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Abstract：
BACKGROUND: Leishmaniasis is mainly prevalent in tropical and subtropical developing countries, where chronic undernutrition often co-exists. Undernutrition is reported to promote the progression of leishmaniasis, but its immune mechanisms have not been fully elucidated.
METHODS: To simulate chronic undernutrition of patients in epidemic areas and explore the immune mechanism of undernutrition promoting leishmaniasis, BALB/c mouse models with different nutritional imbalances were established, including undernutrition 75%, undernutrition 65% and obesity mouse models. After infection with Leishmania donovani in these model mice, we focused on evaluating the progress of leishmaniasis in the spleen and liver, the expression of important immunosuppressive and immunoactivation molecules, and changes of spleen transcriptome. The immune signaling pathways enriched by differentially expressed genes and hub genes were analyzed.
RESULTS: The results showed that among the mouse infection models, undernutrition 75% + infection group had the highest parasite load in the spleen and liver at the 8th week post-infection, possibly due to the continuous increase of PD-1, PD-L1 and TCR. Spleen RNA-seq results suggested that some immune signaling pathways were downregulated in undernutrition 75% + infection group, including neutrophil extracellular trap formation, IL-17 signaling pathway, natural killer cell-mediated cytotoxicity, etc. Among them, neutrophil extracellular trap formation pathway had the largest number of downregulated genes. This also explained why undernutrition 75% + infection group had the highest parasite load. Through PPI network analysis, hub genes such as Lcn2, Ltf, Mpo, Dnaja1, Hspa1a, Hspa1b and Hsph1 were screened out and might play important roles in the process of undernutrition promoting leishmaniasis.
CONCLUSIONS: Undernutrition upregulated PD-1 and PD-L1 expression and downregulated immune signaling pathways in mice with visceral leishmaniasis. The signaling pathways and hub genes may serve as drug targets or intervention targets for the treatment of leishmaniasis patients with undernutrition.
METHODS: To simulate chronic undernutrition of patients in epidemic areas and explore the immune mechanism of undernutrition promoting leishmaniasis, BALB/c mouse models with different nutritional imbalances were established, including undernutrition 75%, undernutrition 65% and obesity mouse models. After infection with Leishmania donovani in these model mice, we focused on evaluating the progress of leishmaniasis in the spleen and liver, the expression of important immunosuppressive and immunoactivation molecules, and changes of spleen transcriptome. The immune signaling pathways enriched by differentially expressed genes and hub genes were analyzed.
RESULTS: The results showed that among the mouse infection models, undernutrition 75% + infection group had the highest parasite load in the spleen and liver at the 8th week post-infection, possibly due to the continuous increase of PD-1, PD-L1 and TCR. Spleen RNA-seq results suggested that some immune signaling pathways were downregulated in undernutrition 75% + infection group, including neutrophil extracellular trap formation, IL-17 signaling pathway, natural killer cell-mediated cytotoxicity, etc. Among them, neutrophil extracellular trap formation pathway had the largest number of downregulated genes. This also explained why undernutrition 75% + infection group had the highest parasite load. Through PPI network analysis, hub genes such as Lcn2, Ltf, Mpo, Dnaja1, Hspa1a, Hspa1b and Hsph1 were screened out and might play important roles in the process of undernutrition promoting leishmaniasis.
CONCLUSIONS: Undernutrition upregulated PD-1 and PD-L1 expression and downregulated immune signaling pathways in mice with visceral leishmaniasis. The signaling pathways and hub genes may serve as drug targets or intervention targets for the treatment of leishmaniasis patients with undernutrition.
摘要：
背景：利什曼病主要流行于热带和亚热带发展中国家，慢性营养不良经常共存。据报道，营养不良会促进利什曼病的进展，但其免疫机制尚未完全阐明。
方法：模拟流行地区患者的慢性营养不足，探讨营养不足促进利什曼病的免疫机制，建立不同营养失衡的BALB/c小鼠模型,包括75%的营养不良,营养不良65%和肥胖小鼠模型。在这些模型小鼠中感染多诺瓦尼利什曼原虫后，我们专注于评估利什曼病在脾脏和肝脏的进展，重要的免疫抑制和免疫活化分子的表达，和脾脏转录组的变化。分析了差异表达基因和hub基因富集的免疫信号通路。
结果：结果显示，在小鼠感染模型中，营养不良75%+感染组在感染后第8周脾脏和肝脏寄生虫负荷最高，可能是由于PD-1、PD-L1和TCR的持续增加。脾脏RNA-seq结果表明，在营养不足75%+感染组中，一些免疫信号通路下调，包括中性粒细胞胞外陷阱的形成，IL-17信号通路,自然杀伤细胞介导的细胞毒性，等。其中,中性粒细胞胞外陷阱形成途径的下调基因数量最多。这也解释了为什么营养不足75%+感染组有最高的寄生虫负荷。通过PPI网络分析，集线器基因，如Lcn2，Ltf，Mpo,Dnaja1,Hspa1a,筛选出Hspa1b和Hsph1可能在营养不足促进利什曼病的过程中起重要作用。
结论：营养不足导致内脏利什曼病小鼠PD-1和PD-L1表达上调，免疫信号通路下调。信号通路和hub基因可作为利什曼病营养不足患者治疗的药物靶点或干预靶点。
方法：模拟流行地区患者的慢性营养不足，探讨营养不足促进利什曼病的免疫机制，建立不同营养失衡的BALB/c小鼠模型,包括75%的营养不良,营养不良65%和肥胖小鼠模型。在这些模型小鼠中感染多诺瓦尼利什曼原虫后，我们专注于评估利什曼病在脾脏和肝脏的进展，重要的免疫抑制和免疫活化分子的表达，和脾脏转录组的变化。分析了差异表达基因和hub基因富集的免疫信号通路。
结果：结果显示，在小鼠感染模型中，营养不良75%+感染组在感染后第8周脾脏和肝脏寄生虫负荷最高，可能是由于PD-1、PD-L1和TCR的持续增加。脾脏RNA-seq结果表明，在营养不足75%+感染组中，一些免疫信号通路下调，包括中性粒细胞胞外陷阱的形成，IL-17信号通路,自然杀伤细胞介导的细胞毒性，等。其中,中性粒细胞胞外陷阱形成途径的下调基因数量最多。这也解释了为什么营养不足75%+感染组有最高的寄生虫负荷。通过PPI网络分析，集线器基因，如Lcn2，Ltf，Mpo,Dnaja1,Hspa1a,筛选出Hspa1b和Hsph1可能在营养不足促进利什曼病的过程中起重要作用。
结论：营养不足导致内脏利什曼病小鼠PD-1和PD-L1表达上调，免疫信号通路下调。信号通路和hub基因可作为利什曼病营养不足患者治疗的药物靶点或干预靶点。
