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

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冠状病毒的知识不足。这种知识差距仍然威胁着卫生和经济繁荣等多个国家的利益。这项工作的核心假设是，大流行冠状病毒是一种含有肽片段的病毒，这些片段可以强烈放大免疫反应，即使在病毒被免疫系统摧毁后，这些片段也可以被释放出来。在初步数据中，使用人工智能方法在SARS-CoV-2病毒（COVID-19病毒）的3种蛋白质中找到了可以模仿宿主放大免疫激活的肽的片段。这些初步研究发现，相对于“普通感冒”冠状病毒，这些能够放大免疫反应的仿生病毒肽在SARS-CoV-2中富集程度很高。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，可以组织成能够放大免疫激活的晶体复合物。这种复合物增强了不同人类细胞类型的免疫反应。通过对约3万个基因的检测，诱导的基因表达模式与京都整理的数据库中的COVID-19基因表达模式吻合良好。本提案的目标是：1)利用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)基于第一性原理研究为什么Omicron变体对宿主的毒性较小。本文的研究课题有利于学术和产业就业的培训。研究实习将通过代表性不足的本科生和退伍军人外展项目提供。这个结果将被纳入PI的高级本科/研究生课程。技术摘要：目前，人们对冠状病毒成为大流行冠状病毒的原因知之甚少，冠状病毒能够引起极其危险的免疫反应。这种知识差距仍然威胁着卫生和经济繁荣等多个国家的利益。这项工作的核心假设是，大流行冠状病毒是一种含有强烈放大免疫反应的肽片段的病毒，即使在病毒被免疫系统水解破坏后，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种原型蛋白（S， M，一种非结构蛋白）中发现片段，这些片段可以模拟宿主的抗菌肽（AMPs），从而放大免疫激活。这些初步研究发现，相对于“普通感冒”冠状病毒，这些能够放大免疫反应的仿生病毒肽（“xenoamp”）在SARS-CoV-2中富集程度很高。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组织成能够放大免疫激活的纳米晶体复合物。这些复合物增强了与COVID-19相关的多种人类细胞类型的免疫反应。暴露于这些复合物的未感染内皮细胞的转录组与京都整理的KEGG数据库中的COVID-19基因表达模式匹配良好。本提案的目标是：1)利用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。本文的研究课题有利于学术和产业就业的培训。研究实习将通过代表性不足的本科生和退伍军人外展项目提供。这个结果将被纳入PI的高级本科/研究生课程。该奖项反映了美国国家科学基金会的法定使命，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.