Leishmania induces survival, proliferation and elevated cellular dNTP levels in human monocytes promoting acceleration of HIV co-infection.
Leishmania induces survival, proliferation and elevated cellular dNTP levels in human monocytes promoting acceleration of HIV co-infection.
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DOI：
10.1371/journal.ppat.1002635
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Kim B
中科院分区：
文献类型：
--
作者：
Mock DJ;Hollenbaugh JA;Daddacha W;Overstreet MG;Lazarski CA;Fowell DJ;Kim B
利什曼病是一种寄生虫病，在世界上许多热带和亚热带地区广泛流行。利什曼原虫感染已被公认为通过尚未完全理解的机制在合并感染个体中诱导人类免疫缺陷病毒1型（HIV-1）感染的显著加速。单核细胞/巨噬细胞谱系的细胞是被两种病原体共感染的主要细胞类型。单核细胞和巨噬细胞含有极低水平的脱氧核苷三磷酸（dNTP），这是由于它们缺乏细胞周期和S期，其中dNTP生物合成被特异性激活。慢病毒，如HIV-1，在逆转录病毒中是独特的，因为它们能够在这些非分裂细胞中复制，至少部分是由于它们的高效逆转录酶（RT）。尽管如此，病毒复制的进展更有效地在设置更高的细胞内dNTP浓度相关的增强酶动力学的病毒RT。在本研究中，在体外感染CD 14+外周血来源的人单核细胞与利什曼原虫重大被发现诱导分化，细胞p53 R2核糖核苷酸还原酶亚基和R2亚基的表达显着升高。R2亚基仅限于细胞周期的S期。我们的dNTP测定表明，与对照细胞相比，利什曼原虫感染的细胞群中细胞内单核细胞衍生的巨噬细胞（MDM）dNTP浓度显著升高。与对照细胞相比，用表达HIV-1的假型GFP感染利什曼原虫成熟的MDM导致利什曼原虫成熟的MDM中GFP+细胞的数量增加。有趣的是，发现利什曼原虫成熟的MDM亚群重新进入细胞周期，如BrdU标记所示。总之，利什曼原虫感染的原代人单核细胞促进诱导的S期环境和升高的dNTP水平与显着升高的HIV-1的表达在设置的共同感染。利什曼病是一种寄生虫病，感染几种人类宿主免疫细胞，包括中性粒细胞，单核细胞和巨噬细胞。此外，虽然HIV-1感染单核细胞和巨噬细胞，但只有感染的巨噬细胞才能有效地释放病毒后代。重要的是，合并感染两种病原体的患者更快地发展为艾滋病。在这项研究中，我们研究了利什曼原虫如何在体外改变单核细胞的细胞环境。我们发现，利什曼原虫感染的单核细胞积极成熟为巨噬细胞在缺乏GM-CSF，这些细胞上调核糖核苷酸还原酶的表达，催化脱氧核苷三磷酸（dNTPs）的形成的酶。我们使用非常灵敏的单核细胞和单核细胞成熟的巨噬细胞dNTP测定法证实了dNTP浓度的升高。总的来说，这些数据支持这样一种模型，其中利什曼原虫感染单核细胞提高了细胞内dNTP池，这是患者单核细胞和巨噬细胞中HIV-1感染的天然抗病毒阻断剂之一。
Leishmaniasis is a parasitic disease that is widely prevalent in many tropical and sub-tropical regions of the world. Infection with Leishmania has been recognized to induce a striking acceleration of Human Immunodeficiency Virus Type 1 (HIV-1) infection in coinfected individuals through as yet incompletely understood mechanisms. Cells of the monocyte/macrophage lineage are the predominant cell types coinfected by both pathogens. Monocytes and macrophages contain extremely low levels of deoxynucleoside triphosphates (dNTPs) due to their lack of cell cycling and S phase, where dNTP biosynthesis is specifically activated. Lentiviruses, such as HIV-1, are unique among retroviruses in their ability to replicate in these non-dividing cells due, at least in part, to their highly efficient reverse transcriptase (RT). Nonetheless, viral replication progresses more efficiently in the setting of higher intracellular dNTP concentrations related to enhanced enzyme kinetics of the viral RT. In the present study, in vitro infection of CD14+ peripheral blood-derived human monocytes with Leishmania major was found to induce differentiation, marked elevation of cellular p53R2 ribonucleotide reductase subunit and R2 subunit expression. The R2 subunit is restricted to the S phase of the cell cycle. Our dNTP assay demonstrated significant elevation of intracellular monocyte-derived macrophages (MDMs) dNTP concentrations in Leishmania-infected cell populations as compared to control cells. Infection of Leishmania-maturated MDMs with a pseudotyped GFP expressing HIV-1 resulted in increased numbers of GFP+ cells in the Leishmania-maturated MDMs as compared to control cells. Interestingly, a sub-population of Leishmania-maturated MDMs was found to have re-entered the cell cycle, as demonstrated by BrdU labeling. In conclusion, Leishmania infection of primary human monocytes promotes the induction of an S phase environment and elevated dNTP levels with notable elevation of HIV-1 expression in the setting of coinfection. Leishmaniasis is a parasitic disease that infects several human host immune cells, including neutrophils, monocytes, and macrophages. Moreover, while HIV-1 infects monocytes and macrophages, only the infected macrophages productively release viral progenies. Importantly, patients coinfected with both pathogens progress more rapidly to AIDS. In this study, we examine how Leishmania major changes the cellular environment of monocytes in vitro. We found that Leishmania-infected monocytes actively mature into macrophages in the absence of GM-CSF, and that these cells up-regulate the expression of ribonucleotide reductase, an enzyme that catalyzes the formation of deoxynucleoside triphosphates (dNTPs). We confirmed the elevation of dNTP concentrations using a very sensitive dNTP assay for monocytes and monocyte-maturated macrophages. Collectively, these data support a model in which infection of monocytes with Leishmania elevates the intracellular dNTP pools, which is one of the natural anti-viral blocks to HIV-1 infection in monocytes and macrophages in patients.
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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
影响因子：
8.6
作者：
Ansari, Nasim Akhtar;Saluja, Sumita;Salotra, Poonam
通讯作者：
Salotra, Poonam
影响因子：
56.9
作者：
FOLKS, TM;JUSTEMENT, J;FAUCI, AS
通讯作者：
FAUCI, AS
DOI：
10.1007/978-0-387-77570-8_12
发表时间：
2008-01-01
期刊：
DRUG TARGETS IN KINETOPLASTID PARASITES
影响因子：
--
作者：
Carter, Nicola S.;Yates, Phillip;Ullman, Buddy
通讯作者：
Ullman, Buddy
DOI：
10.1016/s0035-9203(96)90538-6
发表时间：
1996-07-01
影响因子：
2.2
作者：
Cacopardo, B;Nigro, L;Doerr, HW
通讯作者：
Doerr, HW