Leishmania RNA viruses and pathogenesis

利什曼原虫 RNA 病毒和发病机制

• 批准号: 10159855
• 负责人: Stephen M Beverley
• 金额: $ 66.65万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159855
• 关键词: Acute; Americas; Animal Model; Antiviral Agents; Area; Biochemical; Bunyavirales; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Complement; Curiosities; Data; Dendritic Cells; Disease; Double Stranded RNA Virus; Double-Stranded RNA; Evolution; Experimental Animal Model; Family; Frequencies; Gene Expression Profile; Genetic; Human; IL17 gene; Immune; Infection; Inflammatory Response; Interferon Type I; Interferon Type II; Interferons; Investigation; Knockout Mice; Knowledge; Leishmania; Leishmania guyanensis; Leishmaniavirus; Mediating; Modeling; Modification; Molecular; Molecular Virology; Mucocutaneous leishmaniasis; Neoplasm Metastasis; Open Reading Frames; Orthobunyavirus; Parasite Control; Parasitemia; Parasites; Parasitic Diseases; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Pentamidine; Pharmacotherapy; Prevalence; Proteins; RNA; RNA Interference; RNA Viruses; Rodent Model; Role; Series; Severities; Severity of illness; Signal Transduction; Solid; Structure; Surveys; TLR3 gene; Technology; Testing; Time; Totivirus; Treatment Failure; Ursidae Family; Viannia; Viral Pathogenesis; Virulence; Virulence Factors; Virus; Virus Replication; Work; cytokine; genetic approach; human disease; insight; macrophage; novel; novel diagnostics; parasitism; pathogen; response; targeted agent; tool; transcriptomics; virology

Project summary. Previously we showed that in experimental animal models, the presence of the dsRNA virus LRV1 infecting strains of Leishmania guyanensis confers elevated pathology and metastasis, mediated by a TLR3-dependent inflammatory response. The relevancy of this finding to humans was established by recent findings that patients infected with Leishmania bearing LRV1 show an elevated frequency of drug treatment failures, as well increased pathology and cytokine responses. Here we extend these studies to L. braziliensis, first by developing new animal models and tools. The newly discovered bunyavirus- like virus “TOP” will be a high priority; TOP occurs in >95% of all L. braziliensis strains examined and the majority of related Viannia species. Extensive preliminary data suggest a strong role in virulence, potentially exceeding that of LRV1. In Aim 1 we will study mechanisms of LRV1- and TOP-dependent virulence. A well-chosen series of isogenic lines showing different combinations of LRV1 and/or TOP (virotypes) will be established and their virulence characterized. These will then be used to probe the mechanism of LRV1-dependent virulence, which is associated with a strong macrophage response similar to that induced by type I interferons. TOP-dependent virulence seems to act through a completely different mechanism, independent of interferon and likely involving dendritic cells. In Aim 2 we focus on molecular virology, especially of TOP, as these studies will likely inform efforts to inhibit these viruses directly. We established that TOP is a highly divergent lineage within a new family of the Bunyavirales termed “Leishbunyaviridae”. Since these novel features arose precisely at the time deep in evolution when Leishmania transitioned from monxenous to dixenous/vertebrate parasitism, these structural differences are likely to contribute to the TOP pathogenic mechanism. We will explore their coding potential and the existence and role(s) of predicted proteins, and use genetic approaches to functional test their role in viral replication and virulence.

项目总结。 之前我们表明，在实验动物模型中，存在感染 dsRNA 病毒 LRV1 圭亚那利什曼原虫菌株导致病理学和转移升高，由 TLR3 依赖性介导 最近的研究结果证实了这一发现与人类的相关性。 感染带有 LRV1 的利什曼原虫的患者药物治疗失败的频率也较高 在这里，我们首先将这些研究扩展到巴西乳杆菌。 开发新的动物模型和工具，新发现的布尼亚病毒样病毒“TOP”将是一个很高的目标。 优先；超过 95% 的巴西乳杆菌和大多数相关的维安尼亚菌株均出现 TOP 广泛的初步数据表明其毒力作用很强，可能超过 LRV1。 目标 1 我们将研究 LRV1 和 TOP 依赖性毒力的机制精心挑选的一系列同基因系。 将建立显示 LRV1 和/或 TOP（病毒型）的不同组合及其毒力 然后将这些特征用于探究 LRV1 依赖性毒力的机制。 与 I 型干扰素诱导的强烈巨噬细胞反应相关。 毒力似乎通过完全不同的机制起作用，独立于干扰素并且可能 在目标 2 中，我们重点关注分子病毒学，尤其是涉及 TOP 的分子病毒学，因为这些研究可能会 我们确定 TOP 是一个高度分化的谱系，可直接抑制这些病毒。 Bunyavirales 的新科被称为“Leishbunyaviridae”，因为这些新特征正是在 在进化的深处，利什曼原虫从蜥蜴类/脊椎动物寄生转变为蜥蜴类/脊椎动物寄生， 这些结构差异可能导致 TOP 致病机制。 编码潜力以及预测蛋白质的存在和作用，并使用遗传方法来实现功能 测试它们在病毒复制和毒力中的作用。