Dr. Nikaia Smith - Distinct systemic and mucosal immune responses to SARS-CoV2

Coronavirus disease 2019 (Covid-19) is characterized by distinct patterns of disease progression implying diverse host immune responses. We performed an integrated immune analysis on a cohort of fifty Covid19 patients with various disease severity, in both plasma and the nasopharynx, which reflects the initial site of infection. Using state-of-the-art technologies including ultra-sensitive digital Elisa (Simoa) to measure low levels of interferons (IFN), mass cytometry (CyTOF), ultrasensitive droplet based digital PCR (ddPCR), Nanostring nCounter technology and an ultrasensitive innovative antibody detection technic (S-Flow), we identified a unique phenotype in severe and critical patients. It consisted of a profoundly impaired type I IFN response characterized by low IFN-α production and activity, associated with a persistent blood viral load, an exacerbated inflammatory response, and a strong SARS-CoV2-specific antibody response. Inflammation was partially driven by the transcriptional factor NFκB and characterized by increased tumor necrosis factor (TNF)-α and interleukin (IL)-6 production and signaling. These inflammatory cytokines in all patient groups were significantly correlated with circulating viral levels, which was not associated with systemic type I interferon responses. Furthermore, we determine that while plasma inflammatory cytokine levels were a hallmark of COVID-19 regardless of disease severity, cytokines present in the nasopharynx allowed a better categorization of disease severity. In addition to expected inflammatory markers this also included locally regulated growth factors and chemokines suggesting viral induced mucosal tissue dysregulation. We propose that type-I IFN deficiency in the blood could be a hallmark of severe Covid-19 and provide a rationale for combined therapeutic approaches which may be further optimized with a better understanding of infected tissue immune responses.

Selected references

• Smith N*, Goncalves P*, Charbit B, Grzelak L, Beretta M, Planchais C, Bruel T, Rouilly V, Bondet V, Hadjadj J, Yatim N, Pere H, Merkling SH, Kernéis S, Rieux-Laucat F, Terrier B, Schwartz O, Mouquet H, Duffy D*, Di Santo J*. Distinct systemic and mucosal immune responses to SARS-CoV-2. Nature Immunology 2021
• de Cevins C, Luka M*, Smith N*, Meynier S*, Magérus A*, Carbone F§, Garcia-Paredes V§, Barnabei L§, Batignes M, Boullé A, Stolzenberg MC, Pérot B, Charbit B, Fali T, Pirabarakan V, Sorin B, Riller Q, Abdessalem G, Beretta M, Grzelak L, Goncalves P, Di Santo J, Mouquet H, Schwartz O, Zarhrate M, Parisot M, Bole-Feysot C, Masson C, Cagnard N, Corneau A, Bruneau C, Zhang S, Casanova JL, Bader-Meunier B, Haroche J, Melki I, Lorrot M, Oualha M, Moulin F, Bonnet D, Belhadjer Z, Leruez M, Allali S, Gras Leguen C, de Pontual L, Fischer A, Duffy D*, Rieux-Laucat F*, Toubiana J*, Ménager M*. A monocyte/dendritic cell molecular signature of SARS-CoV-2 related multisystem inflammatory syndrome in children (MIS-C) with severe myocarditis. Med. Cell press, 2021
• Hadjadj J*, Yatim N*, Barnabei L, Corneau A, Boussier J, Smith N, Péré H, Charbit B, Bondet V, Chenevier-Gobeaux C, Breillat P, Carlier N, Gauzit R, Morbieu C, Pène F, Marin N, Roche N, Szwebel TA, Merkling SH, Treluyer JM, Veyer D, Mouthon L, Blanc C, Tharaux PL, Rozenberg F, Fischer A, Duffy D, Rieux-Laucat F, Kernéis S, Terrier B. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients (2020) Science. 369(6504):718-724. DOI: 10.1126/science.abc6027
• Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, Ogishi M, Sabli IKD, Hodeib S, Korol C, Rosain J, Bilguvar K, Ye J, Bolze A, Bigio B, Yang R, Arias AA, Zhou Q, Zhang Y, Onodi F, Korniotis S, Karpf L, Philippot Q, Chbihi M, Bonnet-Madin L, Dorgham K, Smith N,…, Duffy D, Lifton RP, Zhang SY, Gorochov G, Béziat V, Jouanguy E, Sancho-Shimizu V, Rice CM, Abel L, Notarangelo LD, Cobat A, Su HC, Casanova JL.Inborn errors of type I IFN immunity in patients with life-threatening COVID-19 (2020) Science. 370(6515):eabd4570. DOI: 10.1126/science.abd4570