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Publications

Journal Article Research Support, Non-U.S. Gov't Epublish

PubMed: 39737903 DOI: 10.1038/s41467-024-54458-w

Antibodies to the RBD of SARS-CoV-2 spike mediate productive infection of primary human macrophages.

Nat Commun 15(1):10764

Authors: Suzanne Pickering, Harry Wilson, Enrico Bravo, Marianne R Perera, Jeffrey Seow, Carl Graham, Nathalia Almeida, Lazaros Fotopoulos, Thomas Williams, Atlanta Moitra, Helena Winstone, Tinne A D Nissen, Rui Pedro Galão, Luke B Snell, Katie J Doores, Michael H Malim, Stuart J D Neil

Affiliations

  • Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, SE1 9RT, UK.
  • Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, SE1 9RT, UK.
  • The Stem Cell Hotel, King's College London, Guy's Hospital, Floor 28, Tower Wing, Great Maze Pond, London, SE1 9RT, UK. Centre for Gene Therapy and Regenerative Medicine, King's College London, Guy's Hospital, Floor 28, Tower Wing, Great Maze Pond, London, SE1 9RT, UK.
  • The Stem Cell Hotel, King's College London, Guy's Hospital, Floor 28, Tower Wing, Great Maze Pond, London, SE1 9RT, UK.
  • Centre for Gene Therapy and Regenerative Medicine, King's College London, Guy's Hospital, Floor 28, Tower Wing, Great Maze Pond, London, SE1 9RT, UK.
  • Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, SE1 9RT, UK. Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 9RT, UK.
  • Centre for Clinical Infection and Diagnostics Research, Department of Infectious Diseases, Guy's and St Thomas' NHS Foundation Trust, London, SE1 7EH, UK.

Abstract

The role of myeloid cells in the pathogenesis of SARS-CoV-2 is well established, in particular as drivers of cytokine production and systemic inflammation characteristic of severe COVID-19. However, the potential for myeloid cells to act as bona fide targets of productive SARS-CoV-2 infection, and the specifics of entry, remain unclear. Using a panel of anti-SARS-CoV-2 monoclonal antibodies (mAbs) we performed a detailed assessment of antibody-mediated infection of monocytes/macrophages. mAbs with the most consistent potential to mediate infection were those targeting a conserved region of the receptor binding domain (RBD; group 1/class 4). Infection was closely related to the neutralising concentration of the mAbs, with peak infection occurring below the IC50, while pre-treating cells with remdesivir or FcγRI-blocking antibodies inhibited infection. Studies performed in primary macrophages demonstrated high-level and productive infection, with infected macrophages appearing multinucleated and syncytial. Infection was not seen in the absence of antibody with the same quantity of virus. Addition of ruxolitinib significantly increased infection, indicating restraint of infection through innate immune mechanisms rather than entry. High-level production of pro-inflammatory cytokines directly correlated with macrophage infection levels. We hypothesise that infection via antibody-FcR interactions could contribute to pathogenesis in primary infection, systemic virus spread or persistent infection.

MeSH

Cytokines, Cells, Sars-Cov-2, Antibodies, Macrophages, Covid-19, Myeloid Cells, Viruses, Severe Acute Respiratory Syndrome-Related Coronavirus, Infections