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Malaria Parasites Require TLR9 Signaling for Immune Evasion by Activating Regulatory T Cells¹

Hajime Hisaeda^2,*, Kohhei Tetsutani^*, Takashi Imai^*, Chikako Moriya^*, Liping Tu^*, Shinjiro Hamano^*, Xuefeng Duan^*, Bin Chou^*, Hidekazu Ishida^*, Akiko Aramaki^*, Jianying Shen^*, Ken J. Ishii, Cevayir Coban, Shizuo Akira, Kiyoshi Takeda^3,, Koji Yasutomo^¶, Motomi Torii^|| and Kunisuke Himeno^*

^* Department of Parasitology, Graduate School of Medical Sciences and Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukoka; Department of Molecular Parasitology and Department of Host Defense, Institute for Microbial Diseases, Osaka University, and Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Suita; ^¶ Department of Immunology and Parasitology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima; and ^|| Department of Molecular Parasitology, Ehime University, Graduate School of Medicine, Ehime, Japan

Malaria is still a life-threatening infectious disease that continues to produce 2 million deaths annually. Malaria parasites have acquired immune escape mechanisms and prevent the development of sterile immunity. Regulatory T cells (Tregs) have been reported to contribute to immune evasion during malaria in mice and humans, suggesting that activating Tregs is one of the mechanisms by which malaria parasites subvert host immune systems. However, little is known about how these parasites activate Tregs. We herein show that TLR9 signaling to dendritic cells (DCs) is crucial for activation of Tregs. Infection of mice with the rodent malaria parasite Plasmodium yoelii activates Tregs, leading to enhancement of their suppressive function. In vitro activation of Tregs requires the interaction of DCs with parasites in a TLR9-dependent manner. Furthermore, TLR9^–/– mice are partially resistant to lethal infection, and this is associated with impaired activation of Tregs and subsequent development of effector T cells. Thus, malaria parasites require TLR9 to activate Tregs for immune escape.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Ministry of Education, Science, Sport and Culture of Japan (Grants 16017278, 18590400, 19041056), and by the Uehara Memorial Foundation.

² Address correspondence and reprint requests to Dr. Hajime Hisaeda, Department of Parasitology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail address: hisa{at}parasite.med.kyushu-u.ac.jp

³ Current address: Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, 2- Yamada-oka, Suita, 565-0871, Japan.

⁴ Abbreviations used in this paper: DC, dendritic cell; pDC, plasmacytoid DC; PDCA1, anti-plasmacytoid DC Ag-1; pRBC, parasitized RBC; PyL, Plasmodium yoelii 17XL strain; Treg, regulatory T cell; TRIF, Toll/IL-1 receptor domain-containing adaptor-inducing IFN-β.