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

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  • Zhang Y.
    • Other Affiliation: University of California, Los Angeles
  • Bharathi V.
    • Affiliation: School of Medicine, Department of Medicine
  • Dokoshi T.
    • Other Affiliation: University of California San Diego
  • Anda J.D.
    • Other Affiliation: University of California, Los Angeles
  • Ursery L.T.
    • Affiliation: School of Medicine, Department of Medicine
  • Kulkarni N.N.
    • Other Affiliation: University of California San Diego
  • Nakamura Y.
    • Other Affiliation: University of California San Diego
  • Chen J.
    • Other Affiliation: University of California, Los Angeles
  • Luo E.W.C.
    • Other Affiliation: University of California, Los Angeles
  • Wang L.
    • Other Affiliation: Harvard Medical School
  • Xu H.
    • Other Affiliation: Harvard Medical School
  • Coady A.
    • Other Affiliation: University of California San Diego
  • Zurich R.
    • Other Affiliation: University of California San Diego
  • Lee M.W.
    • Other Affiliation: University of California, Los Angeles
  • Lee H.
    • Other Affiliation: Harbor-University of California Los Angeles Medical Center
  • Chan L.C.
    • Other Affiliation: University of California, Los Angeles
  • Matsui T.
    • Other Affiliation: Stanford University
  • Schepmoes A.A.
    • Other Affiliation: Pacific Northwest National Laboratory
  • Lipton M.S.
    • Other Affiliation: Pacific Northwest National Laboratory
  • Zhao R.
    • Other Affiliation: Pacific Northwest National Laboratory
  • Adkins J.N.
    • Other Affiliation: Pacific Northwest National Laboratory
  • Clair G.C.
    • Other Affiliation: Pacific Northwest National Laboratory
  • Thurlow L.R.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Schisler J.C.
    • Affiliation: School of Medicine, Department of Pharmacology
  • Wolfgang M.C.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Hagan R.S.
    • Affiliation: School of Medicine, Department of Medicine
  • Yeaman M.R.
    • Other Affiliation: University of California, Los Angeles
  • Weiss T.M.
    • Other Affiliation: Stanford University
  • Chen X.
    • Other Affiliation: Harvard Medical School
  • Li M.M.H.
    • Other Affiliation: University of California, Los Angeles
  • Nizet V.
    • Other Affiliation: University of California San Diego
  • Antoniak S.
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
  • Mackman N.
    • Affiliation: School of Medicine, Department of Medicine
  • Gallo R.L.
    • Other Affiliation: University of California San Diego
  • Wong G.C.L.
    • Other Affiliation: University of California, Los Angeles
Abstract
  • 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.
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  • Article
Rights statement
  • In Copyright
License
  • Attribution 4.0 International
Journal title
  • Proceedings of the National Academy of Sciences of the United States of America
Journal volume
  • 121
Journal issue
  • 6
Language
  • English
Version
  • Publisher
Funder
  • Pacific Northwest National Laboratory, PNNL
  • OCRC, (21-104)
  • NIH NIAID Systems Biology, (U01 AI-124319-01)
  • Basic Energy Sciences, BES, (DE-AC02-76SF00515)
  • National Cancer Institute, NCI, (U54 CA260543)
  • Office of Science, SC
  • U.S. Department of Energy, USDOE
  • National Institute of General Medical Sciences, NIGMS, (P30GM133894, S10OD021512)
  • National Institutes of Health, NIH, (R01HL142799, R35HL155657, R37AI052453)
  • SLAC National Accelerator Laboratory, SLAC
  • SSRL
  • University of North Carolina at Chapel Hill, UNC-CH
  • Biological and Environmental Research, BER, (DE-AC05-76RL01830)
  • National Science Foundation, NSF, (RAPID CDF2032310)
ISSN
  • 0027-8424
Publisher
  • National Academy of Sciences

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