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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.
Int J Environ Res Public Health ; 19(1)2021 Dec 21.
Article in English | MEDLINE | ID: covidwho-1580860

ABSTRACT

While SARS-CoV-2 infection activity in German kindergartens during the first year of the pandemic appeared to be overall low, outbreaks did occur. We retrospectively investigated an outbreak in November and December 2020 in a Berlin kindergarten participating in the Berlin Corona School and Kindergarten Study (BECOSS). Interviews were conducted with affected families regarding symptomatology, contact persons and possible sources of infection, as well as relevant information on the conditions on-site and infection prevention measures. A chronology of the outbreak was elaborated, and based on data on contacts and symptoms, we mapped the most likely chains of infection. Overall, 24 individuals, including ten educators, seven children, and seven household members, were infected with SARS-CoV-2 in a four-week time interval. Courses of infection ranged from asymptomatic to severe, with children less affected by symptoms. Viral spread within the facility seemed to occur mainly through kindergarten staff, while children primarily transmitted infections within their families. Interviewees reported that hygiene measures were not always adhered to inside the facility. To prevent outbreaks in kindergartens, especially in the light of current and newly emerging viral variants of concern, strict compliance to hygiene rules, staff vaccinations against SARS-CoV-2, and immediate reaction to suspected cases by quarantining and frequent testing seem reasonable measures.


Subject(s)
COVID-19 , Berlin , Child , Disease Outbreaks , Humans , Retrospective Studies , SARS-CoV-2 , Schools
3.
Cell ; 2021 Dec 28.
Article in English | MEDLINE | ID: covidwho-1588146

ABSTRACT

Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathology, and it remains unclear whether T cells contribute to disease pathology. Here, we combined single-cell transcriptomics and single-cell proteomics with mechanistic studies to assess pathogenic T cell functions and inducing signals. We identified highly activated CD16+ T cells with increased cytotoxic functions in severe COVID-19. CD16 expression enabled immune-complex-mediated, T cell receptor-independent degranulation and cytotoxicity not found in other diseases. CD16+ T cells from COVID-19 patients promoted microvascular endothelial cell injury and release of neutrophil and monocyte chemoattractants. CD16+ T cell clones persisted beyond acute disease maintaining their cytotoxic phenotype. Increased generation of C3a in severe COVID-19 induced activated CD16+ cytotoxic T cells. Proportions of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a were associated with fatal outcome of COVID-19, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19.

4.
J Infect Dis ; 2021 Oct 15.
Article in English | MEDLINE | ID: covidwho-1575544

ABSTRACT

The upper respiratory tract (URT) is the primary entry site for SARS-CoV-2 and other respiratory viruses, but its involvement in viral amplification and pathogenesis remains incompletely understood. Here we investigated primary nasal epithelial cultures, as well as vital explanted tissues to scrutinize the tropism of wild-type SARS-CoV-2 and the recently emerged B.1.1.7 variant. Our analyses revealed a widespread replication competence of SARS-CoV-2 in polarized nasal epithelium as well as in the examined URT and salivary gland tissues, which was also shared by the B.1.1.7 virus thereby highlighting the active role of these anatomic sites in COVID-19.

6.
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.

7.
J Infect Dis ; 2021 Oct 15.
Article in English | MEDLINE | ID: covidwho-1470155

ABSTRACT

The upper respiratory tract (URT) is the primary entry site for SARS-CoV-2 and other respiratory viruses, but its involvement in viral amplification and pathogenesis remains incompletely understood. Here we investigated primary nasal epithelial cultures, as well as vital explanted tissues to scrutinize the tropism of wild-type SARS-CoV-2 and the recently emerged B.1.1.7 variant. Our analyses revealed a widespread replication competence of SARS-CoV-2 in polarized nasal epithelium as well as in the examined URT and salivary gland tissues, which was also shared by the B.1.1.7 virus thereby highlighting the active role of these anatomic sites in COVID-19.

9.
Euro Surveill ; 26(34)2021 08.
Article in English | MEDLINE | ID: covidwho-1417055

ABSTRACT

BackgroundSchool attendance during the COVID-19 pandemic is intensely debated.AimIn November 2020, we assessed SARS-CoV-2 infections and seroreactivity in 24 randomly selected school classes and connected households in Berlin, Germany.MethodsWe collected oro-nasopharyngeal swabs and blood samples, examining SARS-CoV-2 infection and IgG antibodies by RT-PCR and ELISA. Household members self-swabbed. We assessed individual and institutional prevention measures. Classes with SARS-CoV-2 infection and connected households were retested after 1 week.ResultsWe examined 1,119 participants, including 177 primary and 175 secondary school students, 142 staff and 625 household members. SARS-CoV-2 infection occurred in eight classes, affecting each 1-2 individuals. Infection prevalence was 2.7% (95% confidence interval (CI): 1.2-5.0; 9/338), 1.4% (95% CI: 0.2-5.1; 2/140), and 2.3% (95% CI: 1.3-3.8; 14/611) among students, staff and household members. Six of nine infected students were asymptomatic at testing. We detected IgG antibodies in 2.0% (95%CI: 0.8-4.1; 7/347), 1.4% (95% CI: 0.2-5.0; 2/141) and 1.4% (95% CI: 0.6-2.7; 8/576). Prevalence increased with inconsistent facemask-use in school, walking to school, and case-contacts outside school. For three of nine households with infection(s), origin in school seemed possible. After 1 week, no school-related secondary infections appeared in affected classes; the attack rate in connected households was 1.1%.ConclusionSchool attendance under rigorously implemented preventive measures seems reasonable. Balancing risks and benefits of school closures need to consider possible spill-over infection into households. Deeper insight is required into the infection risks due to being a schoolchild vs attending school.


Subject(s)
COVID-19 , SARS-CoV-2 , Berlin , Cross-Sectional Studies , Germany/epidemiology , Humans , Pandemics , Schools
10.
Front Pediatr ; 9: 694963, 2021.
Article in English | MEDLINE | ID: covidwho-1413885

ABSTRACT

Background: In Germany, so far the COVID-19 pandemic evolved in two distinct waves, the first beginning in February and the second in July, 2020. The Berlin University Children's Hospital at Charité (BCH) had to ensure treatment for children not infected and infected with SARS-CoV-2. Prevention of nosocomial SARS-CoV-2 infection of patients and staff was a paramount goal. Pediatric hospitals worldwide discontinued elective treatments and established a centralized admission process. Methods: The response of BCH to the pandemic adapted to emerging evidence. This resulted in centralized admission via one ward exclusively dedicated to children with unclear SARS-CoV-2 status and discontinuation of elective treatment during the first wave, but maintenance of elective care and decentralized admissions during the second wave. We report numbers of patients treated and of nosocomial SARS-CoV-2 infections during the two waves of the pandemic. Results: During the first wave, weekly numbers of inpatient and outpatient cases declined by 37% (p < 0.001) and 29% (p = 0.003), respectively. During the second wave, however, inpatient case numbers were 7% higher (p = 0.06) and outpatient case numbers only 6% lower (p = 0.25), compared to the previous year. Only a minority of inpatients were tested positive for SARS-CoV-2 by RT-PCR (0.47% during the first, 0.63% during the second wave). No nosocomial infection of pediatric patients by SARS-CoV-2 occurred. Conclusion: In contrast to centralized admission via a ward exclusively dedicated to children with unclear SARS-CoV-2 status and discontinuation of elective treatments, maintenance of elective care and decentralized admission allowed the almost normal use of hospital resources, yet without increased risk of nosocomial infections with SARS-CoV-2. By this approach unwanted sequelae of withheld specialized pediatric non-emergency treatment to child and adolescent health may be avoided.

11.
Eur J Public Health ; 31(5): 1105-1107, 2021 10 26.
Article in English | MEDLINE | ID: covidwho-1387873

ABSTRACT

Actual surveys in kindergartens on SARS-CoV-2 infections are rare. At the beginning of the second pandemic wave, we screened 12 randomly selected kindergartens in Berlin, Germany. A total of 720 participants (pre-school children, staff and connected household members) were briefly examined and interviewed, and SARS-CoV-2 infections and anti-SARS-Cov-2 IgG antibodies were assessed. About a quarter of the participants showed common cold-resembling symptoms. However, no SARS-CoV-2 infection was detected, and only one childcare worker showed IgG seroreactivity. Against a backdrop of increased pandemic activity in the community, this cross-sectional study does not suggest that kindergartens are silent transmission reservoirs.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , Berlin , Child , Cross-Sectional Studies , Germany/epidemiology , Humans
13.
N Engl J Med ; 385(9): 815-825, 2021 08 26.
Article in English | MEDLINE | ID: covidwho-1373470

ABSTRACT

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor is a small-molecule cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be efficacious in patients with at least one Phe508del allele, which indicates that this combination can modulate a single Phe508del allele. In patients whose other CFTR allele contains a gating or residual function mutation that is already effectively treated with previous CFTR modulators (ivacaftor or tezacaftor-ivacaftor), the potential for additional benefit from restoring Phe508del CFTR protein function is unclear. METHODS: We conducted a phase 3, double-blind, randomized, active-controlled trial involving patients 12 years of age or older with cystic fibrosis and Phe508del-gating or Phe508del-residual function genotypes. After a 4-week run-in period with ivacaftor or tezacaftor-ivacaftor, patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or active control for 8 weeks. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline through week 8 in the elexacaftor-tezacaftor-ivacaftor group. RESULTS: After the run-in period, 132 patients received elexacaftor-tezacaftor-ivacaftor and 126 received active control. Elexacaftor-tezacaftor-ivacaftor resulted in a percentage of predicted FEV1 that was higher by 3.7 percentage points (95% confidence interval [CI], 2.8 to 4.6) relative to baseline and higher by 3.5 percentage points (95% CI, 2.2 to 4.7) relative to active control and a sweat chloride concentration that was lower by 22.3 mmol per liter (95% CI, 20.2 to 24.5) relative to baseline and lower by 23.1 mmol per liter (95% CI, 20.1 to 26.1) relative to active control (P<0.001 for all comparisons). The change from baseline in the Cystic Fibrosis Questionnaire-Revised respiratory domain score (range, 0 to 100, with higher scores indicating better quality of life) with elexacaftor-tezacaftor-ivacaftor was 10.3 points (95% CI, 8.0 to 12.7) and with active control was 1.6 points (95% CI, -0.8 to 4.1). The incidence of adverse events was similar in the two groups; adverse events led to treatment discontinuation in one patient (elevated aminotransferase level) in the elexacaftor-tezacaftor-ivacaftor group and in two patients (anxiety or depression and pulmonary exacerbation) in the active control group. CONCLUSIONS: Elexacaftor-tezacaftor-ivacaftor was efficacious and safe in patients with Phe508del-gating or Phe508del-residual function genotypes and conferred additional benefit relative to previous CFTR modulators. (Funded by Vertex Pharmaceuticals; VX18-445-104 ClinicalTrials.gov number, NCT04058353.).


Subject(s)
Aminophenols/therapeutic use , Benzodioxoles/therapeutic use , Chloride Channel Agonists/therapeutic use , Cystic Fibrosis/drug therapy , Indoles/therapeutic use , Pyrazoles/therapeutic use , Pyridines/therapeutic use , Quinolines/therapeutic use , Adolescent , Adult , Aminophenols/adverse effects , Benzodioxoles/adverse effects , Child , Chloride Channel Agonists/adverse effects , Chlorides/analysis , Cystic Fibrosis/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Double-Blind Method , Drug Combinations , Female , Genotype , Humans , Indoles/adverse effects , Male , Pyrazoles/adverse effects , Pyridines/adverse effects , Quinolines/adverse effects , Sweat/chemistry
14.
Int J Infect Dis ; 110: 261-266, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1373061

ABSTRACT

INTRODUCTION: Containing COVID-19 requires broad-scale testing. However, sample collection requires qualified personnel and protective equipment and may cause transmission. We assessed the sensitivity of SARS-CoV-2-rtPCR applying three self-sampling techniques as compared to professionally collected oro-nasopharyngeal samples (cOP/NP). METHODS: From 62 COVID-19 outpatients, we obtained: (i) multi-swab, MS; (ii) saliva sponge combined with nasal vestibula, SN; (iii) gargled water, GW; (iv) professionally collected cOP/NP (standard). We compared ct-values for E-gene and ORF1ab and analysed variables reducing sensitivity of self-collecting procedures. RESULTS: The median ct-values for E-gene and ORF1ab obtained in cOP/NP samples were 20.7 and 20.2, in MS samples 22.6 and 21.8, in SN samples 23.3 and 22.3, and in GW samples 30.3 and 29.8, respectively. MS and SN samples showed sensitivities of 95.2% (95%CI, 86.5-99.0) and GW samples of 88.7% (78.1-95.3). Sensitivity was inversely correlated with ct-values, and became <90% for samples obtained more than 8 days after symptom onset. For MS and SN samples, false negativity was associated with language problems, sampling errors, and symptom duration. CONCLUSION: Conclusions from this study are limited to the sensitivity of self-sampling in mildly to moderately symptomatic patients. Still, self-collected oral/nasal/saliva samples can facilitate up-scaling of testing in early symptomatic COVID-19 patients if operational errors are minimized.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19 Testing , Humans , Nasopharynx , Outpatients , Saliva , Specimen Handling
15.
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
16.
Int J Environ Res Public Health ; 18(5)2021 03 08.
Article in English | MEDLINE | ID: covidwho-1134153

ABSTRACT

Briefly before the first peak of the COVID-19 pandemic in Berlin, Germany, schools closed in mid-March 2020. Following re-opening, schools resumed operation at a reduced level for nine weeks. During this phase, we aimed at assessing, among students and teachers, infection status, symptoms, individual behaviour, and institutional infection prevention measures. Twenty-four primary and secondary school classes, randomly selected across Berlin, were examined. Oro-nasopharyngeal swabs and capillary blood samples were collected to determine SARS-CoV-2 infection (PCR) and specific IgG (ELISA), respectively. Medical history, household characteristics, leisure activities, fear of infection, risk perception, hand hygiene, facemask wearing, and institutional preventive measures were assessed. Descriptive analysis was performed. Among 535 participants (385 students, 150 staff), one teenager was found to be infected with SARS-CoV-2 (0.2%), and seven individuals exhibited specific IgG (1.3%). Compared to pre-pandemic times, screen time (e.g., TV, gaming, social media) increased, and the majority of primary school students reported reduced physical activity (42.2%). Fear of infection and risk perception were relatively low, acceptance of adapted health behaviors was high. In this post-lockdown period of low SARS-CoV-2 incidence in Berlin, individual and school-level infection prevention measures were largely adhered to. Nevertheless, vigilance and continued preventive measures are essential to cope with future pandemic activity.


Subject(s)
COVID-19 , SARS-CoV-2 , Adolescent , Berlin , Communicable Disease Control , Cross-Sectional Studies , Germany/epidemiology , Humans , Pandemics , Perception , Schools
18.
Nature ; 587(7833): 270-274, 2020 11.
Article in English | MEDLINE | ID: covidwho-684778

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the rapidly unfolding coronavirus disease 2019 (COVID-19) pandemic1,2. Clinical manifestations of COVID-19 vary, ranging from asymptomatic infection to respiratory failure. The mechanisms that determine such variable outcomes remain unresolved. Here we investigated CD4+ T cells that are reactive against the spike glycoprotein of SARS-CoV-2 in the peripheral blood of patients with COVID-19 and SARS-CoV-2-unexposed healthy donors. We detected spike-reactive CD4+ T cells not only in 83% of patients with COVID-19 but also in 35% of healthy donors. Spike-reactive CD4+ T cells in healthy donors were primarily active against C-terminal epitopes in the spike protein, which show a higher homology to spike glycoproteins of human endemic coronaviruses, compared with N-terminal epitopes. Spike-protein-reactive T cell lines generated from SARS-CoV-2-naive healthy donors responded similarly to the C-terminal region of the spike proteins of the human endemic coronaviruses 229E and OC43, as well as that of SARS-CoV-2. This results indicate that spike-protein cross-reactive T cells are present, which were probably generated during previous encounters with endemic coronaviruses. The effect of pre-existing SARS-CoV-2 cross-reactive T cells on clinical outcomes remains to be determined in larger cohorts. However, the presence of spike-protein cross-reactive T cells in a considerable fraction of the general population may affect the dynamics of the current pandemic, and has important implications for the design and analysis of upcoming trials investigating COVID-19 vaccines.


Subject(s)
Betacoronavirus/immunology , CD4-Positive T-Lymphocytes/immunology , Coronavirus Infections/immunology , Pneumonia, Viral/immunology , Spike Glycoprotein, Coronavirus/immunology , Adult , Aged , Aged, 80 and over , COVID-19 , Cell Line , Coronavirus 229E, Human/immunology , Coronavirus NL63, Human/immunology , Coronavirus OC43, Human/immunology , Cross Reactions , Epitopes, T-Lymphocyte/immunology , Female , Healthy Volunteers , Humans , Lymphocyte Activation , Male , Middle Aged , Pandemics , SARS-CoV-2
19.
Infection ; 48(4): 619-626, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-597401

ABSTRACT

PURPOSE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide causing a global health emergency. Pa-COVID-19 aims to provide comprehensive data on clinical course, pathophysiology, immunology and outcome of COVID-19, to identify prognostic biomarkers, clinical scores, and therapeutic targets for improved clinical management and preventive interventions. METHODS: Pa-COVID-19 is a prospective observational cohort study of patients with confirmed SARS-CoV-2 infection treated at Charité - Universitätsmedizin Berlin. We collect data on epidemiology, demography, medical history, symptoms, clinical course, and pathogen testing and treatment. Systematic, serial blood sampling will allow deep molecular and immunological phenotyping, transcriptomic profiling, and comprehensive biobanking. Longitudinal data and sample collection during hospitalization will be supplemented by long-term follow-up. RESULTS: Outcome measures include the WHO clinical ordinal scale on day 15 and clinical, functional, and health-related quality-of-life assessments at discharge and during follow-up. We developed a scalable dataset to (i) suit national standards of care, (ii) facilitate comprehensive data collection in medical care facilities with varying resources, and (iii) allow for rapid implementation of interventional trials based on the standardized study design and data collection. We propose this scalable protocol as blueprint for harmonized data collection and deep phenotyping in COVID-19 in Germany. CONCLUSION: We established a basic platform for harmonized, scalable data collection, pathophysiological analysis, and deep phenotyping of COVID-19, which enables rapid generation of evidence for improved medical care and identification of candidate therapeutic and preventive strategies. The electronic database accredited for interventional trials allows fast trial implementation for candidate therapeutic agents. TRIAL REGISTRATION: Registered at the German registry for clinical studies (DRKS00021688).


Subject(s)
Coronavirus Infections/physiopathology , Pneumonia, Viral/physiopathology , Registries , Berlin/epidemiology , Betacoronavirus , Biological Specimen Banks , COVID-19 , Coronavirus Infections/epidemiology , Disease Management , Humans , Observational Studies as Topic , Pandemics , Phenotype , Pneumonia, Viral/epidemiology , Prospective Studies , Risk Assessment , Risk Factors , SARS-CoV-2 , Time Factors , Treatment Outcome , World Health Organization
20.
NAR Genom Bioinform ; 2(2): lqaa036, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-361183

ABSTRACT

Genome-wide association studies have identified lung disease-associated loci; however, the functions of such loci are not well understood in part because the majority of such loci are located at non-coding regions. Hi-C, ChIP-seq and eQTL data predict potential roles (e.g. enhancer) of such loci; however, they do not elucidate the molecular function. To determine whether these loci function as gene-regulatory regions, CRISPR interference (CRISPRi; CRISPR/dCas9-KRAB) has been recently used. Here, we applied CRISPRi along with Hi-C, ChIP-seq and eQTL to determine the functional roles of loci established as highly associated with asthma, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Notably, Hi-C, ChIP-seq and eQTL predicted that non-coding regions located at chromosome 19q13 or chromosome 17q21 harboring single-nucleotide polymorphisms (SNPs) linked to asthma/CF/COPD and chromosome 11p15 harboring an SNP linked to IPF interact with nearby genes and function as enhancers; however, CRISPRi indicated that the regions with rs1800469, rs2241712, rs12603332 and rs35705950, but not others, regulate the expression of nearby genes (single or multiple genes). These data indicate that CRISPRi is useful to precisely determine the roles of non-coding regions harboring lung disease-associated loci as to whether they function as gene-regulatory regions at a genomic level.

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