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1.
Nature ; 600(7888): 295-301, 2021 12.
Article in English | MEDLINE | ID: covidwho-1626235

ABSTRACT

SARS-CoV-2 is a single-stranded RNA virus that causes COVID-19. Given its acute and often self-limiting course, it is likely that components of the innate immune system play a central part in controlling virus replication and determining clinical outcome. Natural killer (NK) cells are innate lymphocytes with notable activity against a broad range of viruses, including RNA viruses1,2. NK cell function may be altered during COVID-19 despite increased representation of NK cells with an activated and adaptive phenotype3,4. Here we show that a decline in viral load in COVID-19 correlates with NK cell status and that NK cells can control SARS-CoV-2 replication by recognizing infected target cells. In severe COVID-19, NK cells show defects in virus control, cytokine production and cell-mediated cytotoxicity despite high expression of cytotoxic effector molecules. Single-cell RNA sequencing of NK cells over the time course of the COVID-19 disease spectrum reveals a distinct gene expression signature. Transcriptional networks of interferon-driven NK cell activation are superimposed by a dominant transforming growth factor-ß (TGFß) response signature, with reduced expression of genes related to cell-cell adhesion, granule exocytosis and cell-mediated cytotoxicity. In severe COVID-19, serum levels of TGFß peak during the first two weeks of infection, and serum obtained from these patients severely inhibits NK cell function in a TGFß-dependent manner. Our data reveal that an untimely production of TGFß is a hallmark of severe COVID-19 and may inhibit NK cell function and early control of the virus.

2.
Preprint in English | Other preprints | ID: ppcovidwho-295964

ABSTRACT

ABSTRACT Objectives Due to their underlying disease as well as therapeutic immunosuppression, children and adolescents with rheumatic and musculoskeletal diseases (RMD) may be at higher risk for a severe course or worse outcome of COVID-19, and SARS-CoV2 infection may trigger a flare of the RMD. To address these issues, a specific SARS-CoV-2 questionnaire was implemented in the National Pediatric Rheumatology Database (NPRD) in Germany. Methods Demographic, clinical and treatment data from juvenile patients with RMD as well as data about SARS-CoV-2 infection like test date and method, clinical characteristics, disease course, outcome and impact on the disease activity of the RMD documented on this questionnaire were analyzed. Results From April 17th, 2020, to February 14th, 2021, data were collected from 79 patients (53% female) with RMD with median age of 14 years, diagnosed with juvenile idiopathic arthritis (57%), autoinflammatory (23%) and connective tissue disease (8%). Sixty-one patients (77%) received disease-modifying antirheumatic drugs (DMARDs), 43% biologic DMARDs, and 9% systemic glucocorticoids. Sixty patients (76%) developed symptoms of COVID-19. Disease severity was mild and outcome was good in the majority of patients. Two patients were hospitalized, one of whom required intensive care and died of cardiorespiratory failure. In 84% of SARS-CoV-2-positive patients, no relevant increase in disease activity of the RMD was observed. Conclusions In our cohort, COVID-19 in juvenile patients with RMD under various medications was mild with good outcome in the majority of cases. SARS-CoV-2 infection does not appear to have a relevant impact on disease activity of the underlying condition.

3.
Nature ; 600(7888): 295-301, 2021 12.
Article in English | MEDLINE | ID: covidwho-1483137

ABSTRACT

SARS-CoV-2 is a single-stranded RNA virus that causes COVID-19. Given its acute and often self-limiting course, it is likely that components of the innate immune system play a central part in controlling virus replication and determining clinical outcome. Natural killer (NK) cells are innate lymphocytes with notable activity against a broad range of viruses, including RNA viruses1,2. NK cell function may be altered during COVID-19 despite increased representation of NK cells with an activated and adaptive phenotype3,4. Here we show that a decline in viral load in COVID-19 correlates with NK cell status and that NK cells can control SARS-CoV-2 replication by recognizing infected target cells. In severe COVID-19, NK cells show defects in virus control, cytokine production and cell-mediated cytotoxicity despite high expression of cytotoxic effector molecules. Single-cell RNA sequencing of NK cells over the time course of the COVID-19 disease spectrum reveals a distinct gene expression signature. Transcriptional networks of interferon-driven NK cell activation are superimposed by a dominant transforming growth factor-ß (TGFß) response signature, with reduced expression of genes related to cell-cell adhesion, granule exocytosis and cell-mediated cytotoxicity. In severe COVID-19, serum levels of TGFß peak during the first two weeks of infection, and serum obtained from these patients severely inhibits NK cell function in a TGFß-dependent manner. Our data reveal that an untimely production of TGFß is a hallmark of severe COVID-19 and may inhibit NK cell function and early control of the virus.

4.
RMD Open ; 7(2)2021 07.
Article in English | MEDLINE | ID: covidwho-1327713

ABSTRACT

OBJECTIVES: This study aimed to investigate the clinical manifestations, course and outcome of SARS-CoV-2 infection among children and adolescents with rheumatic and musculoskeletal diseases (RMD). Due to their underlying disease as well due to therapeutic immunosuppression, these patients may be at risk for a severe course of COVID-19 or for a flare of the underlying disease triggered by SARS-CoV-2 infection. METHODS: Demographic, clinical and treatment data from juvenile patients with RMD as well as data about SARS-CoV-2 infection like test date and method, clinical characteristics, disease course, outcome and impact on the disease activity of the RMD were documented on a specific SARS-CoV-2 questionnaire implemented in the National Paediatric Rheumatology Database (NPRD) in Germany. The survey data were analysed descriptively. RESULTS: From 17 April 2020 to 16 February 2021, data were collected from 76 patients (52% female) with RMD and laboratory-proven SARS-CoV-2 infection with median age of 14 years, diagnosed with juvenile idiopathic arthritis (58%), autoinflammatory (24%) and connective tissue disease (8%). Fifty-eight patients (76%) received disease-modifying antirheumatic drugs (DMARDs), 41% biological DMARDs and 11% systemic glucocorticoids. Fifty-eight (76%) had symptoms of COVID-19. Disease course of SARS-CoV-2 infection (classified as asymptomatic, mild, moderate, severe, life-threatening) was mild and outcome of COVID-19 (classified as recovered, not yet recovered, permanent damage or deceased) was good (recovered) in the majority of patients. Two patients were hospitalised, one of whom required intensive care and died of cardiorespiratory failure. In 84% of SARS-CoV-2-positive patients, no relevant increase in disease activity of the RMD was observed. CONCLUSIONS: In our cohort, SARS-CoV-2 infection in juvenile patients with RMD under various medications was mild with good outcome in the majority of cases and does not appear to have a relevant impact on disease activity of the underlying condition.


Subject(s)
COVID-19 , Musculoskeletal Diseases , Rheumatology , Adolescent , Child , Female , Germany/epidemiology , Humans , Male , Musculoskeletal Diseases/epidemiology , SARS-CoV-2
5.
J Clin Invest ; 131(14)2021 07 15.
Article in English | MEDLINE | ID: covidwho-1311204

ABSTRACT

Autoantibodies against IFN-α and IFN-ω (type I IFNs) were recently reported as causative for severe COVID-19 in the general population. Autoantibodies against IFN-α and IFN-ω are present in almost all patients with autoimmune polyendocrine syndrome type 1 (APS-1) caused by biallelic deleterious or heterozygous dominant mutations in AIRE. We therefore hypothesized that autoantibodies against type I IFNs also predispose patients with APS-1 to severe COVID-19. We prospectively studied 6 patients with APS-1 between April 1, 2020 and April 1, 2021. Biobanked pre-COVID-19 sera of APS-1 subjects were tested for neutralizing autoantibodies against IFN-α and IFN-ω. The ability of the patients' sera to block recombinant human IFN-α and IFN-ω was assessed by assays quantifying phosphorylation of signal transducer and activator of transcription 1 (STAT1) as well as infection-based IFN-neutralization assays. We describe 4 patients with APS-1 and preexisting high titers of neutralizing autoantibodies against IFN-α and IFN-ω who contracted SARS-CoV-2, yet developed only mild symptoms of COVID-19. None of the patients developed dyspnea, oxygen requirement, or high temperature. All infected patients with APS-1 were females and younger than 26 years of age. Clinical penetrance of neutralizing autoantibodies against type I IFNs for severe COVID-19 is not complete.


Subject(s)
Autoantibodies/immunology , COVID-19/complications , COVID-19/immunology , Interferon Type I/antagonists & inhibitors , Interferon Type I/immunology , Polyendocrinopathies, Autoimmune/complications , Polyendocrinopathies, Autoimmune/immunology , SARS-CoV-2 , Adolescent , Adult , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Autoantibodies/blood , Female , Humans , In Vitro Techniques , Interferon-alpha/antagonists & inhibitors , Interferon-alpha/immunology , Male , Polyendocrinopathies, Autoimmune/genetics , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Severity of Illness Index , Transcription Factors/genetics , Virus Replication/immunology , Young Adult
6.
Nat Commun ; 12(1): 1961, 2021 03 30.
Article in English | MEDLINE | ID: covidwho-1169399

ABSTRACT

The pathogenesis of severe COVID-19 reflects an inefficient immune reaction to SARS-CoV-2. Here we analyze, at the single cell level, plasmablasts egressed into the blood to study the dynamics of adaptive immune response in COVID-19 patients requiring intensive care. Before seroconversion in response to SARS-CoV-2 spike protein, peripheral plasmablasts display a type 1 interferon-induced gene expression signature; however, following seroconversion, plasmablasts lose this signature, express instead gene signatures induced by IL-21 and TGF-ß, and produce mostly IgG1 and IgA1. In the sustained immune reaction from COVID-19 patients, plasmablasts shift to the expression of IgA2, thereby reflecting an instruction by TGF-ß. Despite their continued presence in the blood, plasmablasts are not found in the lungs of deceased COVID-19 patients, nor does patient IgA2 binds to the dominant antigens of SARS-CoV-2. Our results thus suggest that, in severe COVID-19, SARS-CoV-2 triggers a chronic immune reaction that is instructed by TGF-ß, and is distracted from itself.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Transforming Growth Factor beta/immunology , Adult , Aged , Aged, 80 and over , COVID-19/virology , Female , Humans , Immunoglobulin A/immunology , Immunoglobulin G/immunology , Interleukins/immunology , Male , Middle Aged , Plasma Cells/immunology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
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