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)A2 and prostaglandin (PG)F2α. 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.

Role of the Aryl Hydrocarbon Receptor in the Immune Response Profile and Development of Pathology during Plasmodium berghei Anka Infection

“…The suppressor of cytokine signaling (SOCS) family plays an important role in immune responses by modulating cytokine signaling pathways, and AhR has been shown to modulate SOCS2 expression in the mouse model of T. gondii infection (46). SOCS2 is also induced during T. cruzi infection (52) and was shown to be modulated as a result of aspirin treatment (53). Therefore, we examined SOCS1, -2, and -3 expression in the brain tissue of infected mice.…”

Inhibition of Cyclooxygenase-1 and Cyclooxygenase-2 Impairs Trypanosoma cruzi Entry into Cardiac Cells and Promotes Differential Modulation of the Inflammatory Response

“…Previous studies have shown that the release of eicosanoids during infection with T. cruzi regulates host responses and controls disease progression (10,(27)(28)(29)(30)(31). PGs, together with NO and TNF-␣, participate in a complex circuit that controls lymphoproliferative and cytokine responses in T. cruzi infection (28).…”

The Absence of Myocardial Calcium-Independent Phospholipase A 2 γ Results in Impaired Prostaglandin E 2 Production and Decreased Survival in Mice with Acute Trypanosoma cruzi Infection

“…More recent studies by Ashton et al have suggested that TXA 2 is an important parasite-derived eicosanoid that contributes to parasite proliferation and hence the inflammatory response (28). Several studies also suggest that eicosanoids, in conjunction with cytokines, chemokines, and other inflammatory mediators, are essential for the progression and perpetuation of the chronic phase of the disease (9,29). Since PLA 2 is critical for arachidonic acid release and eicosanoid production, it could con- tribute to the pathogenesis of Chagas' disease via the formation of these mediators.…”

“…A key pathological feature of Chagas' disease is inflammation, which is regulated by several mediators, including adhesion molecules, cytokines, eicosanoids, and nitric oxide (6)(7)(8). In the acute stage, these molecules are seen to be important for the development of host resistance, as well as regulating progression to the chronic stages of the disease (9). However, much remains unknown about the host-parasite interactions that contribute to Chagas' disease via these mediators.…”