Tissue specific dual RNA-seq defines host-parasite interplay in murine visceral leishmaniasis caused by Leishmania donovani and Leishmania infantum
Tissue specific dual RNA-seq defines host-parasite interplay in murine visceral leishmaniasis caused by Leishmania donovani and Leishmania infantum
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DOI：
10.1101/2022.02.04.479211
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发表时间：
2022-02
期刊：
影响因子：
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通讯作者：
Sarah Forrester;A. Goundry;Bruna T. Dias;Thyago Leal-Calvo;M. Moraes;P. Kaye;J. Mottram;A. Lima
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作者：
Sarah Forrester;A. Goundry;Bruna T. Dias;Thyago Leal-Calvo;M. Moraes;P. Kaye;J. Mottram;A. Lima
在临床前动物模型和人类中，内脏利什曼病与肝脾肿大以及免疫和血液学参数改变相关。本研究采用双重RNA-seq技术研究了由婴儿利什曼原虫和杜氏利什曼原虫感染的BALB/c小鼠内脏利什曼病，探讨宿主和寄生虫在肝脏和脾脏中的转录应答。我们在脾脏中仅鉴定了4种寄生虫特异性表达基因（SSPEG; log 2FC>1，FDR 1，FDR <0.05），这是两种感染所共有的，IFNγ信号传导和补体和凝血级联途径高度富集，另外还有286和186个DEG对L. donovani和L.婴儿感染。其中，L. donovani感染和IL 1 β增加以及脂肪酸转运的正调节。婴儿感染，虽然没有观察到途径富集。在肝脏中，有1939 DEG在感染L。infantum或L.与未感染的小鼠相比，donovani感染的小鼠中，最丰富的途径是IFNγ信号传导、中性粒细胞介导的免疫、补体和凝血、丝氨酸-趋化因子应答和止血。此外，221个DEG在L. donovani和L.婴儿感染这些数据表明，这两种内脏利什曼病感染模型的宿主反应大致相似，并且约10%的宿主DEG在感染任一寄生虫物种时不同。内脏利什曼病（VL）是由两种利什曼原虫引起的，L。donovani和L.新大陆和地中海沿岸国家的婴儿。虽然肝脾肿大和血液及免疫功能改变等主要特征是明显的，但临床表现可能因地理位置而异，例如在巴西，严重出血通常与VL相关。虽然两种L. donovani和L.虽然婴儿的寄生虫已被广泛用于研究疾病的发病机制，但这些寄生虫物种如何影响感染的宿主和/或它们如何响应哺乳动物感染的应激的直接并排比较先前尚未报道。确定共同的和不同的发病途径将是重要的，以确保新的治疗或预防方法将适用于所有形式的VL。
Visceral leishmaniasis is associated with hepato-splenomegaly and altered immune and haematological parameters in both pre-clinical animal models and humans. We studied mouse experimental visceral leishmaniasis caused by Leishmania infantum and Leishmania donovani in BALB/c mice using dual RNA-seq to investigate the transcriptional response of host and parasite in liver and spleen. We identified only 4 species-specific parasite expressed genes (SSPEGs; log2FC >1, FDR 1, FDR <0.05) in the spleen that were common to both infections, with IFNγ signaling and complement and coagulation cascade pathways highly enriched, and an additional 286 and 186 DEGs that were selective to L. donovani and L. infantum infection respectively. Among those, there were network interactions between genes of amino acid metabolism and PPAR signaling in L. donovani infection and increased IL1β and positive regulation of fatty acid transport in L. infantum infection, although no pathway enrichment was observed. In the liver, there were 1939 DEGs in mice infected with either L. infantum or L. donovani in comparison to uninfected mice, and the most enriched pathways were IFNγ signaling, neutrophil mediated immunity, complement and coagulation, cytokine-chemokine responses and hemostasis. Additionally, 221 DEGs were selective in L. donovani and 429 DEGs in L. infantum infections. These data show that the host response for these two visceral leishmaniasis infection models is broadly similar, and ∼10% of host DEGs vary in infections with either parasite species. Importance Visceral leishmaniasis (VL) is caused by two species of Leishmania parasites, L. donovani in the Old World and L. infantum in the New World and countries bordering the Mediterranean. Although cardinal features such as hepato-splenomegaly and alterations in blood and immune function are evident, clinical presentation may vary by geography, with for example severe bleeding often associated with VL in Brazil. Although animal models of both L. donovani and L. infantum have been widely used to study disease pathogenesis, a direct side-by-side comparison of how these parasites species impact the infected host and/or how they might respond to the stresses of mammalian infection has not been previously reported. Identifying common and distinct pathways to pathogenesis will be important to ensure that new therapeutic or prophylactic approaches will be applicable across all forms of VL.