Abstract
Toxoplasma gondii is an important human and animal pathogen that causes life-threatening toxoplasmosis. The host immune system produces interferon-γ (IFN-γ) to inhibit T. gondii proliferation. IFN-γ-inducible indole-2,3-dioxygenase 1 (IDO1), which mediates tryptophan degradation, has a major role in anti-T. gondii immune responses in various human cells. In response to the host's immune system, T. gondii 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-T. gondii 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 T. gondii-infected THP-1 human monocytes with the brain cell lines inhibited the IDO1-mediated anti-T. gondii 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.
Highlights
Toxoplasma gondii is a widespread protozoan that can infect most warm-blooded vertebrates
To assess whether IL-1β-dependent reduction of IDO1 mRNA is specific to hepatocytes or occurs in other human cell types, we first tested the effect of IL-1β stimulation on downregulation of IFN-γ-induced IDO1 mRNA expression levels in various human cell types (Figure 1B)
Adding IL-1β had either no or a lesser suppressive effect on IFN-γ-induced IDO1 mRNA expression levels in colonic (HCT116, CCK-81), leukocytic (HAP1, THP1), lung (A549, PC-3), breast (MCF7, YMB-1), pancreatic (MIA PaCa-2, KP-2), kidney (293T, KMRC-1), ovarian (RMGI, RKN), placental (BeWo), splenic (OVTOKO), cervical (Ca Ski, HeLa), osteosarcoma (U2OS), foreskin fibroblastic (HFF), and retinoblastic (Y79, WERI-Rb-1) cell lines (Figure 1B). These results suggest that IL-1β regulation reduces IDO1 mRNA in human brain cells as well as hepatocytes
Summary
Toxoplasma gondii is a widespread protozoan that can infect most warm-blooded vertebrates. Infection with T. gondii causes toxoplasmosis in humans and animals (Boothroyd, 2009; Dubey, 2010). One-third of the human population is estimated to be infected with T. gondii. T. gondii infections in healthy individuals remain mostly asymptomatic, immunocompromised individuals often experience damage to their liver, brain, eyes, and other organs, resulting in lethal toxoplasmosis (Weitberg et al, 1979; Frenkel and Remington, 1980). T. gondii infections potentially lead to congenital toxoplasmosis in fetuses and newborn children via their primarily infected pregnant mothers (Montoya and Remington, 2008). T. gondii is a common and important zoonotic pathogen
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