Suppression of Type I Interferon Signaling in Myeloid Cells by Autoantibodies in Severe COVID-19 Patients

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Abstract

Purpose

Auto-antibodies (auto-abs) to type I interferons (IFNs) have been identified in patients with life-threatening coronavirus disease 2019 (COVID-19), suggesting that the presence of auto-abs may be a risk factor for disease severity. We therefore investigated the mechanism underlying COVID-19 exacerbation induced by auto-abs to type I IFNs.

Methods

We evaluated plasma from 123 patients with COVID-19 to measure auto-abs to type I IFNs. We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from the patients with auto-abs and conducted epitope mapping of the auto-abs.

Results

Three of 19 severe and 4 of 42 critical COVID-19 patients had neutralizing auto-abs to type I IFNs. Patients with auto-abs to type I IFNs showed no characteristic clinical features. scRNA-seq from 38 patients with COVID-19 revealed that IFN signaling in conventional dendritic cells and canonical monocytes was attenuated, and SARS-CoV-2-specific BCR repertoires were decreased in patients with auto-abs. Furthermore, auto-abs to IFN-α2 from COVID-19 patients with auto-abs recognized characteristic epitopes of IFN-α2, which binds to the receptor.

Conclusion

Auto-abs to type I IFN found in COVID-19 patients inhibited IFN signaling in dendritic cells and monocytes by blocking the binding of type I IFN to its receptor. The failure to properly induce production of an antibody to SARS-CoV-2 may be a causative factor of COVID-19 severity.

Supplementary Information

The online version contains supplementary material available at 10.1007/s10875-024-01708-7.

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Most cited references 57

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Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Chaolin Huang, Yeming Wang, Xingwang Li … (2020)

Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.

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OpenSAFELY: factors associated with COVID-19 death in 17 million patients

Elizabeth J Williamson, Alex J Walker, Krishnan Bhaskaran … (2020)

COVID-19 has rapidly impacted on mortality worldwide. 1 There is unprecedented urgency to understand who is most at risk of severe outcomes, requiring new approaches for timely analysis of large datasets. Working on behalf of NHS England we created OpenSAFELY: a secure health analytics platform covering 40% of all patients in England, holding patient data within the existing data centre of a major primary care electronic health records vendor. Primary care records of 17,278,392 adults were pseudonymously linked to 10,926 COVID-19 related deaths. COVID-19 related death was associated with: being male (hazard ratio 1.59, 95%CI 1.53-1.65); older age and deprivation (both with a strong gradient); diabetes; severe asthma; and various other medical conditions. Compared to people with white ethnicity, black and South Asian people were at higher risk even after adjustment for other factors (HR 1.48, 1.29-1.69 and 1.45, 1.32-1.58 respectively). We have quantified a range of clinical risk factors for COVID-19 related death in the largest cohort study conducted by any country to date. OpenSAFELY is rapidly adding further patients’ records; we will update and extend results regularly.

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Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19

Daniel Blanco-Melo, Benjamin E. Nilsson-Payant, Wen-Chun Liu … (2021)

Summary Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.

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Author and article information

Contributors

Toshinori Nakayama: tnakayama@faculty.chiba-u.jp

Kiyoshi Hirahara:

ORCID: http://orcid.org/0000-0002-9128-9449

hiraharak@chiba-u.jp

Journal

Journal ID (nlm-ta): J Clin Immunol

Journal ID (iso-abbrev): J Clin Immunol

Title: Journal of Clinical Immunology

Publisher: Springer US (New York )

ISSN (Print): 0271-9142

ISSN (Electronic): 1573-2592

Publication date (Electronic): 22 April 2024

Publication date PMC-release: 22 April 2024

Publication date (Print): 2024

Volume: 44

Issue: 4

Electronic Location Identifier: 104

Affiliations

[1 ]Department of Immunology, Graduate School of Medicine, Chiba University, ( https://ror.org/01hjzeq58) Chiba, 260-8670 Japan

[2 ]Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, ( https://ror.org/04ww21r56) Niigata, 951-8510 Japan

[3 ]Synergy Institute for Futuristic Mucosal Vaccine Research and Development, Chiba University, ( https://ror.org/01hjzeq58) Chiba, Japan

[4 ]Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Chiba University, ( https://ror.org/01hjzeq58) Chiba, 260-8670 Japan

[5 ]GRID grid.258269.2, ISNI 0000 0004 1762 2738, Department of Respiratory Medicine, , Juntendo University Faculty of Medicine and Graduate School of Medicine, ; Tokyo, 113-8431 Japan

[6 ]Funabashi Central Hospital, ( https://ror.org/04sgkca59) Chiba, 273-8556 Japan

[7 ]Department of Infectious Diseases, Japanese Red Cross Narita Hospital, ( https://ror.org/04prxcf74) Chiba, 286-0041 Japan

[8 ]Department of Respiratory Medicine, Eastern Chiba Medical Center, Chiba, 283-8686 Japan

[9 ]Department of Anesthesiology and Critical Care Medicine, School of Medicine, Fujita Health University, ( https://ror.org/046f6cx68) Toyoake, Aichi 470-1192 Japan

[10 ]Funabashi Municipal Medical Center, ( https://ror.org/02nycs597) Chiba, 273-8588 Japan

[11 ]Kimitsu Chuo Hospital, Chiba, 292-0822 Japan

[12 ]Department of Gastroenterology, NHO Chiba Medical Center, Chiba, 260-8606 Japan

[13 ]Department of Pulmonary Medicine, International University of Health and Welfare Narita Hospital, ( https://ror.org/053d3tv41) Chiba, 286-8520 Japan

[14 ]Department of Experimental Immunology, Graduate School of Medicine, Chiba University, ( https://ror.org/01hjzeq58) Chiba, 260-8670 Japan

[15 ]Department of Medical Immunology, Graduate School of Medicine, Chiba University, ( https://ror.org/01hjzeq58) Chiba, 260-8670 Japan

[16 ]Department of Infectious Diseases, Chiba University Hospital, ( https://ror.org/0126xah18) Chiba, 260-8677 Japan

[17 ]COVID-19 Vaccine Center, Chiba University Hospital, ( https://ror.org/0126xah18) Chiba, 260-8677 Japan

[18 ]Department of Pathology, Graduate School of Medicine, Chiba University, ( https://ror.org/01hjzeq58) Chiba, 260-8670 Japan

[19 ]Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, ( https://ror.org/01hjzeq58) Chiba, 260-8670 Japan

[20 ]Department of Respirology, Graduate School of Medicine, Chiba University, ( https://ror.org/01hjzeq58) Chiba, 260-8670 Japan

[21 ]Clinical Research Center, Chiba University Hospital, ( https://ror.org/0126xah18) Chiba, 260-8677 Japan

[22 ]GRID grid.480536.c, ISNI 0000 0004 5373 4593, AMED-CREST, AMED, ; 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670 Japan

[23 ]Department of Endocrinology, Hematology and Gerontology, Graduate School of Medicine, Chiba University, ( https://ror.org/01hjzeq58) Chiba, 260-8670 Japan

Author information

Kiyoshi Hirahara http://orcid.org/0000-0002-9128-9449

Article

Publisher ID: 1708

DOI: 10.1007/s10875-024-01708-7

PMC ID: 11035476

PubMed ID: 38647550

SO-VID: ddb3505f-c2a4-48f7-bb63-da6d61372084

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 7 June 2023

Date accepted : 10 April 2024

Funding

Funded by: Ministry of Education, Culture, Sports, Science and Technology (MEXT Japan) Grants-in-Aid for Scientific Research

Award ID: (S) 26221305

Award ID: (B) 20H03685

Award ID: (C) 17K08876

Award ID: (C) 18K07164

Award ID: 19K16683

Award Recipient : Masahiro Kiuchi Toshinori Nakayama Kiyoshi Hirahara

Funded by: Transformative Research Areas

Award ID: (B) JP21H05120

Award Recipient : Kiyoshi Hirahara

Funded by: Transformative Research Areas

Award ID: (B) JP21H05121

Award Recipient : Kiyoshi Hirahara

Funded by: Practical Research Project for Allergic Diseases and Immunology (Research on Allergic Diseases and Immunology) from the Japan Agency for Medical Research and Development, AMED

Award ID: JP21ek0410060

Award ID: JP21ek0410082

Award ID: JP19ek0410045

Award Recipient : Toshinori Nakayama Kiyoshi Hirahara

Funded by: AMED-PRIME

Award ID: JP20gm6110005

Award Recipient : Kiyoshi Hirahara

Funded by: AMED-CREST

Award ID: JP21gm1210003

Award Recipient : Toshinori Nakayama

Funded by: JST FOREST Project

Award ID: JPMJFR200R

Award Recipient : Kiyoshi Hirahara

Funded by: FundRef http://dx.doi.org/10.13039/501100005865, Mochida Memorial Foundation for Medical and Pharmaceutical Research;

Funded by: FundRef http://dx.doi.org/10.13039/501100013236, MSD Life Science Foundation, Public Interest Incorporated Foundation;

Funded by: FundRef http://dx.doi.org/10.13039/100019085, Japanese Respiratory Foundation;

Funded by: FundRef http://dx.doi.org/10.13039/100007449, Takeda Science Foundation;

Funded by: The Japanese Association for Infectious Diseases, Grant for Clinical Research Promotion

Custom metadata

ScienceOpen disciplines: Immunology

Keywords: covid-19,type i ifns,autoantibody,single-cell rna sequencing,bcr repertoires,epitope mapping

Data availability:

ScienceOpen disciplines: Immunology

Keywords: covid-19, type i ifns, autoantibody, single-cell rna sequencing, bcr repertoires, epitope mapping

Suppression of Type I Interferon Signaling in Myeloid Cells by Autoantibodies in Severe COVID-19 Patients

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Abstract

Purpose

Methods

Results

Conclusion

Supplementary Information

Related collections

Novel Coronavirus Disease COVID-19

Most cited references 57

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

OpenSAFELY: factors associated with COVID-19 death in 17 million patients

Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19

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