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Proc Natl Acad Sci U S A
. 2026 Jan 13;123(2):e2521841122.
doi: 10.1073/pnas.2521841122. Epub 2026 Jan 8. SARS-CoV-2 peptide fragments selectively dysregulate specific immune cell populations via Gaussian curvature targeting
Yue Zhang 1 2 3 4 5 6 , Carlos Silvestre-Roig # 7 , Han Fu # 5 6 , Haleh Alimohamadi # 1 2 3 4 , Taraknath Mandal 8 9 10 11 , Jonathan W Chen 1 2 3 4 , Elizabeth Wei-Chia Luo 1 2 3 4 , Jaime de Anda 1 2 3 4 , Anna Lívia Linard Matos 7 , Mathis Richter 7 , Anna Mennella 12 , HongKyu Lee 13 , Liana C Chan 13 , Yingrui Wang 14 15 16 , Naixin Wang 17 , Hongyu Wang 5 6 , Xiaohan Wang 6 16 18 19 , Calvin K Lee 1 2 3 4 , Susmita Ghosh 20 , Tsutomu Matsui 21 , Thomas M Weiss 21 , Tiannan Guo 14 15 16 , Maomao Zhang 17 , Dapeng Li 6 16 18 19 , Matthew C Wolfgang 22 23 , Robert S Hagan 23 24 , Melody M H Li 3 , Matthias Gunzer 20 25 , Albert Sickmann 20 26 , Loredana Frasca 12 , Michael R Yeaman 13 27 28 29 , Roberto Lande 12 , Qiang Cui 8 9 , Oliver Soehnlein 7 , Gerard C L Wong 1 2 3 4
Affiliations
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.
Keywords: COVID-19; antimicrobial peptides; immune cell dysregulation; membrane elasticity theory; membrane permeation.
. 2026 Jan 13;123(2):e2521841122.
doi: 10.1073/pnas.2521841122. Epub 2026 Jan 8. SARS-CoV-2 peptide fragments selectively dysregulate specific immune cell populations via Gaussian curvature targeting
Yue Zhang 1 2 3 4 5 6 , Carlos Silvestre-Roig # 7 , Han Fu # 5 6 , Haleh Alimohamadi # 1 2 3 4 , Taraknath Mandal 8 9 10 11 , Jonathan W Chen 1 2 3 4 , Elizabeth Wei-Chia Luo 1 2 3 4 , Jaime de Anda 1 2 3 4 , Anna Lívia Linard Matos 7 , Mathis Richter 7 , Anna Mennella 12 , HongKyu Lee 13 , Liana C Chan 13 , Yingrui Wang 14 15 16 , Naixin Wang 17 , Hongyu Wang 5 6 , Xiaohan Wang 6 16 18 19 , Calvin K Lee 1 2 3 4 , Susmita Ghosh 20 , Tsutomu Matsui 21 , Thomas M Weiss 21 , Tiannan Guo 14 15 16 , Maomao Zhang 17 , Dapeng Li 6 16 18 19 , Matthew C Wolfgang 22 23 , Robert S Hagan 23 24 , Melody M H Li 3 , Matthias Gunzer 20 25 , Albert Sickmann 20 26 , Loredana Frasca 12 , Michael R Yeaman 13 27 28 29 , Roberto Lande 12 , Qiang Cui 8 9 , Oliver Soehnlein 7 , Gerard C L Wong 1 2 3 4
Affiliations
- PMID: 41505524
- DOI: 10.1073/pnas.2521841122
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.
Keywords: COVID-19; antimicrobial peptides; immune cell dysregulation; membrane elasticity theory; membrane permeation.