Department of Biochemistry, University of Calcutta, Kolkata, India.
Molecular Virology Laboratory, Indian Institute of Science Education and Research Bhopal, Bhopal, India.
J Infect Dis. 2024 Jul 25;230(1):172-182. doi: 10.1093/infdis/jiae158.
Concerns regarding toxicity and resistance of current drugs in visceral leishmaniasis have been reported. Antimicrobial peptides are considered to be promising candidates and among them human cathelicidin hCAP18/LL-37 showed significant parasite killing on drug-sensitive and resistant Leishmania promastigotes, in addition to its apoptosis-inducing role. Administration of hCAP18/LL-37 to infected macrophages also decreased parasite survival and increased the host favorable cytokine interleukin 12. However, 1,25-dihydroxyvitamin D3 (vitamin D3)-induced endogenous hCAP18/LL-37 production was hampered in infected THP-1 cells. Infection also suppressed the vitamin D3 receptor (VDR), transcription factor of hCAP18/LL-37. cAMP response element modulator (CREM), the repressor of VDR, was induced in infection, resulting in suppression of both VDR and cathelicidin expression. PGE2/cAMP/PKA axis was found to regulate CREM induction during infection and silencing CREM in infected cells and BALB/c mice led to decreased parasite survival. This study documents the antileishmanial potential of cathelicidin and further identifies CREM as a repressor of cathelicidin in Leishmania infection.
目前针对内脏利什曼病中药物毒性和耐药性的问题已有相关报道。抗菌肽被认为是很有前途的候选药物，其中人源杀菌/通透性增强蛋白（cathelicidin） hCAP18/LL-37 对敏感和耐药的利什曼原虫前鞭毛体具有显著的杀伤作用，此外它还具有诱导细胞凋亡的作用。hCAP18/LL-37 给药感染的巨噬细胞也可降低寄生虫的存活并增加有利于宿主的细胞因子白细胞介素 12。然而，1,25-二羟维生素 D3（维生素 D3）诱导的内源性 hCAP18/LL-37 产生在感染的 THP-1 细胞中受到阻碍。感染还抑制了维生素 D3 受体（VDR），即 hCAP18/LL-37 的转录因子。在感染中，环磷酸腺苷反应元件调节物（CREM），即 VDR 的抑制剂被诱导，导致 VDR 和抗菌肽表达均被抑制。研究发现 PGE2/cAMP/PKA 轴在感染过程中调节 CREM 的诱导，沉默感染细胞和 BALB/c 小鼠中的 CREM 可导致寄生虫存活减少。本研究证明了抗菌肽的抗利什曼原虫作用，并进一步确定 CREM 是利什曼原虫感染中抗菌肽的抑制剂。
