Abstract：
BACKGROUND: Visceral leishmaniasis is a neglected tropical disease affecting millions of people worldwide. Macrophages serve as the primary host cells for L. donovani, the immune response capability of these host cells is crucial for parasites\' intracellular survival. L. donovani peptidyl-prolyl cis/trans isomerase Cyclophilin A (LdCypA) is a key protein for L. donovani intracellular proliferation, while the molecular mechanism conducive to intracellular survival of parasites remains elusive.
METHODS: In this study, we generated a macrophage cell line overexpressing LdCyPA to investigate its role in controlling host immunity and promoting intracellular immune escape of L. donovani.
RESULTS: It was discovered that the overexpression of the LdCyPA cell line regulated the host immune response following infection by downregulating the proportion of M1-type macrophages, promoting the secretion of the anti-inflammatory factor IL-4, and inhibiting the secretion of pro-inflammatory factors like IL-12, IFN-γ, TNF-α, and INOS. Transcriptome sequencing and mechanistic validation, meanwhile, demonstrated that cells overexpressing LdCyPA controlled the immune responses that followed infection by blocking the phosphorylation of P38 and JNK1/2 proteins in the MAPK signaling pathway and simultaneously increasing the phosphorylation of ERK proteins, which helped the L. donovani escape immune recognition.
CONCLUSIONS: Our findings thus pave the way for the development of host-directed antiparasitic drugs by illuminating the pro-Leishmania survival mechanism of L. donovani cyclophilin A and exposing a novel immune escape strategy for L. donovani that targets host cellular immune regulation.
METHODS: In this study, we generated a macrophage cell line overexpressing LdCyPA to investigate its role in controlling host immunity and promoting intracellular immune escape of L. donovani.
RESULTS: It was discovered that the overexpression of the LdCyPA cell line regulated the host immune response following infection by downregulating the proportion of M1-type macrophages, promoting the secretion of the anti-inflammatory factor IL-4, and inhibiting the secretion of pro-inflammatory factors like IL-12, IFN-γ, TNF-α, and INOS. Transcriptome sequencing and mechanistic validation, meanwhile, demonstrated that cells overexpressing LdCyPA controlled the immune responses that followed infection by blocking the phosphorylation of P38 and JNK1/2 proteins in the MAPK signaling pathway and simultaneously increasing the phosphorylation of ERK proteins, which helped the L. donovani escape immune recognition.
CONCLUSIONS: Our findings thus pave the way for the development of host-directed antiparasitic drugs by illuminating the pro-Leishmania survival mechanism of L. donovani cyclophilin A and exposing a novel immune escape strategy for L. donovani that targets host cellular immune regulation.
摘要：
背景：内脏利什曼病是一种被忽视的热带病，影响着全世界数百万人。巨噬细胞是多诺瓦尼乳杆菌的主要宿主细胞，这些宿主细胞的免疫反应能力对于寄生虫的细胞内存活至关重要。L.donovani肽基脯氨酸顺式/反式异构酶亲环蛋白A（LdCypA）是多诺瓦尼乳杆菌细胞内增殖的关键蛋白，而有助于寄生虫细胞内生存的分子机制仍然难以捉摸。
方法：在本研究中，我们产生了过表达LdCyPA的巨噬细胞系，以研究其在控制宿主免疫和促进唐氏乳杆菌细胞内免疫逃逸中的作用。
结果：发现LdCyPA细胞系的过表达通过下调M1型巨噬细胞的比例来调节感染后宿主的免疫反应，促进抗炎因子IL-4的分泌,抑制促炎因子IL-12、IFN-γ的分泌,TNF-α,和INOS。转录组测序和机制验证，同时,证明过表达LdCyPA的细胞通过阻断MAPK信号通路中P38和JNK1/2蛋白的磷酸化并同时增加ERK蛋白的磷酸化来控制感染后的免疫反应，帮助L.donovani逃脱了免疫识别。
结论：我们的研究结果通过阐明L.donovani亲环蛋白A的利什曼原虫存活机制并揭示了一种新的免疫逃避策略，为开发针对宿主的抗寄生虫药物铺平了道路。
方法：在本研究中，我们产生了过表达LdCyPA的巨噬细胞系，以研究其在控制宿主免疫和促进唐氏乳杆菌细胞内免疫逃逸中的作用。
结果：发现LdCyPA细胞系的过表达通过下调M1型巨噬细胞的比例来调节感染后宿主的免疫反应，促进抗炎因子IL-4的分泌,抑制促炎因子IL-12、IFN-γ的分泌,TNF-α,和INOS。转录组测序和机制验证，同时,证明过表达LdCyPA的细胞通过阻断MAPK信号通路中P38和JNK1/2蛋白的磷酸化并同时增加ERK蛋白的磷酸化来控制感染后的免疫反应，帮助L.donovani逃脱了免疫识别。
结论：我们的研究结果通过阐明L.donovani亲环蛋白A的利什曼原虫存活机制并揭示了一种新的免疫逃避策略，为开发针对宿主的抗寄生虫药物铺平了道路。
