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一种能够引起极其危险的免疫反应的大流行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，例如健康和经济繁荣。这项工作的中心假设是，大流行冠状病毒是一种含有能够强烈放大免疫反应的多肽片段的病毒，即使在病毒被免疫系统摧毁后，这些片段也可以释放出来。在初步数据中，使用人工智能方法在新冠肺炎病毒(SARS-CoV-2病毒)的3种蛋白质中发现了能够模仿宿主放大免疫激活的多肽的片段。这些初步研究发现，这些能够增强免疫反应的仿生病毒多肽在SARS-CoV-2中相对于‘普通感冒’冠状病毒有很强的富集性。此外，这些来自SARS-CoV-2的多肽，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活性的晶体复合体。这种复合体可以放大不同类型的人类细胞的免疫反应。通过对大约30,000个基因的检测得到的诱导基因表达模式与京都数据库中的新冠肺炎基因表达模式很好地匹配。这项建议的目标是：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)根据第一原理，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产业就业的培训。研究实习将通过人数不足的本科生和退伍军人外展计划提供。这一结果将被纳入PI的高级本科生/研究生课程。技术摘要：目前，关于冠状病毒是一种能够引起极其危险的免疫反应的大流行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，例如健康和经济繁荣。这项工作的中心假设是，大流行冠状病毒是一种含有能够强烈放大免疫反应的多肽片段的病毒，即使在病毒被免疫系统蛋白水解性破坏后，这些片段也可以释放出来。利用人工智能方法，在SARS-CoV-2病毒的3个原型蛋白(S，M，非结构蛋白)中发现了能够模拟宿主抗菌肽的片段，这些抗菌肽能够放大免疫活性。这些初步研究发现，这些能够增强免疫反应的仿生病毒多肽(异种AMPs)相对于‘普通感冒’冠状病毒在SARS-CoV-2中有很强的富集性。此外，这些来自SARS-CoV-2的多肽，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体。这种复合体放大了与新冠肺炎相关的各种人类细胞类型的免疫反应。暴露在这些复合体中的未受感染的内皮细胞的转录组与京都KEGG数据库中的新冠肺炎基因表达模式匹配良好。这项建议的目标是：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)基于静电自组装的第一原理，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产业就业的培训。研究实习将通过人数不足的本科生和退伍军人外展计划提供。这个奖项反映了NSF的法定使命，通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为是值得支持的。

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.