Omega-3 Polyunsaturated Fatty Acids Prevent Toxoplasma gondii Infection by Inducing Autophagy via AMPK Activation.

Choi Choi,Lee Lee,Shin Shin,Lim Lim,Cha Cha,Park Park,Yuk Yuk

doi:10.3390/nu11092137

Abstract

Omega-3 polyunsaturated fatty acids (ω3-PUFAs) have potential protective activity in a variety of infectious diseases, but their actions and underlying mechanisms in Toxoplasma gondii infection remain poorly understood. Here, we report that docosahexaenoic acid (DHA) robustly induced autophagy in murine bone marrow-derived macrophages (BMDMs). Treatment of T. gondii-infected macrophages with DHA resulted in colocalization of Toxoplasma parasitophorous vacuoles with autophagosomes and reduced intracellular survival of T. gondii. The autophagic and anti-Toxoplasma effects induced by DHA were mediated by AMP-activated protein kinase (AMPK) signaling. Importantly, BMDMs isolated from Fat-1 transgenic mice, a well-known animal model capable of synthesizing ω3-PUFAs from ω6-PUFAs, showed increased activation of autophagy and AMPK, leading to reduced intracellular survival of T. gondii when compared with wild-type BMDMs. Moreover, Fat-1 transgenic mice exhibited lower cyst burden in the brain following infection with the avirulent strain ME49 than wild-type mice. Collectively, our results revealed mechanisms by which endogenous ω3-PUFAs and DHA control T. gondii infection and suggest that ω3-PUFAs might serve as therapeutic candidate to prevent toxoplasmosis and infection with other intracellular protozoan parasites.

Highlights

Omega-3 polyunsaturated fatty acids (ω3-PUFAs) are essential nutrients for human health and body homeostasis
In Toxoplasma infection, lipoxin A4, a 5-lipoxygenase-derived eicosanoid mediator derived from the ω6-PUFA arachidonic acid, induces increased tissue cyst burden and reduces lethality associated with encephalitis, which is closely associated with the attenuation of interleukin 12 (IL-12) and interferon gamma (IFN-γ) generation [17]
Based on previous studies showing that ω3-PUFAs have immunomodulatory properties in various infectious diseases [9], we examined whether endogenous ω3-PUFAs exhibit host-protective effects against T. gondii infection using Fat-1 transgenic mice and Fat-1-derived primary macrophages

Summary

Introduction

Omega-3 polyunsaturated fatty acids (ω3-PUFAs) are essential nutrients for human health and body homeostasis. Nutrients 2019, 11, 2137 in infectious diseases, including parasitic, bacterial, and viral infections, have been elaborately demonstrated [9,10], whether ω3-PUFAs are beneficial or harmful in the activation of host-protective immunity against infectious agents remains poorly understood. Toxoplasma gondii can infect a broad range of warm-blooded animals, including avian and mammalian species, and is a major protozoan parasite that affects approximately one-third of the global human population [11]. In addition to PV formation, T. gondii has evolved multiple strategies to escape host immune defense reactions, enabling persistence and replication in even innate immune cells, including human dendritic cells, macrophages, and neutrophils [14,15,16]. In Toxoplasma infection, lipoxin A4 , a 5-lipoxygenase-derived eicosanoid mediator derived from the ω6-PUFA arachidonic acid, induces increased tissue cyst burden and reduces lethality associated with encephalitis, which is closely associated with the attenuation of interleukin 12

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