University of the Ryukyus · Faculty of Medicine · 助教

Research keywordsParasitology・熱帯医学・微生物学・寄生虫学・医動物学・Parasitemia・Malaria・Immune

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• Gut Microbiota Bidirectionally Influences Protection and Severity in Cerebral Malaria in Mice2026 · Tomoyo Taniguchi, Eiji Miyauchi, Reika Kawabata-Iwakawa, Masahiko Nishiyama, Rika Umemiya-Shirafuji, Hiromu Toma, Nobuo Sasaki, Hajime Hisaeda, Haruyoshi Tomita, Hiroshi Ohno, Hidehiro Kishimoto, Hiroshi Suzuki
• Babesia microti alleviates disease manifestations caused by Plasmodium berghei ANKA in murine co-infection model of complicated malaria2023 · Malaria remains one of the most significant health issues worldwide, accounting for 2.6% of the total global disease burden, and efforts to eliminate this threat continue. The key focus is to develop an efficient and long-term immunity to this disease via vaccination or therapeutic approach, and innovative strategies would enable us to achieve this target. Previously, using a mouse co-infection disease model, cross-protection was illustrated between Babesia microti and Plasmodium chabaudi. Hence, this study was planned to elucidate the impact of acute B. microti Peabody mjr and Plasmodium berghei ANKA co-infection on the consequence of complicated malaria in the C57BL/6J mouse model of malaria. Furthermore, immune response and pathological features were analyzed, and the course of the disease was compared among experimental groups. Our study established that acute B. microti infection activated immunity which was otherwise suppressed by P. berghei. The immunosuppressive tissue microenvironment was counteracted as evidenced by the enhanced immune cell population in co-infected mice, in contrast to P. berghei-infected control mice. Parasite sequestration in the brain, liver, lung, and spleen of co-infected mice was significantly decreased and tissue injury was ameliorated. Meanwhile, the serum levels of IFN-γ, TNF-α, and IL-12p70 were reduced while the secretion of IL-10 was promoted in co-infected mice. Eventually, co-infected mice showed an extended rate of survival. Hereby, the principal cytokines associated with the severity of malaria by P. berghei infection were TNF-α, IFN-γ, and IL-12p70. Moreover, it was evident from our flow cytometry results that innate immunity is crucial and macrophages are at the frontline of immunity against P. berghei infection. Our study recommended further investigations to shed light on the effects of babesiosis in suppressing malaria with the goal of developing Babesia-based therapy against malaria.
• Effect of α-Tocopheryloxy Acetic Acid on the Infection of Mice with Plasmodium berghei ANKA In Vivo and Humans with P. falciparum In Vitro.2022 · PURPOSE: Malarial parasites are susceptible to oxidative stress. The effects of α-tocopheryloxy acetic acid (α-TEA), a vitamin E analog, on infection by Plasmodium berghei ANKA and P. falciparum in mice and human red blood cells (RBCs), respectively, were examined in this study. METHODS: For in vivo studies in mice, RBCs infected with P. berghei ANKA were inoculated via intraperitoneal injection and α-TEA was administered to C57BL/6 J male mice after infection. The blood-brain barrier (BBB) permeability was examined by Evans blue staining in experimental cerebral malaria at 7 days after infection. The in vitro inhibitory effect of α-TEA on P. falciparum 3D7 (chloroquine-sensitive strain) and K1 (multidrug-resistant strain) was tested using a SYBR Green I-based assay. RESULTS: When 1.5% α-TEA was administered for 14 days after infection, 88% of P. berghei ANKA-infected mice survived during the experimental period. Nevertheless, all the control mice died within 12 days of infection. Furthermore, the Evans blue intensity in α-TEA-treated mice brains was less than that in untreated mice, indicating that α-TEA might inhibit the destruction of the BBB and progression of cerebral malaria. The in vitro experiment revealed that α-TEA inhibited the proliferation of both the 3D7 and K1 strains. CONCLUSION: This study showed that α-TEA is effective against murine and human malaria in vivo and in vitro, respectively. Although α-TEA alone has a sufficient antimalarial effect, future research could focus on the structure-activity relationship to achieve better pharmacokinetics and decrease the cytotoxicity and/or the combined effect of α-TEA with existing drugs. In addition, the prophylactic antimalarial activity of premedication with α-TEA may also be an interesting perspective in the future.
• The role of autonomously secreted PGE2 and its autocrine/paracrine effect on bone matrix mineralization at the different stages of differentiating MC3T3-E1 cells.2020 · Bone is consisted of osteoblast-linage cells, bone-forming cells in various differentiation stages. However, it is not fully understood how communicate and interact these cells immigrated from bone marrow. In this study, we showed that prostaglandin E2 (PGE2) had a role in autonomous modification of matrix mineralization in osteoblastic cell line, MC3T3-E1, and interactions across the cells in different differentiation stages. Analysis using LC-MS/MS and inhibitors showed the autonomous secretion of PGE2 among the prostanoids in differentiation stages and that depend on COX-2, a key enzyme for production of PGE2. Treatment with inhibitors of PGE2 receptors and COX-2 indicated that secreted PGE2 regulates matrix mineralization in an autocrine/paracrine manner. In addition, we showed that the expression profile of PGE2 receptors (EP1-EP4) and PGE2 effects on matrix mineralization derived from it changed during cell differentiation. Treatment with inhibitors of PGE2 signaling in the early differentiation stage of MC3T3-E1 cells induced significant changes in matrix mineralization several days after. Stimulation with the extracts from culture medium of the matured cells including PGE2 and co-culture with the matured cells secreting PGE2 significantly promoted matrix mineralization of the early stage cells, in contrast, treatment with inhibitor of COX-2 and PGE2 receptors failed to do so. These results support that PGE2 plays important roles in the interaction system of osteoblast-linage cells in bone tissue to regulate matrix mineralization reflecting condition of bone-forming cells, that is, population and maturation.

• 腸内細菌を標的とした脳マラリア予防・治療法の開発に向けた研究2023 · 基盤研究(C)
• 腸内環境理解に基づく新規マラリア感染防御機構の解明2020 · マラリア感染への腸内細菌の関与は国際的に非常に注目されており、近年、報告がなされているが、腸内細菌がどのようにマラリア感染病態に影響を与えているのか、その詳細に関してはほとんど分かっていない。また感染により消化器症状、小腸病変、粘膜バリアーの損傷、腸内細菌叢の劇的な変化が起こるマラリア感染では、腸内細菌だけではなく、他の要素を含む腸管腔内の環境に影響を与える複数因子の関与が想定される。本研究では、腸内環境理解に基づく新規マラリア感染防御機構を解明することを目的としている。本年度は、昨年度に引き続き、これまでに得られている結果および腸内環境に影響を与えることが報告されている因子のうち、抗生剤を用いて検討を行った。抗生剤を2週間、自由飲水投与することにより腸内細菌叢を顕著に変化させたC57BL/6マウスにPlasmodium berghei ANKA株（PbA）を感染させると、脳浮腫および血液脳関門の破綻が有意に軽症化して、7～8割のマウスが脳マラリアによる致死を回避する。抗生剤で変化させた腸内細菌叢が免疫系に与える影響について検討を行い、抗生剤投与群において、脳へのCD8+T細胞含む白血球浸潤が顕著に減少していることを明らかにした。また次世代シーケンサーを用いた菌叢解析により特定した2菌種を、無菌マウスに定着させてPbA感染を行うことにより、脳症状時期が明らかに前後することが観察された。腸内細菌により脳症状の発症時期が制御される可能性が示唆されたことから、今後、引き続き無菌環境下でノトバイオートの研究を進めて、より詳細な作用機序の解明を試みる。
• マラリア感染病態への腸内細菌の作用機序の解明2016 · 若手研究(B)
• マラリアにおける宿主病原体相互作用への腸内細菌の影響の解明2014 · 若手研究(B)

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