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

Division of Parasitology, Department of Pathology, Albert Einstein College of Medicine, New York City, New York, United States of America.
PLoS ONE (Impact Factor: 3.23). 02/2011; 6(2):e16959. DOI: 10.1371/journal.pone.0016959
Source: PubMed


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.

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    ABSTRACT: Chagas disease is caused by Trypanosoma cruzi, a protozoan parasite. Chagas disease remains a serious health problem in large parts of Mexico and Central and South America, where it is a major cause of morbidity and mortality. This disease is being increasingly recognized in non-endemic regions due to immigration. Heart disease develops in 10-30% of infected individuals. It is increasingly clear that parasite- and host-derived bioactive lipids potently modulate disease progression. Many of the changes that occur during acute and chronic Chagas disease can be accounted for by the effects of arachidonic acid (AA)-derived lipids such as leukotrienes, lipoxins, H(P)ETEs, prostaglandins (PGs) and thromboxane. During the course of infection with T. cruzi, changes in circulating levels of AA metabolites are observed. Antagonism of PG synthesis with cyclooxygenase (COX) inhibitors has both beneficial and adverse effects. Treatment with COX inhibitors during acute infection may result in increased parasite load and mortality. However, treatment instituted during chronic infection may be beneficial with no increase in mortality and substantial improvement with cardiac function. Recently, T. cruzi infection of mice deficient in AA biosynthetic enzymes for various pathways has yielded more insightful data than pharmacological inhibition and has highlighted the potential deleterious effects of inhibitors due to "off-target" actions. Using COX-1 null mice, it was observed that parasite biosynthesis is dependent upon host metabolism, that the majority of TXA(2) liberated during T. cruzi infection is derived from the parasite and that this molecule may act as a quorum sensor to control parasite growth/differentiation. Thus, eicosanoids present during acute infection may act as immunomodulators aiding the transition to, and maintenance of, the chronic stage of the disease. It is also likely that the same mediators that initially function to ensure host survival may later contribute to cardiovascular damage. Collectively, the eicosanoids represent a new series of targets for therapy in Chagas disease with defined potential therapeutic windows in which to apply these agents for greatest effect. A deeper understanding of the mechanism of action of non-steroidal anti-inflammatory drugs may provide clues to the differences between host responses in acute and chronic T. cruzi infection.
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