Toxoplasma gondii virulence factor ROP1 reduces parasite susceptibility to murine and human innate immune restriction.
Toxoplasma gondii virulence factor ROP1 reduces parasite susceptibility to murine and human innate immune restriction.
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DOI：
10.1371/journal.ppat.1011021
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发表时间：
2022-12
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
弓形虫是一种细胞内寄生虫，可感染许多宿主物种，是世界范围内人类发病率高的一个原因。T.弓形虫向宿主细胞中分泌多种对感染至关重要的效应蛋白。绝大多数这些分泌的蛋白质没有预测的功能结构域，仍然是未确定的。在这里，我们在T.弓形虫Prugniaud株的体内试验，以鉴定有助于宿主中寄生虫免疫逃避的分泌蛋白。我们证明，ROP 1，第一个确定的棒状蛋白的T。弓形虫是毒力所必需的，并且在寄生虫对干扰素γ介导的先天性免疫限制的抗性中具有先前未认识到的作用。该功能在高毒力RH株T.弓形虫，并有助于寄生虫在鼠和人巨噬细胞中的生长。虽然ROP 1影响棒状体的形态，但它不影响棒状体的分泌。最后，我们发现ROP 1与宿主细胞蛋白C1QBP（一种新兴的先天免疫信号调节剂）共免疫沉淀。总之，我们确定了T。弓形虫Prugniaud菌株的研究表明，ROP 1是一种重要的，以前被忽视的效应蛋白，它可以抵消鼠和人的先天免疫。弓形虫是一种单细胞真核病原体，可以感染许多不同的物种，包括小鼠和人类。T.弓形虫会分泌大量蛋白质到它所感染的宿主细胞中，尽管这些蛋白质中的大多数还没有得到很好的研究。我们已经进行了淘汰筛选，以确定T。这些基因对于寄生虫在感染小鼠期间的存活非常重要。我们发现的一个基因编码寄生虫蛋白ROP 1，该蛋白在30年前被证明可以分泌到宿主细胞中，但其功能仍然未知。我们表明，ROP1的缺失会导致一种致命的感染被宿主免疫系统有效地清除。ROP 1对T.弓形虫逃避人类和小鼠细胞的细胞自主免疫反应，这是常见的，因为控制细胞内病原体的关键机制在人类和小鼠之间不同。ROP1可能与宿主蛋白C1QBP相互作用，表明未来工作的方向是建立与免疫逃避的机制联系。
Toxoplasma gondii is an intracellular parasite that can infect many host species and is a cause of significant human morbidity worldwide. T. gondii secretes a diverse array of effector proteins into the host cell which are critical for infection. The vast majority of these secreted proteins have no predicted functional domains and remain uncharacterised. Here, we carried out a pooled CRISPR knockout screen in the T. gondii Prugniaud strain in vivo to identify secreted proteins that contribute to parasite immune evasion in the host. We demonstrate that ROP1, the first-identified rhoptry protein of T. gondii, is essential for virulence and has a previously unrecognised role in parasite resistance to interferon gamma-mediated innate immune restriction. This function is conserved in the highly virulent RH strain of T. gondii and contributes to parasite growth in both murine and human macrophages. While ROP1 affects the morphology of rhoptries, from where the protein is secreted, it does not affect rhoptry secretion. Finally, we show that ROP1 co-immunoprecipitates with the host cell protein C1QBP, an emerging regulator of innate immune signaling. In summary, we identify putative in vivo virulence factors in the T. gondii Prugniaud strain and show that ROP1 is an important and previously overlooked effector protein that counteracts both murine and human innate immunity. Toxoplasma gondii is a single-celled eukaryotic pathogen that can infect many different species, including mice and humans. T. gondii secretes a large number of proteins into host cells that it infects, although the majority of these proteins are not well studied. We have carried out a knockout screen to identify T. gondii genes that are important for the parasite to survive during infection of a mouse. One of the genes we identified encodes the parasite protein ROP1, which was shown 30 years ago to be secreted into the host cell, but whose function remains unknown. We show that deletion of ROP1 causes an otherwise lethal infection to be efficiently cleared by the host immune system. ROP1 is important for T. gondii to evade the cell autonomous immune responses of both human and murine cells, which is usual as the key mechanisms that control intracellular pathogens differ between humans and mice. ROP1 may interact with the host protein C1QBP, indicating the direction of future work to establish a mechanistic link to immune evasion.
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DOI：
10.1084/jem.20201314
发表时间：
2021-11-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Frickel EM;Hunter CA
通讯作者：
Hunter CA
影响因子：
4.4
作者：
Cox, Juergen;Neuhauser, Nadin;Mann, Matthias
通讯作者：
Mann, Matthias
DOI：
10.1073/pnas.1515966112
发表时间：
2015-10-13
影响因子：
11.1
作者：
Haldar, Arun K.;Foltz, Clemence;Coers, Joern
通讯作者：
Coers, Joern
影响因子：
30.3
作者：
Jensen KD;Wang Y;Wojno ED;Shastri AJ;Hu K;Cornel L;Boedec E;Ong YC;Chien YH;Hunter CA;Boothroyd JC;Saeij JP
通讯作者：
Saeij JP
影响因子：
4.5
作者：
Behnke MS;Khan A;Lauron EJ;Jimah JR;Wang Q;Tolia NH;Sibley LD
通讯作者：
Sibley LD