CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India; School of Medical Science and Technology, Indian Institute of Technology, Kharagpur 721302, India.
CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India.
Cytokine. 2021 Sep;145:155245. doi: 10.1016/j.cyto.2020.155245. Epub 2020 Aug 26.
The disease visceral leishmaniasis (VL) or kala azar is caused by the protozoan parasite, Leishmania donovani (LD). For many decades the pentavalent antimonial drugs countered the successive epidemics of the disease in the Indian sub-continent and elsewhere. With time, antimony resistant LD (LD) developed and the drug in turn lost its efficacy. Infection of mammals with LD gives rise to aggressive infection as compared to its sensitive counterpart (LD) coupled with higher surge of IL-10 and TGF-β. The IL-10 causes upregulation of multidrug resistant protein-1 which causes efflux of antimonials from LD infected cells. This is believed to be a key mechanism of antimony resistance. MicroRNAs (miRNAs) are tiny post-transcriptional regulators of gene expression in mammalian cells and in macrophage play a pivotal role in controlling the expression of cytokines involved in infection process. Therefore, a change in miRNA profiles of macrophages infected with LD or LD could explain the differential cytokine response observed. Interestingly, the outcome of LD infection is also governed by the critical balance of pro- and anti-inflammatory cytokines which is inturn regulated by miRNA-Ago2 or miRNP complex and its antagonist RNA binding protein HuR. Here Ago2 plays the fulcrum whose phosphorylation and de-phosphorylation dictates the process; which in turn is controlled by PP2A and HuR. LD and LD upregulate PP2A and downregulate HuR at different magnitude leading to various levels of anti-inflammatory to proinflammatory cytokine production and resulting pathology in the host. While ectopic HuR expression alone is sufficient to clear LD infection, simultaneous upregulation of HuR and inhibition of PP2A is required to inhibit LD mediated infection. Therefore, tampering with miRNA pathway could be a new strategy to control infection caused by LD parasite.
内脏利什曼病（VL）或黑热病是由原生动物寄生虫利什曼原虫（LD）引起的。几十年来，五价锑药物对抗了印度次大陆和其他地方的疾病的连续流行。随着时间的推移，抗锑 LD（LD）发展起来，药物随之失去了疗效。与敏感的 LD 相比，LD 感染哺乳动物会引起更具侵略性的感染，同时伴有更高水平的白细胞介素 10（IL-10）和转化生长因子-β（TGF-β）的激增。IL-10 导致多药耐药蛋白 1 的上调，从而导致锑从 LD 感染细胞中流出。这被认为是抗锑耐药的一个关键机制。微小 RNA（miRNA）是哺乳动物细胞中转录后基因表达的微小调节因子，在巨噬细胞中在控制感染过程中涉及的细胞因子的表达方面发挥着关键作用。因此，感染 LD 或 LD 的巨噬细胞的 miRNA 谱的变化可以解释观察到的差异细胞因子反应。有趣的是，LD 感染的结果也受到促炎和抗炎细胞因子的关键平衡的控制，而这反过来又受到 miRNA-Ago2 或 miRNP 复合物及其拮抗剂 RNA 结合蛋白 HuR 的调节。在这里，Ago2 起着支点的作用，其磷酸化和去磷酸化决定了这个过程；而这又受到 PP2A 和 HuR 的控制。LD 和 LD 以不同的幅度上调 PP2A 和下调 HuR，导致宿主中抗炎细胞因子向促炎细胞因子产生的不同水平，并导致相应的病理学。虽然异位 HuR 表达本身足以清除 LD 感染，但同时上调 HuR 和抑制 PP2A 是抑制 LD 介导的感染所必需的。因此，干扰 miRNA 途径可能是控制 LD 寄生虫引起的感染的新策略。
