1. TgMAPK1 is a Toxoplasma gondii MAP kinase that hijacks host MKK3 signals to regulate virulence and interferon-γ-mediated nitric oxide production.
- Author
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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, and Curiel TJ
- Subjects
- Animals, Cell Line, Female, Gene Expression Regulation, Enzymologic, Humans, Liver parasitology, Macrophages parasitology, Mice, Mice, Inbred C57BL, Mitogen-Activated Protein Kinase 1 genetics, Nitric Oxide Synthase Type II metabolism, Spleen parasitology, Toxoplasma genetics, Toxoplasma metabolism, Toxoplasma pathogenicity, Toxoplasmosis, Animal immunology, Virulence, Virulence Factors genetics, Virulence Factors physiology, Interferon-gamma physiology, Mitogen-Activated Protein Kinase 1 physiology, Nitric Oxide metabolism, Toxoplasma enzymology, Toxoplasmosis, Animal parasitology
- 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 (TgMAPK1(lo)) 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. TgMAPK1(lo) infection in wild type mice produced ≥ten-fold lower parasite burden versus control parasites with normal TgMAPK1 expression (TgMAPK1(con)). 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., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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