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

Exp Parasitol. 2013 Mar 26. pii: S0014-4894(13)00086-6. doi: 10.1016/j.exppara.2013.03.016. [Epub ahead of print]

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

Brumlik MJ, Pandeswara S, Ludwig SM, Jeansonne DP, Lacey MR, Murthy K, Daniel BJ, Wang RF, Thibodeaux SR, Church KM, Hurez V, Kious MJ, Zhang B, Alagbala A, Xia X, Curiel TJ.

The Cancer Therapy and Research Center/Adult Cancer Program, and the Institute for Drug Development, STRF/8403 Floyd Curl Drive MS 8252/University of Texas Health Science Center, San Antonio, TX 78229, USA. Electronic address: michael.brumlik@sascientific.com.

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.

PMID: 23541881 [PubMed - as supplied by publisher]