BLIMP-1 Plays Important Role in the Regulation of Macrophage Pyroptosis for the Growth and Multiplication of Leishmania donovani
BLIMP-1 Plays Important Role in the Regulation of Macrophage Pyroptosis for the Growth and Multiplication of Leishmania donovani
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DOI：
10.1021/acsinfecdis.9b00186
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发表时间：
2019-12-01
影响因子：
5.3
通讯作者：
Dubey, Vikash Kumar
中科院分区：
文献类型：
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作者：
Saha, Gundappa;Khamar, Bakulesh M.;Dubey, Vikash Kumar
内脏利什曼病是该疾病的致命形式之一，由杜氏利什曼原虫引起，并呈现病态的临床表现。寄生虫通过几种已报道的机制逃避促炎免疫应答，并调节宿主免疫系统以引起致命症状。已经记录了大量与BIMP-1的作用及其参与抑制各种感染性疾病中的免疫应答相关的报道。由于BLIMP-1产量增加而导致的更高的寄生虫负担在疟疾和利什曼病中已有报道，但没有详细信息。我们首次报道了BLIMP-1在抑制L. donovani感染，从而调整NFK β-LRP 3信号通路的严格调节。使用实时PCR和Western印迹法测量了BLIMP-1和NFK κ β的表达分析。已经使用siRNA介导的实验沿着半胱天冬酶1活性、LDH释放测定和感染性指数分析来验证BLIMP-1的重要性。在L. donovani感染，其在感染前鞭毛体的blimp-1缺陷细胞中逆转。以上事实已经用半胱天冬酶1活性测定和LDH释放沿着IFN γ和TNF-α释放测定进一步验证。最后，与野生型感染的细胞相比，在感染的blimp-1缺陷型细胞中已经得出了焦亡恢复的结论。我们推测寄生虫通过利用BLIMP-1依赖性IL-10产生并最终破坏感染细胞中炎症介导的细胞凋亡途径来调节NF κ β-NLRP 3信号通路。
Visceral leishmaniasis, one of the fatal forms of the disease, is caused by Leishmania donovani and presents morbid clinical manifestations. The parasite evades pro inflammatory immune responses by several reported mechanisms and modulates the host immune system to cause fatal symptoms. A plethora of reports related to the role of BLIMP-1 and its involvement in suppressing the immune response in various infectious diseases have been documented. Higher parasitic burden due to increased BLIMP-1 production has been reported earlier for malaria and leishmaniasis with no detailed information. We report for the first time the role of BLIMP-1 in suppressing macrophage pyroptosis during L. donovani infection and thereby tweaking the tight regulation of the NFK beta-LRP3 signaling pathway. Expression analyses of BLIMP-1 and NFK kappa beta have been measured using real-time PCR and Western blotting. The importance of BLIMP-1 has been validated using a siRNA-mediated experiment along with caspase 1 activity, LDH release assay, and infectivity index analyses. An inverse relationship between BLIMP-1 and NF kappa beta expression has been highlighted during L. donovani infection, which is reversed in blimp-1 deficient cells infected with promastigotes. The above fact has been further validated with caspase 1 activity assay, and LDH release along with IFN gamma and TNF-alpha release assay. Finally, resumption of pyroptosis has been concluded in infected blimp-1 deficient cells in contrast to wild type infected cells. We conjecture that parasites modulate the NF kappa beta-NLRP3 signaling pathway by taking advantage of BLIMP-1 dependent IL-10 production and finally disrupting an inflammation mediated pyroptosis cell death pathway in infected cells.