Vitamin D inhibits human immunodeficiency virus type 1 and Mycobacterium tuberculosis infection in macrophages through the induction of autophagy.
Vitamin D inhibits human immunodeficiency virus type 1 and Mycobacterium tuberculosis infection in macrophages through the induction of autophagy.
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DOI：
10.1371/journal.ppat.1002689
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Spector SA
中科院分区：
文献类型：
--
作者：
Campbell GR;Spector SA
人类免疫缺陷病毒1型（HIV）感染者的低维生素D水平与疾病进展更快和结核分枝杆菌感染风险增加有关。我们先前已经证明，1α，25-二羟基胆钙化醇（1，25 D3），维生素D的活性形式，通过诱导自噬抑制HIV在人巨噬细胞中的复制。在这项研究中，我们报道了生理浓度的1，25 D3诱导HIV和M.结核病共感染的人巨噬细胞，其抑制分枝杆菌生长和HIV复制。使用针对Beclin-1和自噬相关的5同源物的RNA干扰，结合自噬通量的化学抑制剂、自噬体-溶酶体融合和随后酸化的抑制剂巴弗洛霉素A1和溶酶体水解酶组织蛋白酶L的抑制剂SID 26681509，我们表明1，在单次感染或双重感染期间，25 D3介导的HIV复制和分枝杆菌生长的抑制不仅依赖于自噬的诱导，而且还通过吞噬体成熟。此外，通过使用RNA干扰CAMP，我们证明cathelicidin是必不可少的1，25 D3诱导的自噬流量和抑制HIV复制和分枝杆菌生长。目前的研究结果为维生素D充足在HIV和M中的益处和重要性提供了生物学解释。本研究为预防和治疗艾滋病毒感染和相关机会性感染的新方法提供了新的见解。巨自噬（自噬- '自食'，溶酶体依赖性降解和细胞内组分的再循环以响应应激）是抵抗病毒和分枝杆菌感染的重要宿主防御机制。最近的研究已经描述了巨噬细胞中自噬的激活由于密切的自噬-吞噬作用相互作用而降低结核分枝杆菌和HIV的活力。血清中25-羟基胆钙化醇形式的维生素D水平低与活动性结核病和HIV疾病进展以及M.结核易感性在这项研究中，我们报告了维生素D的活性形式1α，25-二羟基胆钙化醇抑制HIV和M.结核病以浓度依赖的方式。此外，通过抑制自噬途径中的关键阶段，我们证明了在单次感染或双重感染期间对HIV和分枝杆菌生长的抑制不仅依赖于自噬的诱导，而且还依赖于吞噬体的成熟。此外，通过对人凯萨林菌素微生物肽进行RNA干扰，我们证明凯萨林菌素对于1α，25-二羟基胆钙化醇诱导的自噬通量以及抑制HIV复制和分枝杆菌生长是必需的。这些发现表明，诱导自噬有可能用于治疗HIV和M.结核
Low vitamin D levels in human immunodeficiency virus type-1 (HIV) infected persons are associated with more rapid disease progression and increased risk for Mycobacterium tuberculosis infection. We have previously shown that 1α,25-dihydroxycholecalciferol (1,25D3), the active form of vitamin D, inhibits HIV replication in human macrophages through the induction of autophagy. In this study, we report that physiological concentrations of 1,25D3 induce the production of the human cathelicidin microbial peptide (CAMP) and autophagic flux in HIV and M. tuberculosis co-infected human macrophages which inhibits mycobacterial growth and the replication of HIV. Using RNA interference for Beclin-1 and the autophagy-related 5 homologue, combined with the chemical inhibitors of autophagic flux, bafilomycin A1, an inhibitor of autophagosome-lysosome fusion and subsequent acidification, and SID 26681509 an inhibitor of the lysosome hydrolase cathepsin L, we show that the 1,25D3-mediated inhibition of HIV replication and mycobacterial growth during single infection or dual infection is dependent not only upon the induction of autophagy, but also through phagosomal maturation. Moreover, through the use of RNA interference for CAMP, we demonstrate that cathelicidin is essential for the 1,25D3 induced autophagic flux and inhibition of HIV replication and mycobacterial growth. The present findings provide a biological explanation for the benefits and importance of vitamin D sufficiency in HIV and M. tuberculosis-infected persons, and provide new insights into novel approaches to prevent and treat HIV infection and related opportunistic infections. Macroautophagy (autophagy - ‘self-eating’, lysosome-dependent degradation and recycling of the intracellular components in response to stress) is an important host defense mechanism against viral and mycobacterial infections. Recent studies have described that activation of autophagy in macrophages reduces the viability of Mycobacterium tuberculosis and HIV due to an intimate autophagy-phagocytosis interaction. Low serum levels of the 25-hydroxycholecalciferol form of vitamin D have been associated with an increased risk for active tuberculosis and HIV disease progression as well as M. tuberculosis susceptibility. In this study, we report that the active form of vitamin D, 1α,25-dihydroxycholecalciferol inhibits the replication of HIV and M. tuberculosis in a concentration dependent manner. Moreover, by inhibiting key stages in the autophagy pathway, we demonstrate that the inhibition of HIV and mycobacterial growth during single infection or dual infection is dependent not only upon the induction of autophagy, but also through phagosomal maturation. Furthermore, through the use of RNA interference for the human cathelicidin microbial peptide we demonstrate that cathelicidin is essential for the 1α,25-dihydroxycholecalciferol induced autophagic flux and inhibition of HIV replication and mycobacterial growth. These findings suggest that the induction of autophagy has the potential to be useful in the treatment of persons co-infected with HIV and M. tuberculosis.
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影响因子：
17.1
作者：
Fabri M;Stenger S;Shin DM;Yuk JM;Liu PT;Realegeno S;Lee HM;Krutzik SR;Schenk M;Sieling PA;Teles R;Montoya D;Iyer SS;Bruns H;Lewinsohn DM;Hollis BW;Hewison M;Adams JS;Steinmeyer A;Zügel U;Cheng G;Jo EK;Bloom BR;Modlin RL
通讯作者：
Modlin RL
影响因子：
2.8
作者：
de Noronha, Almerio L. L.;Bafica, Andre;Barral-Netto, Manoel
通讯作者：
Barral-Netto, Manoel
DOI：
10.1016/j.jsbmb.2006.12.052
发表时间：
2007-03-01
影响因子：
4.1
作者：
Martineau, Adrian R.;Honecker, Friedemann U.;Griffiths, Christopher J.
通讯作者：
Griffiths, Christopher J.
影响因子：
56.9
作者：
Liu, PT;Stenger, S;Modlin, RL
通讯作者：
Modlin, RL
p62/SQSTM1形成自噬降解的蛋白质聚集体，并对亨廷顿蛋白诱导的细胞死亡具有保护作用。
影响因子：
7.8
作者：
Bjorkoy, Geir;Lamark, Trond;Brech, Andreas;Outzen, Heidi;Perander, Maria;Overvatn, Aud;Stenmark, Harald;Johansen, Terje
通讯作者：
Johansen, Terje