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Studies in Poxvirus Evasion of SAMD9 Pathway

痘病毒逃避 SAMD9 通路的研究

基本信息

批准号：
10534756
负责人：
Jia Liu
金额：
$ 37.27万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10534756
关键词：
Affect Antiviral Response Binding Bioterrorism Cell Culture Techniques Cell membrane Cells Clinical Cyclic GMP Cytoplasm DNA DNA Binding DNA Binding Domain DNA Replication Inhibition DNA Viruses DNA biosynthesis Data Defect Desmosomes Development Effectiveness Environment European Functional disorder Goals Health Human IRF3 gene Immune Evasion Immune response Immunity Infection Innate Immune Response Intercellular Junctions Interferon Type I Interferons Interruption Knowledge Lateral Left Life Cycle Stages Link Malignant Neoplasms Mediating Membrane Modeling Molecular Monitor Mutagenesis Mutation Myxoma virus Natural Immunity Oncolytic viruses Orthopoxvirus Oryctolagus cuniculus Pathogenesis Pathway interactions Penetration Play Population Poxviridae Poxviridae Infections Predisposition Productivity Property Proteins Proteomics Regulation Role SAM Domain Signal Transduction Single-Stranded DNA Stimulator of Interferon Genes Stimulus Structure Testing Tropism Vaccination Variola major virus Vial device Viral Viral Pathogenesis Viral Physiology Viral Proteins Virus Virus Diseases Virus Inhibitors desmoplakin ds-DNA immunotherapeutic virotherapy improved model organism novel novel therapeutics pathogenic virus prevent response therapy outcome tool tumor viral DNA

项目摘要

PROJECT SUMMARY/ABSTRACT The more than 40-year cessation in smallpox virus vaccinations after the eradication of variola virus (VARV) has left a growing population in the US and globally vulnerable to orthopoxvirus infection. Concerns of bioterrorism usage of VARV or other species of orthopoxvirus necessitate an in-depth understanding of poxvirus immune evasion of the host. With the current immunity gap identification of new treatment targets for development of novel therapeutics remains a critical task. On the other hand, clinical use of poxviruses to treat cancer requires comprehensive knowledge of poxvirus-induced cellular response that can improve therapeutic outcome. Our long-term goal is to improve understanding of the host intrinsic immunity that not only protects the host from viral infection but also can be stimulated to facilitate the elimination of malignancy. The goal of the proposed study is to understand how additional mechanisms enforce species barrier that can prevent cross-species viral infection and how we discover and investigate new antiviral pathways using poxviruses as model organisms. More importantly, sensing of cytoplasmic DNA leads to induction of type 1 interferon (IFN-I) and while we found new regulation of host DNA sensing pathway we investigate viral strategy to evade it that affects pathogenesis. We will study species barrier function and the antiviral function of a host protein, sterile α motif domain-containing protein 9 (SAMD9). SAMD9 plays a central role in human health and possesses antiviral effect to a broad-spectrum of viral pathogens. However, its function is poorly characterized. To study SAMD9's antiviral properties, we utilize myxoma virus (MYXV) as the model organism. MYXV is a rabbit-specific poxvirus causing lethal infection in European rabbits and a candidate oncolytic virus to treat human cancers. We previously identified MYXV M062 as the viral inhibitor of SAMD9. We thus utilize viral M062 and M062R-null MYXV as probing tools to study SAMD9 function. Our central hypothesis is that SAMD9 detects poxvirus infection and DNA replication, and once it binds to poxvirus DNA it inhibits DNA replication while inducing IFN-I responses that affects viral pathogenesis. To test our hypothesis, we propose the following studies: (1) To understand the mechanism of SAMD9 for the inhibition of viral DNA replication and for induction of IFN-I; (2) To investigate how inhibiting SAMD9 affects pathogenesis; and (3) to study how SAMD9 mediates the host species barrier function. Through the completion of the proposed study, we will fill a critical gap in our knowledge of host regulation linking the inducible antiviral response and the intrinsic immunity. This improves our understanding of the mechanism for immunotherapeutic virotherapy using MYXV. We also characterize a novel class of viral evasion of host immune response.

项目总结/摘要天花病毒根除后，天花病毒疫苗接种停止了40多年（VARV）使美国和全球人口不断增长，易受正痘病毒感染。关切 VARV或其他正痘病毒物种的生物恐怖主义使用需要深入了解痘病毒对宿主的免疫逃避。随着目前免疫差距的确定，新的治疗目标，新型疗法的开发仍然是一项关键任务。另一方面，临床上使用痘病毒来治疗癌症需要全面了解痘病毒诱导的细胞反应，结果。我们的长期目标是提高对宿主固有免疫的理解，不仅保护使宿主免受病毒感染，而且还可以受到刺激，促进恶性肿瘤的消除。拟议研究的目标是了解其他机制如何加强物种屏障可以预防跨物种病毒感染以及我们如何发现和研究新的抗病毒途径使用痘病毒作为模式生物。更重要的是，细胞质DNA的传感导致诱导型 1干扰素（IFN-I），虽然我们发现了宿主DNA传感途径的新调节，但我们研究了病毒策略，以避免它的影响发病机制。我们将研究物种屏障功能和抗病毒功能，一种宿主蛋白，不育α基序结构域蛋白9（SAMD 9）。SAMD 9在人类免疫系统中起着重要作用。对广谱病毒病原体具有抗病毒作用。然而，其功能较差表征了为了研究SAMD 9的抗病毒特性，我们利用粘液瘤病毒（MYXV）作为模式生物。 MYXV是一种兔特异性痘病毒，可引起欧洲兔的致死性感染，也是一种候选的溶瘤病毒来治疗人类癌症。我们先前鉴定MYXV M062为SAMD 9的病毒抑制剂。因此，我们利用病毒M062和M062 R-null MYXV作为探测工具来研究SAMD 9功能。我们的核心假设是， SAMD 9检测痘病毒感染和DNA复制，一旦它与痘病毒DNA结合，它就会抑制DNA 复制，同时诱导影响病毒发病机制的IFN-I应答。为了验证我们的假设，我们建议主要研究内容如下：（1）了解SAMD 9抑制病毒DNA复制的机制和诱导IFN-1;（2）研究抑制SAMD 9如何影响发病机制;（3）研究如何 SAMD 9介导宿主物种屏障功能。通过完成拟议的研究，我们将填补我们对主机知识的一个关键空白调节连接诱导的抗病毒反应和固有免疫。这增进了我们对使用MYXV进行免疫病毒治疗的机制。我们还描述了一类新的病毒逃避宿主的免疫反应。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Evolutionary potential of the monkeypox genome arising from interactions with human APOBEC3 enzymes.

DOI：
10.1093/ve/vead047
发表时间：
2023
期刊：
Virus evolution
影响因子：
5.3
作者：
通讯作者：

Evolutionary potential of the monkeypox genome arising from interactions with human APOBEC3 enzymes.

猴痘基因组因与人类 APOBEC3 酶相互作用而产生的进化潜力。

DOI：
10.1101/2023.06.27.546779
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Delamonica,Brenda;Davalos,Liliana;Larijani,Mani;Anthony,SimonJ;Liu,Jia;MacCarthy,Thomas
通讯作者：
MacCarthy,Thomas

Myxoma virus lacking the host range determinant M062 stimulates cGAS-dependent type 1 interferon response and unique transcriptomic changes in human monocytes/macrophages.

DOI：
10.1371/journal.ppat.1010316
发表时间：
2022-09
期刊：
PLoS pathogens
影响因子：
6.7
作者：
通讯作者：

Synergistic Combination of Oncolytic Virotherapy and Immunotherapy for Glioma.

DOI：
10.1158/1078-0432.ccr-18-3626
发表时间：
2020-05-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Tang B;Guo ZS;Bartlett DL;Yan DZ;Schane CP;Thomas DL;Liu J;McFadden G;Shisler JL;Roy EJ
通讯作者：
Roy EJ

Stress Beyond Translation: Poxviruses and More.

翻译之外的压力：痘病毒等。