Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients
Jérôme Hadjadj, Nader Yatim, Laura Barnabei, Aurélien Corneau, Jeremy Boussier, Nikaïa Smith, Hélène Péré, Bruno Charbit, Vincent Bondet, Camille Chenevier-Gobeaux, Paul Breillat, Nicolas Carlier, Rémy Gauzit, Caroline Morbieu, Frédéric Pène, Nathalie Marin, Nicolas Roche, Tali-Anne Szwebel, Sarah H Merkling, Jean-Marc Treluyer, David Veyer, Luc Mouthon, Catherine Blanc, Pierre-Louis Tharaux, Flore Rozenberg, Alain Fischer, Darragh Duffy, Frédéric Rieux-Laucat, Solen Kernéis, Benjamin Terrier, Jérôme Hadjadj, Nader Yatim, Laura Barnabei, Aurélien Corneau, Jeremy Boussier, Nikaïa Smith, Hélène Péré, Bruno Charbit, Vincent Bondet, Camille Chenevier-Gobeaux, Paul Breillat, Nicolas Carlier, Rémy Gauzit, Caroline Morbieu, Frédéric Pène, Nathalie Marin, Nicolas Roche, Tali-Anne Szwebel, Sarah H Merkling, Jean-Marc Treluyer, David Veyer, Luc Mouthon, Catherine Blanc, Pierre-Louis Tharaux, Flore Rozenberg, Alain Fischer, Darragh Duffy, Frédéric Rieux-Laucat, Solen Kernéis, Benjamin Terrier
Abstract
Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression that suggest diverse host immune responses. We performed an integrated immune analysis on a cohort of 50 COVID-19 patients with various disease severity. A distinct phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-β and low IFN-α production and activity), which was associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor nuclear factor-κB and characterized by increased tumor necrosis factor-α and interleukin-6 production and signaling. These data suggest that type I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches.
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Figures
References
- Guan W.-J., Ni Z.-Y., Hu Y., Liang W.-H., Ou C.-Q., He J.-X., Liu L., Shan H., Lei C.-L., Hui D. S. C., Du B., Li L.-J., Zeng G., Yuen K.-Y., Chen R.-C., Tang C.-L., Wang T., Chen P.-Y., Xiang J., Li S.-Y., Wang J.-L., Liang Z.-J., Peng Y.-X., Wei L., Liu Y., Hu Y.-H., Peng P., Wang J.-M., Liu J.-Y., Chen Z., Li G., Zheng Z.-J., Qiu S.-Q., Luo J., Ye C.-J., Zhu S.-Y., Zhong N.-S., China Medical Treatment Expert Group for Covid-19 , Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 382, 1708–1720 (2020). 10.1056/NEJMoa2002032
- Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., Zhang L., Fan G., Xu J., Gu X., Cheng Z., Yu T., Xia J., Wei Y., Wu W., Xie X., Yin W., Li H., Liu M., Xiao Y., Gao H., Guo L., Xie J., Wang G., Jiang R., Gao Z., Jin Q., Wang J., Cao B., Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506 (2020). 10.1016/S0140-6736(20)30183-5
- Salje H., Tran Kiem C., Lefrancq N., Courtejoie N., Bosetti P., Paireau J., Andronico A., Hozé N., Richet J., Dubost C.-L., Le Strat Y., Lessler J., Levy-Bruhl D., Fontanet A., Opatowski L., Boelle P.-Y., Cauchemez S., Estimating the burden of SARS-CoV-2 in France. Science eabc3517 (2020). 10.1126/science.abc3517
- Chow E. J., Doyle J. D., Uyeki T. M., Influenza virus-related critical illness: Prevention, diagnosis, treatment. Crit. Care 23, 214 (2019). 10.1186/s13054-019-2491-9
- Wu C., Chen X., Cai Y., Xia J., Zhou X., Xu S., Huang H., Zhang L., Zhou X., Du C., Zhang Y., Song J., Wang S., Chao Y., Yang Z., Xu J., Zhou X., Chen D., Xiong W., Xu L., Zhou F., Jiang J., Bai C., Zheng J., Song Y., Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern. Med. 10.1001/jamainternmed.2020.0994 (2020). 10.1001/jamainternmed.2020.0994
- Li Q., Guan X., Wu P., Wang X., Zhou L., Tong Y., Ren R., Leung K. S. M., Lau E. H. Y., Wong J. Y., Xing X., Xiang N., Wu Y., Li C., Chen Q., Li D., Liu T., Zhao J., Liu M., Tu W., Chen C., Jin L., Yang R., Wang Q., Zhou S., Wang R., Liu H., Luo Y., Liu Y., Shao G., Li H., Tao Z., Yang Y., Deng Z., Liu B., Ma Z., Zhang Y., Shi G., Lam T. T. Y., Wu J. T., Gao G. F., Cowling B. J., Yang B., Leung G. M., Feng Z., Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N. Engl. J. Med. 382, 1199–1207 (2020). 10.1056/NEJMoa2001316
- Grasselli G., Zangrillo A., Zanella A., Antonelli M., Cabrini L., Castelli A., Cereda D., Coluccello A., Foti G., Fumagalli R., Iotti G., Latronico N., Lorini L., Merler S., Natalini G., Piatti A., Ranieri M. V., Scandroglio A. M., Storti E., Cecconi M., Pesenti A., Nailescu A., Corona A., Zangrillo A., Protti A., Albertin A., Forastieri Molinari A., Lombardo A., Pezzi A., Benini A., Scandroglio A. M., Malara A., Castelli A., Coluccello A., Micucci A., Pesenti A., Sala A., Alborghetti A., Antonini B., Capra C., Troiano C., Roscitano C., Radrizzani D., Chiumello D., Coppini D., Guzzon D., Costantini E., Malpetti E., Zoia E., Catena E., Agosteo E., Barbara E., Beretta E., Boselli E., Storti E., Harizay F., Della Mura F., Lorini F. L., Donato Sigurtà F., Marino F., Mojoli F., Rasulo F., Grasselli G., Casella G., De Filippi G., Castelli G., Aldegheri G., Gallioli G., Lotti G., Albano G., Landoni G., Marino G., Vitale G., Battista Perego G., Evasi G., Citerio G., Foti G., Natalini G., Merli G., Sforzini I., Bianciardi L., Carnevale L., Grazioli L., Cabrini L., Guatteri L., Salvi L., Dei Poli M., Galletti M., Gemma M., Ranucci M., Riccio M., Borelli M., Zambon M., Subert M., Cecconi M., Mazzoni M. G., Raimondi M., Panigada M., Belliato M., Bronzini N., Latronico N., Petrucci N., Belgiorno N., Tagliabue P., Cortellazzi P., Gnesin P., Grosso P., Gritti P., Perazzo P., Severgnini P., Ruggeri P., Sebastiano P., Covello R. D., Fernandez-Olmos R., Fumagalli R., Keim R., Rona R., Valsecchi R., Cattaneo S., Colombo S., Cirri S., Bonazzi S., Greco S., Muttini S., Langer T., Alaimo V., Viola U., COVID-19 Lombardy ICU Network , Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy. JAMA 323, 1574 (2020). 10.1001/jama.2020.5394
- Mehta P., McAuley D. F., Brown M., Sanchez E., Tattersall R. S., Manson J. J.; HLH Across Speciality Collaboration, UK , COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet 395, 1033–1034 (2020). 10.1016/S0140-6736(20)30628-0
- Amir A. D., Davis K. L., Tadmor M. D., Simonds E. F., Levine J. H., Bendall S. C., Shenfeld D. K., Krishnaswamy S., Nolan G. P., Pe’er D., viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia. Nat. Biotechnol. 31, 545–552 (2013). 10.1038/nbt.2594
- Müller U., Steinhoff U., Reis L. F., Hemmi S., Pavlovic J., Zinkernagel R. M., Aguet M., Functional role of type I and type II interferons in antiviral defense. Science 264, 1918–1921 (1994). 10.1126/science.8009221
- Jeremiah N., Neven B., Gentili M., Callebaut I., Maschalidi S., Stolzenberg M.-C., Goudin N., Frémond M.-L., Nitschke P., Molina T. J., Blanche S., Picard C., Rice G. I., Crow Y. J., Manel N., Fischer A., Bader-Meunier B., Rieux-Laucat F., Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J. Clin. Invest. 124, 5516–5520 (2014). 10.1172/JCI79100
- Rodero M. P., Decalf J., Bondet V., Hunt D., Rice G. I., Werneke S., McGlasson S. L., Alyanakian M.-A., Bader-Meunier B., Barnerias C., Bellon N., Belot A., Bodemer C., Briggs T. A., Desguerre I., Frémond M.-L., Hully M., van den Maagdenberg A. M. J. M., Melki I., Meyts I., Musset L., Pelzer N., Quartier P., Terwindt G. M., Wardlaw J., Wiseman S., Rieux-Laucat F., Rose Y., Neven B., Hertel C., Hayday A., Albert M. L., Rozenberg F., Crow Y. J., Duffy D., Detection of interferon α protein reveals differential levels and cellular sources in disease. J. Exp. Med. 214, 1547–1555 (2017). 10.1084/jem.20161451
- Lebon P., Ponsot G., Aicardi J., Goutières F., Arthuis M., Early intrathecal synthesis of interferon in herpes encephalitis. Biomedicine 31, 267–271 (1979).
- Reizis B., Plasmacytoid Dendritic Cells: Development, Regulation, and Function. Immunity 50, 37–50 (2019). 10.1016/j.immuni.2018.12.027
- Z. Zhou, L. Ren, L. Zhang, J. Zhong, Y. Xiao, Z. Jia, L. Guo, J. Yang, C. Wang, S. Jiang, D. Yang, G. Zhang, H. Li, F. Chen, Y. Xu, M. Chen, Z. Gao, J. Yang, J. Dong, B. Liu, X. Zhang, W. Wang, K. He, Q. Jin, M. Li, J. Wang, Overly exuberant innate immune response to SARS-CoV-2 infection. (2020); available at 10.2139/ssrn.3551623.10.2139/ssrn.3551623
- Pedersen S. F., Ho Y.-C., SARS-CoV-2: A storm is raging. J. Clin. Invest. 130, 2202–2205 (2020). 10.1172/JCI137647
- Chen G., Wu D., Guo W., Cao Y., Huang D., Wang H., Wang T., Zhang X., Chen H., Yu H., Zhang X., Zhang M., Wu S., Song J., Chen T., Han M., Li S., Luo X., Zhao J., Ning Q., Clinical and immunological features of severe and moderate coronavirus disease 2019. J. Clin. Invest. 130, 2620–2629 (2020). 10.1172/JCI137244
- Rehwinkel J., Gack M. U., RIG-I-like receptors: Their regulation and roles in RNA sensing. Nat. Rev. Immunol. (2020). 10.1038/s41577-020-0288-3
- Liu S.-Y., Sanchez D. J., Aliyari R., Lu S., Cheng G., Systematic identification of type I and type II interferon-induced antiviral factors. Proc. Natl. Acad. Sci. U.S.A. 109, 4239–4244 (2012). 10.1073/pnas.1114981109
- Heinonen S., Velazquez V. M., Ye F., Mertz S., Acero-Bedoya S., Smith B., Bunsow E., Garcia-Mauriño C., Oliva S., Cohen D. M., Moore-Clingenpeel M., Peeples M. E., Ramilo O., Mejias A., Immune profiles provide insights into respiratory syncytial virus disease severity in young children. Sci. Transl. Med. 12, eaaw0268 (2020). 10.1126/scitranslmed.aaw0268
- Blanco-Melo D., Nilsson-Payant B. E., Liu W.-C., Uhl S., Hoagland D., Møller R., Jordan T. X., Oishi K., Panis M., Sachs D., Wang T. T., Schwartz R. E., Lim J. K., Albrecht R. A., tenOever B. R., Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell 181, 1036–1045.e9 (2020). 10.1016/j.cell.2020.04.026
- Terán-Cabanillas E., Hernández J., Role of leptin and SOCS3 in inhibiting the type I interferon response during obesity. Inflammation 40, 58–67 (2017). 10.1007/s10753-016-0452-x
- Galkina E., Ley K., Immune and inflammatory mechanisms of atherosclerosis. Annu. Rev. Immunol. 27, 165–197 (2009). 10.1146/annurev.immunol.021908.132620
- Ciancanelli M. J., Huang S. X. L., Luthra P., Garner H., Itan Y., Volpi S., Lafaille F. G., Trouillet C., Schmolke M., Albrecht R. A., Israelsson E., Lim H. K., Casadio M., Hermesh T., Lorenzo L., Leung L. W., Pedergnana V., Boisson B., Okada S., Picard C., Ringuier B., Troussier F., Chaussabel D., Abel L., Pellier I., Notarangelo L. D., García-Sastre A., Basler C. F., Geissmann F., Zhang S.-Y., Snoeck H.-W., Casanova J.-L., Infectious disease. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency. Science 348, 448–453 (2015). 10.1126/science.aaa1578
- Clohisey S., Baillie J. K., Host susceptibility to severe influenza A virus infection. Crit. Care 23, 303 (2019). 10.1186/s13054-019-2566-7
- Prokunina-Olsson L., Alphonse N., Dickenson R. E., Durbin J. E., Glenn J. S., Hartmann R., Kotenko S. V., Lazear H. M., O’Brien T. R., Odendall C., Onabajo O. O., Piontkivska H., Santer D. M., Reich N. C., Wack A., Zanoni I., COVID-19 and emerging viral infections: The case for interferon-λ. J. Exp. Med. 217, e20200653 (2020). 10.1084/jem.20200653
- Roumier M., Paule R., Groh M., Vallee A., Ackermann F., medRxiv, 2020.04.20.20061861 [Preprint] 22 April 2020. 10.1101/2020.04.20.20061861.10.1101/2020.04.20.20061861
- Feldmann M., Maini R. N., Woody J. N., Holgate S. T., Winter G., Rowland M., Richards D., Hussell T., Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed. Lancet 395, 1407–1409 (2020). 10.1016/S0140-6736(20)30858-8
- Bost P., Giladi A., Liu Y., Bendjelal Y., Xu G., David E., Blecher-Gonen R., Cohen M., Medaglia C., Li H., Deczkowska A., Zhang S., Schwikowski B., Zhang Z., Amit I., Host-viral infection maps reveal signatures of severe COVID-19 patients. Cell 181, 1475–1488.e12 (2020). 10.1016/j.cell.2020.05.006
- Yang X., Yu Y., Xu J., Shu H., Xia J., Liu H., Wu Y., Zhang L., Yu Z., Fang M., Yu T., Wang Y., Pan S., Zou X., Yuan S., Shang Y., Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study. Lancet Respir. Med. 8, 475–481 (2020). 10.1016/S2213-2600(20)30079-5
- Vandesompele J., De Preter K., Pattyn F., Poppe B., Van Roy N., De Paepe A., Speleman F., Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 3, H0034 (2002). 10.1186/gb-2002-3-7-research0034
- Rasch D., Teuscher F., Guiard V., How robust are tests for two independent samples? J. Stat. Plan. Inference 137, 2706–2720 (2007). 10.1016/j.jspi.2006.04.011
- Darnell M. E. R., Taylor D. R., Evaluation of inactivation methods for severe acute respiratory syndrome coronavirus in noncellular blood products. Transfusion 46, 1770–1777 (2006). 10.1111/j.1537-2995.2006.00976.x
Source: PubMed