Identifying host and viral correlates for coronavirus pathogenesis
识别冠状病毒发病机制的宿主和病毒相关性
基本信息
- 批准号:10192654
- 负责人:
- 金额:$ 49.79万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-06-15 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AttenuatedAutomobile DrivingBindingBody Weight decreasedCellsChimera organismChiropteraClustered Regularly Interspaced Short Palindromic RepeatsCoronavirusCoronavirus InfectionsCoronavirus spike proteinDataDiseaseDrug usageEpidemicFamilyGoalsHumanImmune responseImpairmentIn VitroInfectionIntegration Host FactorsLungMediatingMiddle East Respiratory Syndrome CoronavirusModelingMonitorMusMutationPathogenesisPeptide HydrolasesPharmacotherapyProteinsSARS coronavirusSerine ProteaseSevere Acute Respiratory SyndromeStructural ModelsStructureSystemTestingTropismViralVirulenceVirusWorkZoonosesattenuationbasecoronavirus receptorcross-species transmissionexperimental studyin vivoinsightknockout genemutantnovelnovel coronavirusreceptorreceptor bindingrestorationreverse geneticstransmission processzoonotic coronavirus
项目摘要
Abstract
The coronavirus (CoV) spike protein is a key viral determinant responsible for receptor binding and
fusion/entry. The spike protein has also been predicted to be the major factor driving cross-species
transmission, allowing the emergence of epidemic strains like SARS- and MERS-CoV. In the first decade after
SARS-CoV emergence, changes to the epidemic spike that allowed binding to a new host receptor were
thought to underlie this zoonotic emergence. However, our work has shown that bat species already harbor
SARS-like CoVs with spike proteins capable of infecting human cells. These results argue that for a subset of
bat CoVs, receptor binding and infection of human cells is not the major barrier for emergence.
We found that despite equivalent replication in vitro, chimeric viruses containing bat CoV spikes have reduced
virulence in vivo. Mice infected with a chimeric SARS-CoV expressing the bat derived SHC014-CoV spike had
reduced weight loss and lethality compared to SARS-CoV controls. Importantly, this attenuation occurs despite
equivalent replication to SARS-CoV in the lung. The results indicate that virulence is dictated by more than
just the ability to infect host cells in vitro. Notably, we also found that the SHC014 spike chimera has reduced
infection of the large airways of the lung. These preliminary data shaped our central hypothesis that SARS-
CoV virulence is predicated on both host interactions with and viral motifs in the CoV spike protein.
Understanding the host and viral mechanisms that drive reduced airway infection may predict in vivo
pathogenesis and have critical implications for zoonotic emergence.
In this proposal, we explore the host factors and CoV spike changes that attenuate the zoonotic SHC014 spike
in vivo. In part one, we examine tropism changes finding that the zoonotic SHC014 spike has impaired upper
airway infection. We predict that this incompatibility relates to differences in host protease activity. We
subsequently define the specific host proteases that mediate this attenuation using both in vitro and in vivo
approaches. In part two, we use mouse-adaptation and structural analysis to predict spike changes
responsible for attenuation of the SHC014 spike. We subsequently generate mutant viruses and restore the
SHC014 spike or attenuate the SARS spike in vivo. Finally, we evaluate the mechanism of attenuation
focusing on spike interactions with host proteases. Together, the proposal identifies host proteases and spike
interactions that alter airway infection and dictate virulence following coronavirus infection. These findings
provide critical insights for understanding virulence as well as have important implications for emergence and
transmission of coronaviruses.
摘要
冠状病毒(CoV)刺突蛋白是负责受体结合的关键病毒决定簇,
融合/进入。刺突蛋白也被预测为驱动跨物种的主要因素
传播,允许出现流行菌株,如SARS和MERS-CoV。在第一个十年后,
SARS-CoV出现后,允许与新的宿主受体结合的流行峰发生了变化,
被认为是这种动物传染病出现的基础。然而,我们的研究表明蝙蝠物种已经
具有能够感染人类细胞的刺突蛋白的SARS样CoV。这些结果表明,对于
蝙蝠冠状病毒,受体结合和感染人类细胞不是出现的主要障碍。
我们发现,尽管在体外复制相当,但含有蝙蝠冠状病毒刺突的嵌合病毒减少了
体内毒力用表达蝙蝠来源的SHC 014-CoV刺突的嵌合SARS-CoV感染小鼠,
与SARS-CoV对照组相比,体重减轻和致死率降低。重要的是,这种衰减发生,尽管
在肺中的复制与SARS-CoV相当。结果表明,毒力是由多个
仅仅是体外感染宿主细胞的能力。值得注意的是,我们还发现,SHC 014刺突嵌合体减少了
肺部大气道感染。这些初步数据形成了我们的核心假设,即SARS-
CoV的毒力取决于宿主与CoV刺突蛋白的相互作用和病毒基序。
了解减少气道感染的宿主和病毒机制可以预测体内
发病机制和人畜共患病的出现具有重要意义。
在这个提议中,我们探索了减弱人畜共患病SHC 014峰的宿主因素和CoV峰的变化
in vivo.在第一部分中,我们研究了向性变化,发现人畜共患SHC 014锋电位已经损害了上
呼吸道感染我们预测,这种不相容性与宿主蛋白酶活性的差异有关。我们
随后使用体外和体内两者来定义介导这种减毒的特定宿主蛋白酶
接近。在第二部分中,我们使用了小鼠适应和结构分析来预测锋电位的变化
负责SHC 014尖峰的衰减。我们随后产生突变病毒,
SHC 014在体内可使SARS峰电位升高或减弱。最后,我们评估了衰减的机制
集中于刺突与宿主蛋白酶的相互作用。总之,该提案确定了宿主蛋白酶和穗
这些相互作用改变了呼吸道感染并决定了冠状病毒感染后的毒力。这些发现
为理解毒力提供了重要的见解,并对出苗和
冠状病毒的传播。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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VINEET D MENACHERY其他文献
VINEET D MENACHERY的其他文献
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{{ truncateString('VINEET D MENACHERY', 18)}}的其他基金
Discovery of novel broad-spectrum coronavirus inhibitors
新型广谱冠状病毒抑制剂的发现
- 批准号:
10845862 - 财政年份:2022
- 资助金额:
$ 49.79万 - 项目类别:
Discovery of novel broad-spectrum coronavirus inhibitors
新型广谱冠状病毒抑制剂的发现
- 批准号:
10514153 - 财政年份:2022
- 资助金额:
$ 49.79万 - 项目类别:
Identifying host and viral correlates for coronavirus pathogenesis
识别冠状病毒发病机制的宿主和病毒相关性
- 批准号:
10034189 - 财政年份:2020
- 资助金额:
$ 49.79万 - 项目类别:
Identifying host and viral correlates for coronavirus pathogenesis
识别冠状病毒发病机制的宿主和病毒相关性
- 批准号:
10424483 - 财政年份:2020
- 资助金额:
$ 49.79万 - 项目类别:
The Host Genetics of Age-Dependent Susceptibility
年龄依赖性易感性的宿主遗传学
- 批准号:
10007171 - 财政年份:2020
- 资助金额:
$ 49.79万 - 项目类别:
The Host Genetics of Age-Dependent Susceptibility
年龄依赖性易感性的宿主遗传学
- 批准号:
10204940 - 财政年份:2020
- 资助金额:
$ 49.79万 - 项目类别:
Identifying host and viral correlates for coronavirus pathogenesis
识别冠状病毒发病机制的宿主和病毒相关性
- 批准号:
10642898 - 财政年份:2020
- 资助金额:
$ 49.79万 - 项目类别:
Systems Based Analysis of Host Factors that Contribute to Aging Pathogenesis
导致衰老发病机制的宿主因素的系统分析
- 批准号:
9108230 - 财政年份:2015
- 资助金额:
$ 49.79万 - 项目类别:
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