Nature Communications (May 2024)

Sustained IFN signaling is associated with delayed development of SARS-CoV-2-specific immunity

  • Elsa Brunet-Ratnasingham,
  • Sacha Morin,
  • Haley E. Randolph,
  • Marjorie Labrecque,
  • Justin Bélair,
  • Raphaël Lima-Barbosa,
  • Amélie Pagliuzza,
  • Lorie Marchitto,
  • Michael Hultström,
  • Julia Niessl,
  • Rose Cloutier,
  • Alina M. Sreng Flores,
  • Nathalie Brassard,
  • Mehdi Benlarbi,
  • Jérémie Prévost,
  • Shilei Ding,
  • Sai Priya Anand,
  • Gérémy Sannier,
  • Amanda Marks,
  • Dick Wågsäter,
  • Eric Bareke,
  • Hugo Zeberg,
  • Miklos Lipcsey,
  • Robert Frithiof,
  • Anders Larsson,
  • Sirui Zhou,
  • Tomoko Nakanishi,
  • David Morrison,
  • Dani Vezina,
  • Catherine Bourassa,
  • Gabrielle Gendron-Lepage,
  • Halima Medjahed,
  • Floriane Point,
  • Jonathan Richard,
  • Catherine Larochelle,
  • Alexandre Prat,
  • Janet L. Cunningham,
  • Nathalie Arbour,
  • Madeleine Durand,
  • J. Brent Richards,
  • Kevin Moon,
  • Nicolas Chomont,
  • Andrés Finzi,
  • Martine Tétreault,
  • Luis Barreiro,
  • Guy Wolf,
  • Daniel E. Kaufmann

DOI
https://doi.org/10.1038/s41467-024-48556-y
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 19

Abstract

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Abstract Plasma RNAemia, delayed antibody responses and inflammation predict COVID-19 outcomes, but the mechanisms underlying these immunovirological patterns are poorly understood. We profile 782 longitudinal plasma samples from 318 hospitalized patients with COVID-19. Integrated analysis using k-means reveals four patient clusters in a discovery cohort: mechanically ventilated critically-ill cases are subdivided into good prognosis and high-fatality clusters (reproduced in a validation cohort), while non-critical survivors segregate into high and low early antibody responders. Only the high-fatality cluster is enriched for transcriptomic signatures associated with COVID-19 severity, and each cluster has distinct RBD-specific antibody elicitation kinetics. Both critical and non-critical clusters with delayed antibody responses exhibit sustained IFN signatures, which negatively correlate with contemporaneous RBD-specific IgG levels and absolute SARS-CoV-2-specific B and CD4+ T cell frequencies. These data suggest that the “Interferon paradox” previously described in murine LCMV models is operative in COVID-19, with excessive IFN signaling delaying development of adaptive virus-specific immunity.