SARS-CoV-2 peptide fragments selectively dysregulate specific immune cell populations via Gaussian curvature targeting
Abstract
Immune cell populations are dysregulated in COVID-19 for currently unknown reasons: Plasmacytoid dendritic cell (pDC) populations are reduced, thus hampering antiviral responses. CD8 + T cell populations are reduced, the level of which has emerged as an index of disease severity. Recent work has shown that the proteome of SARS-CoV-2 is a rich reservoir of antimicrobial peptide-like sequence motifs (xenoAMPs) which can chaperone and organize dsRNA for amplified Toll-Like Receptor 3 (TLR3)-mediated inflammation in vitro and in vivo. Here, we demonstrate that proteolytic digestion of the SARS-CoV-2 spike protein by host trypsin-like serine proteases directly produces xenoAMPs. Synchrotron Small Angle X-ray Scattering, mass spectrometry, and a theoretical analysis based on continuum membrane elasticity show that proteolytically generated xenoAMPs from SARS-CoV-2 proteins in vitro and machine learning-predicted high-scoring xenoAMPs all induce negative Gaussian curvature (NGC) necessary for pore formation in membranes. We find that xenoAMPs alone as well as xenoAMPs synergistically with endogenous AMP LL-37 can induce NGC in membranes. A computational analysis of immune cells with morphologically complex shapes (e.g., pDC, CD8 + , and CD4 + T cells) suggests that surfaces with high local NGC can concentrate AMP-like sequences and promote selective membrane disruption. Consistent with this hypothesis, experiments with freshly isolated human peripheral blood mononuclear cells confirm that viable pDCs, DCs, and T cells are significantly depleted after xenoAMP exposure, in contrast to monocytes and neutrophils, the immune cell subsets with spheroidal morphology. Structural data from Omicron variant xenoAMP homologs indicate reduced pore formation, consistent with clinical observations of reduced T cell cytopenia in Omicron variant infections.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (35)
Yue Zhang
Carlos Silvestre-Roig
Han Fu
Material Science and Engineering, School of Engineering, Westlake University
Haleh Alimohamadi
Department of Bioengineering
Taraknath Mandal
Department of Physics
Jonathan W. Chen
Department of Bioengineering, University of California
Elizabeth Wei-Chia Luo
Department of Bioengineering
Jaime de Anda
Department of Bioengineering, University of California
Anna Lívia Linard Matos
Institute of Experimental Pathology, Center for Molecular Biology of Inflammation, University Hospital Münster, University of Münster
Mathis Richter
Anna Mennella
Istituto Superiore di Sanità, National Center for Global Health
HongKyu Lee
Division of Molecular Medicine, Harbor-University of California Los Angeles Medical Center Los Angeles County
Liana C. Chan
Division of Molecular Medicine, Harbor-University of California Los Angeles Medical Center Los Angeles County
Yingrui Wang
Naixin Wang
Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University
Hongyu Wang
School of Pharmacy & State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering
Xiaohan Wang
Calvin K. Lee
Department of Bioengineering, University of California
Susmita Ghosh
Leibniz-Institut für Analytische Wissenschaften
Tsutomu Matsui
Stanford Synchrotron Radiation Lightsource, Stanford Linear Accelerator Center National Accelerator Laboratory
Thomas M. Weiss
Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Stanford University
Tiannan Guo
Maomao Zhang
Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University
Dapeng Li
Research Center for Industries of the Future, Westlake University Hangzhou
Matthew C. Wolfgang
Department of Microbiology and Immunology, University of North Carolina School of Medicine
Robert S. Hagan
Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine, University of North Carolina at Chapel Hill
Melody M. H. Li
Department of Microbiology, Immunology and Molecular Genetics, University of California
Matthias Gunzer
Leibniz-Institut für Analytische Wissenschaften
Albert Sickmann
Loredana Frasca
Istituto Superiore di Sanità, National Center for Global Health
Michael R. Yeaman
Division of Molecular Medicine, Harbor-University of California Los Angeles Medical Center Los Angeles County
Roberto Lande
Istituto Superiore di Sanità, National Center for Global Health
Qiang Cui
Department of Chemistry
Oliver Soehnlein
Gerard C. L. Wong
Department of Bioengineering