Myxoma virus lacking the host range determinant M062 stimulates cGAS-dependent type 1 interferon response and unique transcriptomic changes in human monocytes/macrophages.
Myxoma virus lacking the host range determinant M062 stimulates cGAS-dependent type 1 interferon response and unique transcriptomic changes in human monocytes/macrophages.
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DOI：
10.1371/journal.ppat.1010316
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发表时间：
2022-09
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
痘病毒在进化上的成功具有有效和多样的策略来规避或克服宿主的防御机制。痘病毒编码许多免疫调节蛋白以逃避宿主免疫以建立生产性感染，并且具有抑制DNA感测依赖性1型干扰素（IFN-I）应答的独特手段，鉴于其dsDNA基因组和仅胞质生命周期，这是必需的。我们发现，痘病毒感染的关键DNA感应抑制在DNA复制之前的痘病毒感染早期阶段占主导地位。为了鉴定抑制抗病毒促炎反应的痘病毒基因产物（例如，IFN-I应答），我们研究了一个早期基因的功能，该基因是来自高度保守的痘病毒宿主范围C7 L超家族粘液瘤病毒（MYXV）M062的已知宿主范围决定簇。宿主范围因子是痘病毒的独特特征，决定了痘病毒的种属和细胞类型嗜性。几乎所有测序的哺乳动物痘病毒都保留了痘病毒宿主范围C7 L超家族的至少一个同源物。在兔特异性痘病毒MYXV中，C7 L超家族的优势和广谱宿主范围决定因子是M062 R基因。M062 R基因产物在来自不同哺乳动物物种的几乎所有检测细胞中对MYXV感染都是必需的，并且特异性抑制宿主含不育α基序结构域9（SAMD 9）的功能，因为M062 R无效（Δ M062 R）MYXV以SAMD 9依赖性方式引起流产感染。在这项研究中，我们研究了Δ M062 R的免疫刺激特性。我们发现，复制缺陷型Δ M062 R在感染期间以cGAS依赖性方式激活宿主DNA传感通路，并且敲低SAMD 9表达减弱促炎反应。此外，转录组学分析显示了不同于单独dsDNA刺激的炎症状态的宿主基因表达景观的独特特征。这项研究建立了SAMD 9的抗肿瘤功能和先天免疫应答调节之间的联系。痘病毒编码一组称为宿主范围决定因子的基因，以维持或扩大其宿主向性。许多病毒宿主范围因子发挥作用的机制仍不清楚。一些宿主范围因子具有免疫调节功能，负责逃避或破坏宿主免疫防御机制。大多数已知的痘病毒编码的免疫调节蛋白是病毒在体外复制所必需的。MYXV M062 R的独特之处在于它是体外病毒感染所必需的，并且属于最保守的痘病毒宿主范围家族之一，C7 L超家族。MYXV M062蛋白有一个已知的宿主靶标SAMD 9。SAMD 9在哺乳动物细胞中组成型表达，并仅存在于细胞质中，具有抗肿瘤功能。在SAMD 9中具有有害突变的人呈现的疾病范围从年轻时的致死性到通常需要骨髓移植的骨髓增生异常综合征（MDS）的易感性。更重要的是，SAMD 9是许多病毒的重要抗病毒内在分子。SAMD 9的细胞功能仍然不清楚，主要是由于研究这种蛋白质的困难，即，其大尺寸、长半衰期和其在大多数细胞中的组成型表达。在这项研究中，我们使用M062 R-null MYXV作为研究SAMD 9功能的工具，并报告了SAMD 9与cGAS依赖性DNA传感触发的促炎反应调节之间的功能联系。
The evolutionarily successful poxviruses possess effective and diverse strategies to circumvent or overcome host defense mechanisms. Poxviruses encode many immunoregulatory proteins to evade host immunity to establish a productive infection and have unique means of inhibiting DNA sensing-dependent type 1 interferon (IFN-I) responses, a necessity given their dsDNA genome and exclusively cytoplasmic life cycle. We found that the key DNA sensing inhibition by poxvirus infection was dominant during the early stage of poxvirus infection before DNA replication. In an effort to identify the poxvirus gene products which subdue the antiviral proinflammatory responses (e.g., IFN-I response), we investigated the function of one early gene that is the known host range determinant from the highly conserved poxvirus host range C7L superfamily, myxoma virus (MYXV) M062. Host range factors are unique features of poxviruses that determine the species and cell type tropism. Almost all sequenced mammalian poxviruses retain at least one homologue of the poxvirus host range C7L superfamily. In MYXV, a rabbit-specific poxvirus, the dominant and broad-spectrum host range determinant of the C7L superfamily is the M062R gene. The M062R gene product is essential for MYXV infection in almost all cells tested from different mammalian species and specifically inhibits the function of host Sterile α Motif Domain-containing 9 (SAMD9), as M062R-null (ΔM062R) MYXV causes abortive infection in a SAMD9-dependent manner. In this study we investigated the immunostimulatory property of the ΔM062R. We found that the replication-defective ΔM062R activated host DNA sensing pathway during infection in a cGAS-dependent fashion and that knocking down SAMD9 expression attenuated proinflammatory responses. Moreover, transcriptomic analyses showed a unique feature of the host gene expression landscape that is different from the dsDNA alone-stimulated inflammatory state. This study establishes a link between the anti-neoplastic function of SAMD9 and the regulation of innate immune responses. Poxviruses encode a group of genes called host range determinants to maintain or expand their host tropism. The mechanism by which many viral host range factors function remains elusive. Some host range factors possess immunoregulatory functions responsible for evading or subduing host immune defense mechanisms. Most known immunoregulatory proteins encoded by poxviruses are dispensable for viral replication in vitro. The uniqueness of MYXV M062R is that it is essential for viral infection in vitro and belongs to one of the most conserved poxvirus host range families, the C7L superfamily. There is one known host target of the MYXV M062 protein, SAMD9. SAMD9 is constitutively expressed in mammalian cells and exclusively present in the cytoplasm with an anti-neoplastic function. Humans with deleterious mutations in SAMD9 present disease that ranges from lethality at a young age to a predisposition to myelodysplastic syndromes (MDS) that often require bone marrow transplantation. More importantly, SAMD9 serves as an important antiviral intrinsic molecule to many viruses. The cellular function of SAMD9 remains unclear mostly due to the difficulty of studying this protein, i.e., its large size, long half-life, and its constitutive expression in most cells. In this study we used M062R-null MYXV as a tool to study SAMD9 function and report a functional link between SAMD9 and the regulation of the proinflammatory responses triggered by cGAS-dependent DNA sensing.
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影响因子：
11.3
作者：
Chan WM;McFadden G
通讯作者：
McFadden G
影响因子：
28.3
作者：
Albarnaz JD;Ren H;Torres AA;Shmeleva EV;Melo CA;Bannister AJ;Brember MP;Chung BY;Smith GL
通讯作者：
Smith GL
影响因子：
2
作者：
Kwiecien, Jacek M.;Dabrowski, Wojciech;Lucas, Alexandra R.
通讯作者：
Lucas, Alexandra R.
影响因子：
5.4
作者：
Johnston, JB;Barrett, JW;McFadden, G
通讯作者：
McFadden, G
DOI：
10.1073/pnas.1710336114
发表时间：
2017-08-29
影响因子：
11.1
作者：
Kerr, Peter J.;Cattadori, Isabella M.;Read, Andrew F.
通讯作者：
Read, Andrew F.