two important aspects of Chagas disease: control of replication of the parasite in the host tissue and progress of the inflammatory reaction. The latter, in turn, has been considered to be 2 the main cause of tissue damage and dysfunction of certain organs in the host [11]. Some studies in experimental models of infection of T. cruzi suggest that the potent immune response to Th-1 CD4 and CD8 cells, with the production of specific inflammatory cytokines, such as interferon gamma (IFN-γ), tumour necrosis factor (TNF-α), and interleukin 12 (IL-12), as well as the production of reactive nitrogen species such as nitric oxide (NO), plays an important role in the control of parasitemia during the initial stage of the disease [4, 10–13]. Moreover, cells of innate immunity, such as natural killer (NK) cells, dendritic cells, and macrophages, are also key elements in the initial control of parasite replication [10–13]. In recent years, research on Chagas disease has focused on the investigation of the role of pathogen-associated molecular patterns (PAMPs) of protozoa, which are the targets of innate immune receptors. Also, the problem of identifying relevant receptors in innate immunity-parasite interactions during the evolution of the disease in the host has been addressed by several laboratories. This strategy ultimately aims at the development of therapeutic interventions through the use of PAMPs derived from parasites. Glycosyl-phosphatidyl-inositol (GPI) is the name given to the first glycoconjugate in T. brucei that was identified with the function of anchoring proteins on the cell surface [14– 17]. PAMPs widely studied in T. cruzi are, in fact, GPI anchors. All evolutive forms of this parasite express on their surface GPI-anchored glycoproteins [14–17]. Some studies have identified GPI anchors isolated from trypomastigotederived mucin-like glycoproteins (GPI-mucins) of T. cruzi as the molecules primarily responsible for stimulating the host immune system [18, 19]. Thus, T. cruzi GPI-mucins are able to activate macrophages and stimulate the production of proinflammatory cytokines, chemokines, and NO [20– 22]. Innate immune response to T. cruzi has been studied extensively and is based on the activation of signaling pathways triggered by Toll-like receptors (TLRs). TLRs are proteins that recognize conserved motifs associated with several different pathogens; they trigger intracellular signaling cascades that ultimately lead to a complex host immune response [11, 12]. There are 10 TLRs described in humans and 12 in mice [11, 12]. Generally, the stimulus induced by GPI molecules occurs during the early phase of infection, where macrophages respond to trypomastigotes in a TLR-dependent mechanism and ultimately induce the production of IL-12 and TNF-α and trigger the responses of CD4 (...truncated)