Department of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China.
Department of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China; Sichuan-Chongqing jointly-established Research Platform of Zoonosis, Chengdu, China.
Immunobiology. 2023 Sep;228(5):152725. doi: 10.1016/j.imbio.2023.152725. Epub 2023 Aug 6.
Most of the existing Leishmania-related research about TLR-2 agonists was focusing on their role as adjuvants in the vaccine, few studied its therapeutic effect. This paper aims to explore the therapeutic effect of TLR-2 agonist Pam3CSK4 on Leishmania-infected mice and the underlying immune molecular mechanisms. In L. donovani-infected BALB/c mice, one group was treated with Pam3CSK4 after infection and the other group was not treated. Normal uninfected mice treated with Pam3CSK4 or untreated were used as controls. Parasite load, hepatic pathology and serum antibodies were detected to assess the severity of the infection. The expression of immune-related genes, spleen lymphocyte subsets and liver RNA-seq were employed to reveal possible molecular mechanisms. The results showed that the liver and spleen parasite load of infected mice in Pam3CSK4 treated and untreated groups had no statistical difference, indicating Pam3CSK4 might have no therapeutic effect on visceral leishmaniasis. Infected mice treated with Pam3CSK4 possessed more hepatic inflammation focus, lower IgG and IgG2a antibody titers, and a lower proportion of spleen CD3CD4 T cells. Transcriptome analysis revealed that Th1/Th2 differentiation, NK cells, Th17 cell, complement system and calcium signaling pathways were down-regulated post-treatment of Pam3CSK4. In this study, TLR-2 agonist Pam3CSK4 showed no therapeutic effect on visceral leishmaniasis in BALB/c mice and might enhance the pathogenesis of the disease possibly due to the down-regulation of several immune-related pathways, which can improve our understanding of the role of TLR-2 in both treatment and vaccine development.
大多数与 TLR-2 激动剂相关的利什曼原虫研究都集中在其作为疫苗佐剂的作用上，很少有研究其治疗效果。本文旨在探讨 TLR-2 激动剂 Pam3CSK4 对感染利什曼原虫的小鼠的治疗效果及其潜在的免疫分子机制。在感染 L. donovani 的 BALB/c 小鼠中，一组在感染后用 Pam3CSK4 治疗，另一组未治疗。正常未感染的小鼠用 Pam3CSK4 治疗或未治疗作为对照。检测寄生虫载量、肝病理和血清抗体，以评估感染的严重程度。检测免疫相关基因的表达、脾淋巴细胞亚群和肝 RNA-seq，以揭示可能的分子机制。结果表明，Pam3CSK4 治疗和未治疗组感染小鼠的肝和脾寄生虫载量无统计学差异，表明 Pam3CSK4 对内脏利什曼病可能没有治疗作用。用 Pam3CSK4 治疗的感染小鼠具有更多的肝炎症焦点、更低的 IgG 和 IgG2a 抗体滴度以及更低比例的脾 CD3CD4 T 细胞。转录组分析显示，Th1/Th2 分化、NK 细胞、Th17 细胞、补体系统和钙信号通路在 Pam3CSK4 治疗后下调。在这项研究中，TLR-2 激动剂 Pam3CSK4 对 BALB/c 小鼠的内脏利什曼病没有治疗作用，并且可能由于几种免疫相关途径的下调而增强疾病的发病机制，这可以提高我们对 TLR-2 在治疗和疫苗开发中的作用的理解。
