title: Thromboxane A2 is a key regulator of pathogenesis during Trypanosoma cruzi infection.
abstract: Chagas' disease is caused by infection with the parasite Trypanosoma cruzi. We report that infected, but not uninfected, human endothelial cells (ECs) released thromboxane A(2) (TXA(2)). Physical chromatography and liquid chromatography-tandem mass spectrometry revealed that TXA(2) is the predominant eicosanoid present in all life stages of T. cruzi. Parasite-derived TXA(2) accounts for up to 90% of the circulating levels of TXA(2) in infected wild-type mice, and perturbs host physiology. Mice in which the gene for the TXA(2) 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 TXA(2) 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 TXA(2) in T. cruzi infection is possibly an important determinant of mortality and parasitism. A deeper understanding of the role of TXA(2) may result in novel therapeutic targets for a disease with limited treatment options.
authors.affiliation: Department of Medicine, Divisions of Cardiology and Infectious Disease, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Ashton
authors.forename: Shankar
authors.initials: S
authors.lastname: Mukherjee
authors.forename: F N U
authors.initials: FN
authors.lastname: Nagajyothi
authors.forename: Huan
authors.initials: H
authors.lastname: Huang
authors.forename: Vicki L
authors.initials: VL
authors.lastname: Braunstein
authors.forename: Mahalia S
authors.initials: MS
authors.lastname: Desruisseaux
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Factor
authors.forename: Lillie
authors.initials: L
authors.lastname: Lopez
authors.forename: Joan W
authors.initials: JW
authors.lastname: Berman
authors.forename: Murray
authors.initials: M
authors.lastname: Wittner
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.forename: Valerie
authors.initials: V
authors.lastname: Capra
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Coffman
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
authors.forename: Katherine
authors.initials: K
authors.lastname: Gotlinger
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Wu
authors.forename: Louis M
authors.initials: LM
authors.lastname: Weiss
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Tanowitz
mesh_terms: D000208:Acute Disease; D000818:Animals; D002478:Cells, Cultured; D014355:Chagas Disease / Q000235:genetics / Q000378:metabolism* / Q000469:parasitology / Q000473:pathology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000378:metabolism; D015398:Signal Transduction; D013928:Thromboxane A2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014349:Trypanosoma cruzi / Q000472:pathogenicity* / Q000502:physiology
chemical_list: D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013928:Thromboxane A2; D043802:GTP-Binding Protein alpha Subunits, Gq-G11