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

• Published in: Nature communications Vol. 15; no. 1; p. 4177
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.05.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 14/1; 38; 38/91; 631/250/254; 631/250/255/2514; Adaptive immunity; Adult; Aged; Animal models; Antibodies; Antibodies, Viral - blood; Antibodies, Viral - immunology; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Clusters; COVID-19; COVID-19 - immunology; Fatalities; Female; Humanities and Social Sciences; Humans; Immunity; Immunoglobulin G; Immunoglobulin G - blood; Immunoglobulin G - immunology; Inflammation; Inflammatory response; Interferon; Interferons - immunology; Interferons - metabolism; Kinetics; Lymphocytes; Lymphocytes T; Male; Medicin och hälsovetenskap; Middle Aged; multidisciplinary; SARS-CoV-2 - immunology; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Signal Transduction - immunology; Signatures; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - immunology; Spike Glycoprotein, Coronavirus - metabolism; Transcriptomics; Ventilation; Viral diseases
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-48556-y

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 role of IFN signaling in SARS-CoV-2 infection and outcome is still debated. Here, the authors longitudinally profiled plasma samples from hospitalized patients and show that a persistent inflammatory response is linked to delayed generation of adaptive immunity and increased risk of death when coupled with severe infection.