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

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

doi:10.1038/s41467-024-48556-y

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

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Zeberg, Hugo
Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Max Planck Society;

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Citation

Brunet-Ratnasingham, E., Morin, S., Randolph, H. E., Labrecque, M., Bélair, J., Lima-Barbosa, R., et al. (2024). Sustained IFN signaling is associated with delayed development of SARS-CoV-2-specific immunity. Nature Communications, 15: 4177. doi:10.1038/s41467-024-48556-y.

Cite as: https://hdl.handle.net/21.11116/0000-000F-58BB-C

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. © The Author(s) 2024.