Toxoplasma Effector GRA15-Dependent Suppression of IFN-γ-Induced Antiparasitic Response in Human Neurons

• Published in: Frontiers in cellular and infection microbiology 2019-05, Vol.9, p.140
• Main Authors: Bando, Hironori, Lee, Youngae, Sakaguchi, Naoya, Pradipta, Ariel, Sakamoto, Ryoma, Tanaka, Shun, Ma, Ji Su, Sasai, Miwa, Yamamoto, Masahiro
• Format: Article
• Language: English
• Subjects: Antigens, Protozoan - immunology; Antigens, Protozoan - metabolism; Antiparasitic Agents - metabolism; Antiparasitic Agents - pharmacology; Cell Line; Cellular and Infection Microbiology; GRA15; Hepatocytes - immunology; Host-Parasite Interactions - immunology; human; Humans; IDO1; IFN-γ; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Indoleamine-Pyrrole 2,3,-Dioxygenase - pharmacology; Interferon-gamma - immunology; Interferon-gamma - metabolism; Interleukin-1beta - metabolism; Monocytes - immunology; neuron; Neurons - metabolism; Nitric Oxide Synthase Type II - metabolism; Protozoan Proteins - immunology; Protozoan Proteins - metabolism; RNA, Messenger - metabolism; Toxoplasma - drug effects; Toxoplasma - immunology; Toxoplasma - metabolism; toxoplasmosis; Toxoplasmosis - immunology; Virulence
• ISSN: 2235-2988; 2235-2988
• DOI: 10.3389/fcimb.2019.00140

is an important human and animal pathogen that causes life-threatening toxoplasmosis. The host immune system produces interferon-γ (IFN-γ) to inhibit proliferation. IFN-γ-inducible indole-2,3-dioxygenase 1 (IDO1), which mediates tryptophan degradation, has a major role in anti- immune responses in various human cells. In response to the host's immune system, secretes many virulence molecules into the host cells to suppress IFN-γ-dependent antiparasitic immune responses. The GRA15-induced proparasitic mechanism for suppressing IDO1-dependent immune responses has previously been tested only in human hepatocyte and monocyte co-cultures. Thus, whether human cells other than hepatocytes contain this virulence mechanism remains unclear. Here, we show that the GRA15-dependent virulence mechanism for suppressing the IDO1-dependent anti- response operates in human neuronal cell lines and primary human neurons. Analysis of various human cell lines revealed that IL-1β-induced iNOS-dependent reduction of IDO1 mRNA expression occurred in brain cell lines (A172; glioblastoma, IMR-32; neuroblastoma, and T98G; glioblastoma) and liver cell lines (Huh7 and HepG2), but not in other cell lines. Moreover, co-culturing type II -infected THP-1 human monocytes with the brain cell lines inhibited the IDO1-mediated anti- response in a GRA15-dependent manner. These data suggest that a GRA15-dependent virulence mechanism antagonizes the IDO1-dependent host immune response in human brain cells.