title: TgMAPK1 is a Toxoplasma gondii MAP kinase that hijacks host MKK3 signals to regulate virulence and interferon-γ-mediated nitric oxide production.
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.
authors.affiliation: The Cancer Therapy and Research Center/Adult Cancer Program, and Institute for Drug Development, STRF/8403 Floyd Curl Drive MS 8252/University of Texas Health Science Center, San Antonio, TX 78229, USA. michael.brumlik@sascientific.com
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Brumlik
authors.forename: Srilakshmi
authors.initials: S
authors.lastname: Pandeswara
authors.forename: Sara M
authors.initials: SM
authors.lastname: Ludwig
authors.forename: Duane P
authors.initials: DP
authors.lastname: Jeansonne
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Lacey
authors.forename: Kruthi
authors.initials: K
authors.lastname: Murthy
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Daniel
authors.forename: Rong-Fu
authors.initials: RF
authors.lastname: Wang
authors.forename: Suzanne R
authors.initials: SR
authors.lastname: Thibodeaux
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Church
authors.forename: Vincent
authors.initials: V
authors.lastname: Hurez
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kious
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Adebusola
authors.initials: A
authors.lastname: Alagbala
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Xia
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Curiel
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D008099:Liver / Q000469:parasitology; D008264:Macrophages / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D013154:Spleen / Q000469:parasitology; D014122:Toxoplasma / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D014124:Toxoplasmosis, Animal / Q000276:immunology / Q000469:parasitology*; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000502:physiology
chemical_list: D037521:Virulence Factors; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D019950:Mitogen-Activated Protein Kinase 1
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