Viral afterlife: SARS-CoV-2 as a reservoir of immunomimetic peptides that reassemble into proinflammatory supramolecular complexes

• 成果类型: Article
• 署名作者: Zhang, Yue; Bharathi, Vanthana; Dokoshi, Tatsuya; de Anda, Jaime; Ursery, Lauryn Tumey; Kulkarni, Nikhil N.; Nakamura, Yoshiyuki; Chen, Jonathan; Luo, Elizabeth W. C.; Wang, Lamei; Xu, Hua; Coady, Alison; Zurich, Raymond; Lee, Michelle W.; Matsui, Tsutomu; Lee, Hongkyu; Chan, Liana C.; Schepmoes, Athena A.; Lipton, Mary S.; Zhao, Rui; Adkins, Joshua N.; Clair, Geremy C.; Thurlow, Lance R.; Schisler, Jonathan C.; Wolfgang, Matthew C.; Hagan, Robert S.; Yeaman, Michael R.; Weiss, Thomas M.; Chen, Xinhua; Li, Melody M. H.; Nizet, Victor; Antoniak, Silvio; Mackman, Nigel; Gallo, Richard L.; Wong, Gerard C. L.
• 署名单位: University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; Westlake University; University of North Carolina; University of North Carolina Chapel Hill; University of California System; University of California San Diego; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard Medical School; University of California System; University of California San Diego; Stanford University; United States Department of Energy (DOE); SLAC National Accelerator Laboratory; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; United States Department of Energy (DOE); Pacific Northwest National Laboratory; United States Department of Energy (DOE); Pacific Northwest National Laboratory; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12846
• DOI: 10.1073/pnas.2300644120
• 发表日期: 2024-02-06
• 关键词: antimicrobial peptide; ebola-virus; persistence; mechanisms; efficacy; themes; cells; fluid; rna

摘要

It is unclear how severe acute respiratory syndrome coronavirus 2 (SARS- CoV- 2) infection leads to the strong but ineffective inflammatory response that characterizes severe Coronavirus disease 2019 (COVID- 19), with amplified immune activation in diverse cell types, including cells without angiotensin- converting enzyme 2 receptors necessary for infection. Proteolytic degradation of SARS- CoV- 2 virions is a milestone in host viral clearance, but the impact of remnant viral peptide fragments from high viral loads is not known. Here, we examine the inflammatory capacity of fragmented viral components from the perspective of supramolecular self- organization in the infected host environment. Interestingly, a machine learning analysis to SARS- CoV- 2 proteome reveals sequence motifs that mimic host antimicrobial peptides (xenoAMPs), especially highly cationic human cathelicidin LL- 37 capable of augmenting inflammation. Such xenoAMPs are strongly enriched in SARS- CoV- 2 relative to low- pathogenicity coronaviruses. Moreover, xenoAMPs from SARS- CoV- 2 but not low- pathogenicity homologs assemble double- stranded RNA (dsRNA) into nanocrystalline complexes with lattice constants commensurate with the steric size of Toll- like receptor (TLR)- 3 and therefore capable of multivalent binding. Such complexes amplify cytokine secretion in diverse uninfected cell types in culture (epithelial cells, endothelial cells, keratinocytes, monocytes, and macrophages), similar to cathelicidin's role in rheumatoid arthritis and lupus. The induced transcriptome matches well with the global gene expression pattern in COVID- 19, despite using <0.3% of the viral proteome. Delivery of these complexes to uninfected mice boosts plasma interleukin- 6 and CXCL1 levels as observed in COVID- 19 patients.