TgMAPK1 is a Toxoplasma gondii MAP kinase that hijacks host MKK3 signals to regulate virulence and interferon-γ-mediated nitric oxide production

Michael J. Brumlik, Srilakshmi Pandeswara, Sara M. Ludwig, Duane P. Jeansonne, Michelle R. Lacey, Kruthi Murthy, Benjamin J. Daniel, Rong Fu Wang, Suzanne R. Thibodeaux, Kristina M. Church, Vincent Hurez, Mark J. Kious, Bin Zhang, Adebusola Alagbala, Xiaojun Xia, Tyler J. Curiel

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

The parasite Toxoplasma gondii controls tissue-specific nitric oxide (NO), thereby augmenting virulence and immunopathology through poorly-understood mechanisms. We now identify TgMAPK1, a Toxoplasma mitogen-activated protein kinase (MAPK), as a virulence factor regulating tissue-specific parasite burden by manipulating host interferon (IFN)-γ-mediated inducible nitric oxide synthase (iNOS). Toxoplasma with reduced TgMAPK1 expression (TgMAPK1lo) demonstrated that TgMAPK1 facilitates IFN-γ-driven p38 MAPK activation, reducing IFN-γ-generated NO in an MKK3-dependent manner, blunting IFN-γ-mediated parasite control. TgMAPK1lo infection in wild type mice produced ≥ten-fold lower parasite burden versus control parasites with normal TgMAPK1 expression (TgMAPK1con). Reduced parasite burdens persisted in IFN-γ KO mice, but equalized in normally iNOS-replete organs from iNOS KO mice. Parasite MAPKs are far less studied than other parasite kinases, but deserve additional attention as targets for immunotherapy and drug discovery.

Original languageEnglish (US)
Pages (from-to)389-399
Number of pages11
JournalExperimental Parasitology
Volume134
Issue number3
DOIs
StatePublished - Jul 1 2013

    Fingerprint

Keywords

  • INOS
  • MAPK
  • Toxoplasma gondii
  • Virulence

ASJC Scopus subject areas

  • Parasitology
  • Immunology
  • Infectious Diseases

Cite this

Brumlik, M. J., Pandeswara, S., Ludwig, S. M., Jeansonne, D. P., Lacey, M. R., Murthy, K., Daniel, B. J., Wang, R. F., Thibodeaux, S. R., Church, K. M., Hurez, V., Kious, M. J., Zhang, B., Alagbala, A., Xia, X., & Curiel, T. J. (2013). TgMAPK1 is a Toxoplasma gondii MAP kinase that hijacks host MKK3 signals to regulate virulence and interferon-γ-mediated nitric oxide production. Experimental Parasitology, 134(3), 389-399. https://doi.org/10.1016/j.exppara.2013.03.016