SARS-CoV-2 peptide fragments selectively dysregulate specific immune cell populations via Gaussian curvature targeting

Immune cell populations are dysregulated in COVID-19 for currently unknown reasons: Plasmacytoid dendritic cell (pDC) populations are reduced, thus hampering antiviral responses. CD8<sup>+</sup> 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<sup>+</sup>, and CD4<sup>+</sup> 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.

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Journal
Proceedings of the National Academy of Sciences
Published
2026-01-08
DOI
https://doi.org/10.1073/pnas.2521841122
Primary Topic
vaccines and immunoinformatics approaches
Type
article
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article

SARS-CoV-2 peptide fragments selectively dysregulate specific immune cell populations via Gaussian curvature targeting

Dapeng Li, Elizabeth Wei-Chia Luo, Tsutomu Matsui, Oliver Soehnlein et al.
Proceedings of the National Academy of Sciences
vaccines and immunoinformatics approaches
article

SARS-CoV-2 peptide fragments selectively dysregulate specific immune cell populations via Gaussian curvature targeting

Dapeng Li, Elizabeth Wei-Chia Luo, Tsutomu Matsui, Oliver Soehnlein, Mathis Richter, Carlos Silvestre-Roig, Jonathan W. Chen, Anna Lívia Linard Matos, Loredana Frasca, S.F. Hayes, Yue Zhang, Thomas Weiss, H. Alimohamadi, Jaime de Anda, H. Lee, Gerard C. L. Wong, Taraknath Mandal, Anna Mennella, Maomao Zhang, Susmita Ghosh, Yanru Wang, Melody M. H. Li, Tiannan Guo, Liana C. Chan, Han Fu, Xiaohan Wang, Roberto Lande, Qiang Cui, Naixin Wang, Michael R. Yeaman, Albert Sickmann, Hongyu Wang
article en

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<sup>+</sup> 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<sup>+</sup>, and CD4<sup>+</sup> 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.

Proceedings of the National Academy of SciencesVol. 123(2)
Boston University (US), University of North Carolina at Chapel Hill (US), LAC+USC Medical Center (US), California NanoSystems Institute (US), Harbin Medical University (CN), Istituto Superiore di Sanità (IT), SLAC National Accelerator Laboratory (US), Westlake University (CN), Los Angeles Medical Center (US), University Hospital Münster (DE), Westlake Health Center (US), Stanford Synchrotron Radiation Lightsource (US), Second Affiliated Hospital of Harbin Medical University (CN), Affiliated Hangzhou First People's Hospital, Westlake University, School of Medicine (CN), Beijing Proteome Research Center (CN), Institute of Infection and Immunity (CA), University of Duisburg-Essen (DE), Ruhr University Bochum (DE), Indian Institute of Technology Kanpur (IN), University of California, Berkeley (US), Leibniz Institute for Neurobiology (DE), Stanford University (US)
Good health and well-being
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vaccines and immunoinformatics approaches
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