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

Elsa Brunet-RatnasinghamSacha MorinHaley E RandolphMarjorie LabrecqueJustin BélairRaphaël Lima-BarbosaAmélie PagliuzzaLorie MarchittoMichael HultströmJulia NiesslRose CloutierAlina M Sreng FloresNathalie BrassardMehdi BenlarbiJérémie PrévostShilei DingSai Priya AnandGérémy SannierAmanda MarksDick WågsäterEric BarekeHugo ZebergMiklos LipcseyRobert FrithiofAnders O LarssonSirui ZhouTomoko NakanishiDavid R MorrisonDani VézinaCatherine BourassaGabrielle Gendron-LepageHalima MedjahedFloriane PointJonathan RichardCatherine LarochelleAlexandre PratJanet L CunninghamNathalie ArbourMadeleine DurandJohn Brent RichardsKevin MoonNicolas ChomontAndrés FinziMartine TétreaultLuis B BarreiroGuy WolfDaniel E Kaufmann
Published in: Nature communications (2024)
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.
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