Antimalarial activity of vitamin D3 (VD3) does not result from VD3-induced antimicrobial agents including nitric oxide or cathelicidin
Antimalarial activity of vitamin D3 (VD3) does not result from VD3-induced antimicrobial agents including nitric oxide or cathelicidin
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DOI：
10.1016/j.exppara.2019.03.005
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发表时间：
2019-06-01
影响因子：
2.1
通讯作者：
Ohta, Nobuo
中科院分区：
文献类型：
--
作者：
Yamamoto, Kiichi;Takahashi, Kentaro;Ohta, Nobuo
最近的证据表明，1 α，25-二羟基维生素D3（VD 3），维生素D的活性形式，抑制微生物增殖。以前，我们使用体内小鼠模型来研究VD 3的抗疟活性，并证实了在急性期的有效抗疟活性。本研究旨在阐明VD 3体内抗疟活性的机制，特别是在急性期广泛抑制寄生虫血症，重点是一氧化氮（NO），一种有效的抗疟分子。VD 3是一种良好的NO诱导剂。当大多数用VD 3处理的夏氏疟原虫AS（PcAS）感染的小鼠存活时，在感染后2天和/或3天，从VD 3处理的小鼠获得的血液样品中存在的NO的速率显著高于媒介物处理的对照小鼠。为了验证NO参与VD 3的抗疟活性，我们使用氨基胍（AG），诱导型NO合酶（iNOS）抑制剂，以消除VD 3的抗疟活性。然而，尽管AG诱导的NO水平的降低，寄生虫血症仍然抑制在急性期，即使在AG的存在下，和VD 3的抗疟原虫能力没有消融。VD 3介导的抗疟活性与NO无关，迫使我们考虑另一种候选药物。在先导实验中，我们使用抗菌肽凯萨林菌素（CAMP），因为已知VD 3诱导CAMP合成。血清CAMP水平在感染后第4天或第5天增加，有或没有VD 3给药，但使用外源性CAMP的实验在PcAS感染的小鼠中没有显示疗效。因此，本研究使用VD 3靶向疟疾寄生虫，提出了一种治疗疟疾感染的潜在新方法。
Recent evidence suggests that 1 alpha,25-dihydroxyvitamin D3 (VD3), the active form of vitamin D, inhibits microbial proliferation. Previously, we used in vivo murine models to investigate the antimalarial activity of VD3 and confirmed potent antimalarial activity in the acute phase. This study aimed to clarify the mechanisms underlying the antimalarial activity of VD3 in vivo, particularly extensive inhibition of parasitemia in the acute phase, focusing on nitric oxide (NO), a potent antimalarial molecule. VD3 is a good NO inducer. When most Plasmodium chabaudi AS (PcAS)-infected mice treated with VD3 survived, NO was present in blood samples obtained from VD3-treated mice at a significantly higher rate at 2 and/or 3 days post-infection than that in vehicle-treated control mice. To verify the involvement of NO in the antimalarial activity of VD3, we used aminoguanidine (AG), an inducible NO synthase (iNOS) inhibitor, to abrogate the antimalarial activity of VD3. However, despite AG-induced reductions in NO levels, parasitemia remained inhibited during the acute phase, even in the presence of AG, and the antiplasmodial faculty of VD3 was not ablated. VD3-mediated antimalarial activity irrelevant of NO compelled us to consider another candidate. In a pilot experiment, we used cathelicidin (CAMP), an antimicrobial peptide, since it is known that VD3 induces CAMP synthesis. Serum CAMP levels increased on days 4 or 5 post-infection with or without VD3 administration, but experiments using exogenous CAMP did not display curative effects in PcAS-infected mice. The present study using VD3 to target the malarial parasite thus suggests a potential novel approach to treat malarial infections.