Thromboxane A2 is a key regulator of pathogenesis during Trypanosoma cruzi infection

Anthony W. Ashton, Shankar Mukherjee, F. N U Nagajyothi, Huan Huang, Vicki L. Braunstein, Mahalia S. Desruisseaux, Stephen M. Factor, Lillie Lopez, Joan W. Berman, Murray Wittner, Philipp E. Scherer, Valerie Capra, Thomas M. Coffman, Charles N. Serhan, Katherine Gotlinger, Kenneth K. Wu, Louis M. Weiss, Herbert B. Tanowitz

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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 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 TXA 2 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. JEM

Original languageEnglish (US)
Pages (from-to)929-940
Number of pages12
JournalJournal of Experimental Medicine
Volume204
Issue number4
DOIs
StatePublished - Apr 16 2007

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Ashton, A. W., Mukherjee, S., Nagajyothi, F. N. U., Huang, H., Braunstein, V. L., Desruisseaux, M. S., Factor, S. M., Lopez, L., Berman, J. W., Wittner, M., Scherer, P. E., Capra, V., Coffman, T. M., Serhan, C. N., Gotlinger, K., Wu, K. K., Weiss, L. M., & Tanowitz, H. B. (2007). Thromboxane A2 is a key regulator of pathogenesis during Trypanosoma cruzi infection. Journal of Experimental Medicine, 204(4), 929-940. https://doi.org/10.1084/jem.20062432