Toll-Like Receptor- and Protein Kinase R-Induced Type I Interferon Sustains Infection of Leishmania donovani in Macrophages.
Toll-Like Receptor- and Protein Kinase R-Induced Type I Interferon Sustains Infection of Leishmania donovani in Macrophages.
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TOLL样受体和蛋白激酶R诱导的I型干扰素持续巨噬细胞中的Leishmania Donovani感染。
DOI：
10.3389/fimmu.2022.801182
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发表时间：
2022
影响因子：
7.3
通讯作者：
Lima APCA
中科院分区：
文献类型：
--
作者：
Dias BT;Goundry A;Vivarini AC;Costa TFR;Mottram JC;Lopes UG;Lima APCA
杜氏利什曼原虫是一种原生动物寄生虫，引起内脏利什曼病，引起肝脏和脾脏组织破坏，如果不治疗是致命的。寄生虫在巨噬细胞中复制并调节宿主杀微生物反应。我们以前曾报道中性粒细胞弹性蛋白酶（NE）是维持L。通过诱导干扰素β（IFN-β），在巨噬细胞中的donovani细胞内生长。在这里，我们表明，当TLR4通过中和抗体预处理或在来自tlr2-/-小鼠的巨噬细胞中被阻断时，感染的巨噬细胞的IFN-β的基因表达减少一半，而来自myd88-/-小鼠的巨噬细胞中的水平与来自野生型C57BL/6小鼠的水平相当。TLR4在tlr2-/-巨噬细胞中的中和完全消除了寄生虫感染后IFN-β基因表达的诱导，表明两种TLR的相加作用。L. I型干扰素（IFN-I）、OASL 2、SOD 1和IL 10基因表达的诱导。在NE基因敲除小鼠（ela2-/-）和蛋白激酶R（PKR）基因敲除小鼠（pkr-/-）的巨噬细胞中，以及在感染转基因L.表达丝氨酸肽酶2（ISP 2）抑制剂的donovani。与129Sv/Ev背景小鼠相比，pkr-/-巨噬细胞中的寄生虫细胞内生长受损，但通过加入外源性IFN-β完全恢复，并且pkr-/-小鼠脾脏中的寄生虫负荷在7天时减少。此外，寄生虫不能在缺乏TLR3的巨噬细胞中生长，这与缺乏IFN-I基因表达有关。因此，L. donovani通过下游PKR经由TLR2、TLR4和TLR3参与感染的巨噬细胞中的先天性应答，以诱导宿主细胞中促存活基因的表达，并保证寄生虫细胞内发育。
Leishmania donovani is a protozoan parasite that causes visceral leishmaniasis, provoking liver and spleen tissue destruction that is lethal unless treated. The parasite replicates in macrophages and modulates host microbicidal responses. We have previously reported that neutrophil elastase (NE) is required to sustain L. donovani intracellular growth in macrophages through the induction of interferon beta (IFN-β). Here, we show that the gene expression of IFN-β by infected macrophages was reduced by half when TLR4 was blocked by pre-treatment with neutralizing antibodies or in macrophages from tlr2 -/- mice, while the levels in macrophages from myd88-/- mice were comparable to those from wild-type C57BL/6 mice. The neutralization of TLR4 in tlr2 -/- macrophages completely abolished induction of IFN-β gene expression upon parasite infection, indicating an additive role for both TLRs. Induction of type I interferon (IFN-I), OASL2, SOD1, and IL10 gene expression by L. donovani was completely abolished in macrophages from NE knock-out mice (ela2 -/-) or from protein kinase R (PKR) knock-out mice (pkr -/-), and in C57BL/6 macrophages infected with transgenic L. donovani expressing the inhibitor of serine peptidase 2 (ISP2). Parasite intracellular growth was impaired in pkr -/- macrophages but was fully restored by the addition of exogenous IFN-β, and parasite burdens were reduced in the spleen of pkr -/- mice at 7 days, as compared to the 129Sv/Ev background mice. Furthermore, parasites were unable to grow in macrophages lacking TLR3, which correlated with lack of IFN-I gene expression. Thus, L. donovani engages innate responses in infected macrophages via TLR2, TLR4, and TLR3, via downstream PKR, to induce the expression of pro-survival genes in the host cell, and guarantee parasite intracellular development.
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影响因子：
56.9
作者：
Blander, JM;Medzhitov, R
通讯作者：
Medzhitov, R
DOI：
10.1126/science.1199326
发表时间：
2011-02-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Ives A;Ronet C;Prevel F;Ruzzante G;Fuertes-Marraco S;Schutz F;Zangger H;Revaz-Breton M;Lye LF;Hickerson SM;Beverley SM;Acha-Orbea H;Launois P;Fasel N;Masina S
通讯作者：
Masina S
影响因子：
30.5
作者：
Ato, M;Stäger, S;Kaye, PM
通讯作者：
Kaye, PM
影响因子：
7.3
作者：
Kawasaki T;Kawai T
通讯作者：
Kawai T
影响因子：
3.4
作者：
Dermine, JF;Scianimanico, S;Desjardins, M
通讯作者：
Desjardins, M