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

作者：Yue Zhang, Vanthana Bharathi, Tatsuya Dokoshi, Jaime de Anda, Lauryn Ursery, Nikhil N Kulkarni, Yoshiyuki Nakamura, Jonathan H. Chen, Elizabeth Wei-Chia Luo, Lamei Wang, Hua Xu, Alison Coady, Raymond Zurich, Michelle W. Lee, Tsutomu Matsui, Hong-Kyu Lee, Liana C. Chan, Athena Schepmoes, Mary Lipton, Rui Zhao, Joshua Adkins, Gérémy Clair, Lance R. Thurlow, Jonathan C. Schisler, Matthew C. Wolfgang, Robert S. Hagan, Michael R. Yeaman, Thomas Weiß, Xinhua Chen, Melody M. H. Li, Victor Nizet, Silvio Antoniak, Nigel Mackman, Richard L. Gallo, Gerard C. L. Wong · 发表于：Proceedings of the National Academy of Sciences · 年份：2024 · DOI：10.1073/pnas.2300644120 · 被引用次数：33 · 研究领域：Antimicrobial Peptides and Activities、SARS-CoV-2 and COVID-19 Research、Immune Response and Inflammation

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 rheumatoi...