Aspirin Treatment of Mice Infected with Trypanosoma cruzi and Implications for the Pathogenesis of Chagas Disease

et al. (2011) Aspirin Treatment of Mice Infected with Trypanosoma cruzi and Implications for the Pathogenesis of Chagas Disease. PLoS ONE 6(2): e16959. doi:10.1371/journal.pone.0016959 Aspirin Treatment of Mice Infected with Trypanosoma cruzi and Implications for the Pathogenesis of Chagas Disease Shankar Mukherjee 0 Fabiana S. Machado 0 Huang Huang 0 Helieh S. Oz 0 Linda A. Jelicks 0 Cibele M. 0 Prado 0 Wade Koba 0 Eugene J. Fine 0 Dazhi Zhao 0 Stephen M. Factor 0 J. Elias Collado 0 Louis M. 0 Weiss 0 Herbert B. Tanowitz 0 Anthony W. Ashton 0 Photini Sinnis, New York University School of Medicine, United States of America 0 1 Division of Parasitology, Department of Pathology, Albert Einstein College of Medicine, New York City, New York, United States of America, 2 Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais , Belo Horizonte , Brazil , 3 Center for Oral Health Research, University of Kentucky Medical Center, Lexington, Kentucky, United States of America, 4 Department of Nuclear Medicine and the M. Donald Blaufox Laboratory for Molecular Imaging, Physiology and Biophysics, Albert Einstein College of Medicine, New York City, New York, United States of America, 5 Division of Infectious Disease, Department of Medicine, Albert Einstein College of Medicine, New York City, New York, United States of America, 6 Department of Pathology, University of Sa o Paulo, Ribeira o Preto, Brazil, 7 Division of Perinatal Research, Kolling Institute for Medical Research, University of Sydney , Sydney , Australia Chagas disease, caused by infection with Trypanosoma cruzi, is an important cause of cardiovascular disease. It is increasingly clear that parasite-derived prostaglandins potently modulate host response and disease progression. Here, we report that treatment of experimental T. cruzi infection (Brazil strain) beginning 5 days post infection (dpi) with aspirin (ASA) increased mortality (2-fold) and parasitemia (12-fold). However, there were no differences regarding histopathology or cardiac structure or function. Delayed treatment with ASA (20 mg/kg) beginning 60 dpi did not increase parasitemia or mortality but improved ejection fraction. ASA treatment diminished the profile of parasite- and host-derived circulating prostaglandins in infected mice. To distinguish the effects of ASA on the parasite and host bio-synthetic pathways we infected cyclooxygenase-1 (COX-1) null mice with the Brazil-strain of T. cruzi. Infected COX-1 null mice displayed a reduction in circulating levels of thromboxane (TX)A2 and prostaglandin (PG)F2a. Parasitemia was increased in COX-1 null mice compared with parasitemia and mortality in ASA-treated infected mice indicating the effects of ASA on mortality potentially had little to do with inhibition of prostaglandin metabolism. Expression of SOCS-2 was enhanced, and TRAF6 and TNFa reduced, in the spleens of infected ASA-treated mice. Ablation of the initial innate response to infection may cause the increased mortality in ASA-treated mice as the host likely succumbs more quickly without the initiation of the ''cytokine storm'' during acute infection. We conclude that ASA, through both COX inhibition and other ''off-target'' effects, modulates the progression of acute and chronic Chagas disease. Thus, eicosanoids present during acute infection may act as immunomodulators aiding the transition to and maintenance of the chronic phase of the disease. A deeper understanding of the mechanism of ASA action may provide clues to the differences between host response in the acute and chronic T. cruzi infection. - Funding: This work was supported by grants from the United States National Institutes of Health (HBT [AI-76248]) and the National Health and Medical Research Council of Australia (AWA [512154]). The work was also supported by a Career Development Award from the American Heart Association (SM [0735252N]), the National Health and Medical Research Council of Australia (AWA [402847]), the Conselho Nacional de Desenvolvimento Cientfico e Tecnolo gico (CNPq) (FSM [576200/2008-5, 473670/2008-9]), and the Fundacao de Amparo a` Pesquisa do Estado de Minas Gerais (FAPEMIG) (FSM [14916]). CMP was supported by a Fogarty International Training Grant (HBT [D43TW007129]). The funding bodies indicated had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work In Latin America millions of people are at risk of infection with the parasite Trypanosoma cruzi, the cause of Chagas disease. The cardiac manifestations are the most prominent symptoms of disease. Acute myocarditis is accompanied by an intense inflammatory response including upregulation of inflammatory mediators such as cytokines, chemokines, nitric oxide and endothelin-1 [16]. As the acute infection wanes individuals may remain asymptomatic; however, 10 to 30% of infected individuals ultimately develop chronic cardiomyopathy [7]. Manifestations during this stage of the disease include congestive heart failure, conduction abnormalities and thrombo-embolic events [7,8]. The etiology of the chronic cardiomyopathy is primarily the result of parasite persistence but may also result from microvascular spasm with focal ischemia and autoimmune mechanisms [4,5,911]. Our group has investigated the etiology of vascular spasm in the setting of T. cruzi infection. In this regard, we suggested as early as 1990 that the eicosanoid, thromboxane (TX)A2 contributed to T. cruziassociated vasospasm and platelet aggregation [12]. Eicosanoids are a family of lipid mediators that participate in a wide range of biological activities including vascular tone, inflammation, ischemia and tissue homeostasis [13]. In mammals, the biosynthetic pathways for these important biological mediators are well described. Arachidonic acid (AA), derived from membrane phospholipids on the inner leaflet of the plasma membrane by phospholipase A2, is hydrolyzed by the prostaglandin (PG)H synthase/cyclooxygenase (COX) enzymes to PGH2 [14]. PGH2 is the central substrate for subsequent eicosanoid synthesis which is mediated by species-specific synthases to generate PGs and TXA2 [15]. Enzymes in the COX family are structurally and enzymatically similar but have different pathophysiological roles. COX-1 is constitutive and mediates gastric mucus production, platelet activation and vascular tone while COX-2 is inducible and functions in inflammation, cancer and tissue damage [13,14]. The relevance of these enzymes, and the bioactive lipids they produce, are not well understood in parasitic disease. Phospholipase A1 (PLA1) the enzyme that initiates the AA metabolic pathway by cleaving the Sn-1 acyl chain was reported in T. brucei [16,17]. PGF2a synthases have been identified in Leishmania, T. cruzi (Old Yello (...truncated)