Viral afterlife: Pandemic viruses as rich reservoirs of immunomimetic peptide fragments capable of re-assembly into pro-inflammatory supramolecular complexes

非技术摘要：关于是什么使冠状病毒成为能够引起极其危险的免疫反应的大流行性冠状病毒的知识是不够的。这种知识差距仍然威胁着多个国家的利益，如健康和经济繁荣。这项工作的核心假设是，大流行性冠状病毒是一种含有强烈增强免疫反应的肽片段的病毒，即使在病毒被免疫系统破坏后，这些片段也可以被释放出来。在初步数据中，人工智能方法被用于寻找SARS-CoV-2病毒（COVID-19病毒）中3种蛋白质中的片段，这些片段可以模拟来自宿主的增强免疫激活的肽。这些初步研究发现，这些能够增强免疫反应的仿生病毒肽相对于“普通感冒”冠状病毒而言，在SARS-CoV-2中强烈富集。此外，这些来自SARS-CoV-2的肽，而不是来自“普通感冒”冠状病毒的相应类似物，可以组织成能够增强免疫激活的结晶复合物。这种复合物在不同的人类细胞类型中放大免疫应答。从对约30，000个基因的检查中诱导的基因表达模式与京都策展数据库中的COVID-19基因表达模式非常匹配。本提案的目标是：1）使用X射线和免疫激活实验分析冠状病毒的所有蛋白质，以及2）基于第一原理检查为什么Omicron变体对宿主的毒性较小。这里的研究课题有利于学术和工业就业的培训。研究实习将通过代表性不足的本科生和退伍军人外展计划提供。由此产生的结果将被纳入PI的高级本科/研究生课程。技术摘要：关于是什么使冠状病毒成为能够引起极其危险的免疫反应的大流行性冠状病毒的知识目前还不充分。这种知识差距仍然威胁着多个国家的利益，如健康和经济繁荣。这项工作的核心假设是，大流行性冠状病毒是一种携带强烈增强免疫反应的肽片段的病毒，即使在病毒被免疫系统蛋白水解破坏后，这些片段也可以被释放出来。利用人工智能方法在SARS-CoV-2病毒的3个原型蛋白（S，M，一种非结构蛋白）中找到了能够模拟宿主抗菌肽（AMP）的片段，这些抗菌肽可以放大免疫激活。这些初步研究发现，这些能够增强免疫反应的仿生病毒肽（“xenoAMP”）相对于“普通感冒”冠状病毒在SARS-CoV-2中强烈富集。此外，这些来自SARS-CoV-2的肽，而不是来自“普通感冒”冠状病毒的相应同源物，可以将病毒感染中常见的dsRNA组织成能够增强免疫激活的纳米晶体复合物。这种复合物放大了与COVID-19相关的多种人类细胞类型中的免疫应答。来自暴露于这些复合物的未感染内皮细胞的转录组与来自京都策展的KEGG数据库的COVID-19基因表达模式非常匹配。本提案的目标是：1）使用X射线和免疫激活实验分析冠状病毒的所有蛋白质，2）基于静电自组装的第一原理，研究为什么Omicron变体对宿主的毒性较小。这里的研究课题有利于学术和工业就业的培训。研究实习将通过代表性不足的本科生和退伍军人外展计划提供。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Non-technical Abstract:The knowledge of what makes a coronavirus a pandemic coronavirus capable of causing a profoundly dangerous immune response is inadequate. This knowledge gap remains a threat to multiple national interests, such as health and economic prosperity. The central hypothesis in this work is that a pandemic coronavirus is one that harbors peptide fragments that strongly amplify immune responses, fragments that can be liberated even after the virus is destroyed by the immune system. In preliminary data, artificial intelligence methods are used to find fragments in 3 proteins in the SARS-CoV-2 virus (the COVID-19 virus) that can mimic peptides from the host that amplify immune activation. These preliminary studies found that these biomimetic viral peptides capable of amplifying immune responses are strongly enriched in SARS-CoV-2 relative to ‘common cold’ coronaviruses. Moreover, these peptides from SARS-CoV-2 but not corresponding analogs from ‘common cold’ coronaviruses can organize into crystalline complexes capable of such amplified immune activation. Such complexes amplify immune responses in diverse human cell types. The induced gene expression pattern from an examination of ~30,000 genes matches well with the COVID-19 gene expression pattern from the curated database in Kyoto. The goals of this present proposal are: 1) to analyze all proteins of the coronavirus using x-ray and immune activation experiments, and 2) to examine why the Omicron variant is less toxic to hosts, based on first principles. The research topics here are conducive to training for academic and industrial employment. Research internships will be provided through underrepresented undergraduate and veteran outreach programs. Results from this will be incorporated into the PI’s advanced undergraduate/graduate classes. Technical Abstract:The knowledge of what makes a coronavirus a pandemic coronavirus capable of causing a profoundly dangerous immune response is at present inadequate. This knowledge gap remains a threat to multiple national interests, such as health and economic prosperity. The central hypothesis in this work is that a pandemic coronavirus is one that harbors peptide fragments that strongly amplify immune responses, fragments that can be liberated even after the virus is proteolytically destroyed by the immune system. Artificial intelligence methods were used to find fragments in 3 prototypical proteins (S, M, a non-structural protein) in the SARS-CoV-2 virus that can mimic antimicrobial peptides (AMPs) from the host that amplify immune activation. These preliminary studies found that these biomimetic viral peptides (‘xenoAMPs’) capable of amplifying immune responses are strongly enriched in SARS-CoV-2 relative to ‘common cold’ coronaviruses. Moreover, these peptides from SARS-CoV-2 but not corresponding homologs from ‘common cold’ coronaviruses can organize dsRNA commonly found in viral infections into nanocrystalline complexes capable of amplified immune activation. Such complexes amplify immune responses in diverse human cell types relevant to COVID-19. The transcriptome from uninfected endothelial cells exposed to these complexes matches well with the COVID-19 gene expression pattern from the curated KEGG database in Kyoto. The goals of this present proposal are: 1) to analyze all proteins of the coronavirus using x-ray and immune activation experiments, and 2) to examine why the Omicron variant is less toxic to hosts, based on first principles of electrostatic self assembly. The research topics here are conducive to training for academic and industrial employment. Research internships will be provided through underrepresented undergraduate and veteran outreach programs. Results from this will be incorporated into the PI’s advanced undergraduate/graduate classes.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.