Immune Evasion Mechanisms of Zoonotic Protozoan Parasite Toxoplasma Gondii in Mammalian Host

概要

Toxoplasma gondii is a zoonotic pathogen that causes toxoplasmosis, a contagious disease aff ecting most mammals, including livestock, wild animals, and humans. Toxoplasmosis in livestock causes miscarriages or stillbirths, resulting in economic damage to farmers, and posing a challenge in animal husbandry. Moreover, cases of transmission to humans have recently shown an increasing trend annually. Thus T. gondii is now an important pathogen that requires immediate attention, both from animal and public health perspectives. However, there is still no vaccine or preventative medicine. Therefore, it is required to promote research on the development of novel treatment methods for toxoplasmosis and the elucidation of the host immune responses–parasite interactions in host cells. Interferon-γ (IFN-γ) is critical for anti-T. gondii responses in mammalian host, however, detailed mechanisms of host immune responses and parasite virulence mechanisms are still unclear. In this study, at fi rst, we showed that IFN-γ induced tryptophan degradation by indole-2,3-dioxygenase (IDO1) plays an important role in the IFN-γ-induced anti-T. gondii response. Next, we focused on T. gondii virulence mechanisms and analyzed the role of TgGRA15 to suppress IFN-γ-dependent immunity. We generated GRA15 deficient T. gondii by Cas9/CRISPR system, and showed that IDO1-dependent anti-T. gondii response is inhibited TgGRA15-dependently. We also showed that T. gondii infection indirectly reduces IDO1 protein levels via iNOS expressed in hepatocytes stimulated with IL-1β that is produced from infected monocytes in a manner dependent on GRA15. Thus, we have demonstrated that iNOS in humans is a pro-Toxoplasma host factor that promotes the growth of the parasite.

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