Inducible nitric oxide synthase is a key host factor for Toxoplasma GRA15-dependent disruption of the gamma interferon-induced antiparasitic human response

Hironori Bando, Youngae Lee, Naoya Sakaguchi, Ariel Pradipta, Ji Su Ma, Shun Tanaka, Yihong Cai, Jianfa Liu, Jilong Shen, Yoshifumi Nishikawa, Miwa Sasai, Masahiro Yamamoto

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)


Although Toxoplasma virulence mechanisms targeting gamma interferon (IFN-γ)-induced cell-autonomous antiparasitic immunity have been extensively characterized in mice, the virulence mechanisms in humans remain uncertain, partly because cell-autonomous immune responses against Toxoplasma differ markedly between mice and humans. Despite the identification of inducible nitric oxide synthase (iNOS) as an anti-Toxoplasma host factor in mice, here we show that iNOS in humans is a pro-Toxoplasma host factor that promotes the growth of the parasite. The GRA15 Toxoplasma effector-dependent disarmament of IFN-γ-induced parasite growth inhibition was evident when parasite-infected monocytes were cocultured with hepatocytes. Interleukin-1β (IL-1β), produced from monocytes in a manner dependent on GRA15 and the host’s NLRP3 inflammasome, combined with IFN-γ to strongly stimulate iNOS expression in hepatocytes; this dramatically reduced the levels of indole 2,3-dioxygenase 1 (IDO1), a critically important IFN-γ-inducible anti-Toxoplasma protein in humans, thus allowing parasite growth. Taking the data together, Toxoplasma utilizes human iNOS to antagonize IFN-γ-induced IDO1-mediated cell-autonomous immunity via its GRA15 virulence factor. IMPORTANCE Toxoplasma, an important intracellular parasite of humans and animals, causes life-threatening toxoplasmosis in immunocompromised individuals. Gamma interferon (IFN-γ) is produced in the host to inhibit the proliferation of this parasite and eventually cause its death. Unlike mouse disease models, which involve well-characterized virulence strategies that are used by Toxoplasma to suppress IFN-γ-dependent immunity, the strategies used by Toxoplasma in humans remain unclear. Here, we show that GRA15, a Toxoplasma effector protein, suppresses the IFN-γ-induced indole-2,3-dioxygenase 1-dependent antiparasite immune response in human cells. Because NLRP3-dependent production of IL-1β and nitric oxide (NO) in Toxoplasma-infected human cells is involved in the GRA15-dependent virulence mechanism, blocking NO or IL-1β production in the host could represent a novel therapeutic approach for treating human toxoplasmosis.

Original languageEnglish
Article numbere01738-18
Issue number5
Publication statusPublished - 2018 Sep 1
Externally publishedYes


  • Cell-autonomous immunity
  • Host-parasite interaction
  • Human immunology
  • Immune suppression
  • Interferon
  • Toxoplasma gondii

ASJC Scopus subject areas

  • Microbiology
  • Virology


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