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Leishmania amazonensis sabotages host SUMOylation: a novel virulence mechanism for macrophage invasion

Leishmania amazonensis sabotages host SUMOylation: a novel virulence mechanism for macrophage invasion
亚马逊利什曼原虫破坏宿主 SUMO 化:巨噬细胞入侵的新型毒力机制
批准号:
10042732
负责人:
Kendi Okuda
金额:
$25.13万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-05-22 至 2022-04-30

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中文摘要
翻译
本建议的重点是研究一种新的利什曼原虫毒力策略
英文摘要
This proposal is focused in the study a novel Leishmania virulence strategy involved in the successful infection of mammalian macrophages — inhibition of protein SUMOylation. This virulence mechanism was discovered has a result of a cell-based genome-wide RNAi screen using Drosophila cells. The knockdown of several SUMOylation factors affected infection by amastigotes forms of Leishmania amazonensis, and further studies in mammalian macrophages revealed that L. amazonensis infection inhibited host cell SUMOylation and depletion of SUMO factor enhanced parasite replication. SUMOylation is a post-translational modification in which a member of Small Ubiquitin-like MOdifier protein (SUMO) is conjugated to target proteins. SUMOylation regulates numerous protein functions or activities, and over six thousand different SUMOylated proteins have been cataloged in HeLa and U2OS cell lines. Given its ubiquitous role in cells, we hypothesize that SUMOylation inhibition is one important virulence mechanisms of L. amazonensis. Supporting this idea, infection of SUMO depleted macrophages produced larger parasitophorous vacuoles (the replicative niche) and higher parasite proliferation. The participation of SUMOylation in parasitophorous biogenesis and in parasite replication will be studied in more detail. In a broader context, we will also determine how parasites affect SUMOylation and what is the relevance of this virulence strategy in mouse infection. Briefly, we will determine what components of the host SUMO machinery are targeted by parasites and identify parasitic virulence factors. The relevance of SUMOylation inhibition in leishmaniasis will be evaluated in infections of mice deficient in SUMOylation factors and in studies correlating virulence of different leishmania strains and SUMOylation inhibition capacity.
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Leishmania amazonensis sabotages host SUMOylation: a novel virulence mechanism for macrophage invasion
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