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¹ Department of Medicine, Divisions of Cardiology and Infectious Disease, ² Department of Pathology, Parasitology and Tropical Medicine Section, ³ Department of Microbiology and Immunology, and ⁴ Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461
⁵ Department of Pharmacological Sciences, University of Milan, Milan 20133, Italy
⁶ Division of Nephrology, Department of Medicine, Duke University and Durham Veterans Affairs Medical Centers, Durham, NC 27705
⁷ Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, The Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
⁸ Vascular Biology Research Center, Institute of Molecular Medicine, Division of Hematology, University of Texas Health Science Center, Houston, TX 77030

CORRESPONDENCE Herbert B. Tanowitz: tanowitz{at}aecom.yu.edu

Chagas' disease is caused by infection with the parasite Trypanosoma cruzi. We report that infected, but not uninfected, human endothelial cells (ECs) released thromboxane A₂ (TXA₂). Physical chromatography and liquid chromatography-tandem mass spectrometry revealed that TXA₂ is the predominant eicosanoid present in all life stages of T. cruzi. Parasite-derived TXA₂ accounts for up to 90% of the circulating levels of TXA₂ in infected wild-type mice, and perturbs host physiology. Mice in which the gene for the TXA₂ receptor (TP) has been deleted, exhibited higher mortality and more severe cardiac pathology and parasitism (fourfold) than WT mice after infection. Conversely, deletion of the TXA₂ synthase gene had no effect on survival or disease severity. TP expression on somatic cells, but not cells involved in either acquired or innate immunity, was the primary determinant of disease progression. The higher intracellular parasitism observed in TP-null ECs was ablated upon restoration of TP expression. We conclude that the host response to parasite-derived TXA₂ in T. cruzi infection is possibly an important determinant of mortality and parasitism. A deeper understanding of the role of TXA₂ may result in novel therapeutic targets for a disease with limited treatment options.

Abbreviations used: AA, arachidonic acid; BFT, blood form trypomastigote; EC, endothelial cell; HUVEC, human umbilical vein endothelial cell; I-BOP, [1S-1,2(Z),3ß(1E,3S*),4]]- 7-[3-[3-hydroxy-4-(4- iodophenoxy)-1-butenyl]-7- oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid; ICAM, intercellular adhesion molecule; KO, knockout; LC-MS-MS, liquid chromatography-tandem mass spectrometry; PG, prostaglandin; PGF₂, prostaglandin F₂; SQ29548, [1S[1,2(Z),3,4]]-7-[3-[[2-[(phenylamino)carbonyl] hydrazine]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid; TcOYE, T. cruzi old yellow enzyme; TP, TXA₂ receptor; Trp, trypomastigotes; TXA₂, thromboxane A₂; TXA₂S, TXA₂ synthase; TXB2, thromboxane B₂; VCAM, vascular cell adhesion molecule.

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