title: Aspirin treatment of mice infected with Trypanosoma cruzi and implications for the pathogenesis of Chagas disease.
abstract: 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)A(2) and prostaglandin (PG)F(2α). 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 TNFα 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.
authors.affiliation: Division of Parasitology, Department of Pathology, Albert Einstein College of Medicine, New York City, New York, United States of America.
authors.forename: Shankar
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Fabiana S
authors.initials: FS
authors.lastname: Machado
authors.forename: Huang
authors.initials: H
authors.lastname: Huang
authors.forename: Helieh S
authors.initials: HS
authors.lastname: Oz
authors.forename: Linda A
authors.initials: LA
authors.lastname: Jelicks
authors.forename: Cibele M
authors.initials: CM
authors.lastname: Prado
authors.forename: Wade
authors.initials: W
authors.lastname: Koba
authors.forename: Eugene J
authors.initials: EJ
authors.lastname: Fine
authors.forename: Dazhi
authors.initials: D
authors.lastname: Zhao
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Factor
authors.forename: J Elias
authors.initials: JE
authors.lastname: Collado
authors.forename: Louis M
authors.initials: LM
authors.lastname: Weiss
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Tanowitz
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Ashton
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D001241:Aspirin / Q000494:pharmacology* / Q000627:therapeutic use; D014355:Chagas Disease / Q000188:drug therapy* / Q000378:metabolism / Q000469:parasitology / Q000503:physiopathology; D002908:Chronic Disease; D051545:Cyclooxygenase 1 / Q000172:deficiency / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D015777:Eicosanoids / Q000096:biosynthesis; D017353:Gene Deletion; D008297:Male; D051379:Mice; D018512:Parasitemia / Q000188:drug therapy / Q000378:metabolism / Q000469:parasitology / Q000503:physiopathology; D013318:Stroke Volume / Q000187:drug effects; D013930:Thromboxane-A Synthase / Q000172:deficiency / Q000235:genetics; D013997:Time Factors; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000472:pathogenicity*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D015777:Eicosanoids; D051545:Cyclooxygenase 1; D013930:Thromboxane-A Synthase; D001241:Aspirin