Experimental Trypanosoma cruzi infection in platelet-activating factor receptor-deficient mice

Abstract

The generation of an inflammatory response driven by Trypanosoma cruzi or its subproducts appears to be essential for tissue injury and disease pathogenesis. However, this inflammatory response is also relevant in the control of T. cruzi replication. The lipid mediator platelet-activating factor (PAF) has been implicated in a number of pathological conditions characterized by tissue inflammation. In the present study, we aimed at evaluating the role of PAF during T. cruzi infection by using mice that were genetically deficient in the PAF receptor. We observed that infected hearts of PAFR(-/-) mice had an increased number of parasite nests, associated with a more intense inflammatory infiltrate. This was associated with greater parasitemia and lethality. When wild-type and PAFR(-/-) mice were compared, there were no marked changes in the kinetics of the expression of MCP-1, RANTES, IFN-gamma and TNF-alpha in heart tissue of infected animals. Moreover, serum concentrations of TNF-alpha, nitrate and parasite-specific IgM were similar in both groups of mice. In vitro, macrophages from PAFR(-/-) animals did not phagocytose trypomastigote forms when activated with PAF, leukotriene B(4) or MCP-1 and produced less nitric oxide when infected and activated with IFN-gamma. These results are consistent with the hypothesis that endogenous synthesis of PAF and activation of PAF receptors control T. cruzi replication in mice in great part via facilitation of the uptake of the parasite and consequent activation of macrophages.

Attenuation of Folic Acid-Induced Renal Inflammatory Injury in Platelet-Activating Factor Receptor-Deficient Mice

“…20 On the other hand, PAFR-KO mice showed exacerbation of infection models such as pulmonary gramnegative bacteria infection 41 and cardiac Trypanosoma infection. 42 Those reports, along with the present study, indicate that PAF causes both beneficial and deleterious effects by activating leukocytes in different circumstances.…”

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

“…It has been suggested that PAF induces the production of nitric oxide in T. cruzi-infected macrophages and hence is protective (36). PAFR Ϫ/Ϫ mice infected with T. cruzi were shown to have an increased number of parasite pseudocysts and inflammation in the heart and hence are more susceptible to infection than WT mice (37). In this study, cardiac myocytes infected with T. cruzi did not show a significant increase in PAF production.…”

Essential role of platelet-activating factor receptor in the pathogenesis of Dengue virus infection

“…In all experiments using PAFR Ϫ/Ϫ mice, experiments with the relevant WT controls were performed in parallel. The PAFR antagonist UK-74,505 (10 mg/kg/dose) (29,30) or vehicle (HCl 0.1%) were given orally twice a day from day 0, 3, 5, or 7 after infection. Mice were also treated with the structurally-distinct PAFR antagonist PCA-…”