Thromboxane A2 is a key regulator of pathogenesis during Trypanosoma cruzi infection.
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.
Ashton
Anthony W
AW
Department of Medicine, Divisions of Cardiology and Infectious Disease, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Mukherjee
Shankar
S
Nagajyothi
F N U
FN
Huang
Huan
H
Braunstein
Vicki L
VL
Desruisseaux
Mahalia S
MS
Factor
Stephen M
SM
Lopez
Lillie
L
Berman
Joan W
JW
Wittner
Murray
M
Scherer
Philipp E
PE
Capra
Valerie
V
Coffman
Thomas M
TM
Serhan
Charles N
CN
Gotlinger
Katherine
K
Wu
Kenneth K
KK
Weiss
Louis M
LM
Tanowitz
Herbert B
HB
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
D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013928:Thromboxane A2; D043802:GTP-Binding Protein alpha Subunits, Gq-G11