Inducible Nitric Oxide Synthase Is a Key Host Factor for Toxoplasma GRA15-Dependent Disruption of the Gamma Interferon-Induced Antiparasitic Human Response

• Published in: mBio 2018-10, Vol.9 (5)
• Main Authors: Bando, Hironori, Lee, Youngae, Sakaguchi, Naoya, Pradipta, Ariel, Ma, Ji Su, Tanaka, Shun, Cai, Yihong, Liu, Jianfa, Shen, Jilong, Nishikawa, Yoshifumi, Sasai, Miwa, Yamamoto, Masahiro
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Protozoan - immunology; Cell Line; Coculture Techniques; CRISPR-Cas Systems; Hepatocytes - drug effects; Hepatocytes - immunology; Hepatocytes - parasitology; Host-Microbe Biology; Host-Parasite Interactions - immunology; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Interferon-gamma - pharmacology; Interleukin-1beta - metabolism; Mice; Mice, Inbred C57BL; Monocytes - immunology; Monocytes - parasitology; Nitric Oxide Synthase Type II - immunology; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Protozoan Proteins - immunology; Toxoplasma - immunology; Toxoplasma - pathogenicity; Virulence Factors - immunology
• ISSN: 2161-2129; 2150-7511
• DOI: 10.1128/mBio.01738-18

Although 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 differ markedly between mice and humans. Despite the identification of inducible nitric oxide synthase (iNOS) as an anti- host factor in mice, here we show that iNOS in humans is a pro- host factor that promotes the growth of the parasite. The GRA15 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- protein in humans, thus allowing parasite growth. Taking the data together, utilizes human iNOS to antagonize IFN-γ-induced IDO1-mediated cell-autonomous immunity via its GRA15 virulence factor. 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 to suppress IFN-γ-dependent immunity, the strategies used by in humans remain unclear. Here, we show that GRA15, a 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 -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.