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

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.