Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 28
Filter
1.
Commun Biol ; 5(1): 1133, 2022 Oct 26.
Article in English | MEDLINE | ID: covidwho-2087324

ABSTRACT

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as "Respiratory or thoracic disease", supporting their link with COVID-19 severity outcome.


Subject(s)
COVID-19 , Humans , COVID-19/genetics , Genome-Wide Association Study , Genetic Predisposition to Disease , Whole Exome Sequencing , Phenotype
2.
J Med Virol ; 94(11): 5225-5243, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-1925945

ABSTRACT

Heterogeneity in symptoms associated with COVID-19 in infected patients remains unclear. ACE2 and TMPRSS2 gene variants are considered possible risk factors for COVID-19. In this study, a retrospective comparative genome analysis of the ACE2 and TMPRSS2 variants from 946 whole-exome sequencing data was conducted. Allele frequencies of all variants were calculated and filtered to remove variants with allele frequencies lower than 0.003 and to prioritize functional coding variants. The majority of detected variants were intronic, only two ACE2 and three TMPRSS2 nonsynonymous variants were detected in the analyzed cohort. The main ACE2 variants that putatively have a protective or susceptibility effect on SARS-CoV-2 have not yet been determined in the Turkish population. The Turkish genetic makeup likely lacks any ACE2 variant that increases susceptibility to SARS-CoV-2 infection. TMPRSS2 rs75603675 and rs12329760 variants that were previously defined as common variants that have different allele frequencies among populations and may have a role in SARS-CoV-2 attachment to host cells were determined in the population. Overall, these data will contribute to the formation of a national variation database and may also contribute to further studies of ACE2 and TMPRSS2 in the Turkish population and differences in SARS-CoV-2 infection among other populations.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19 , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/genetics , COVID-19/epidemiology , COVID-19/genetics , Humans , Peptidyl-Dipeptidase A/genetics , Retrospective Studies , Risk Factors , SARS-CoV-2/genetics , Serine Endopeptidases/genetics , Whole Exome Sequencing
3.
Sci Rep ; 12(1): 10369, 2022 06 20.
Article in English | MEDLINE | ID: covidwho-1900655

ABSTRACT

Rare variants affecting host defense against pathogens could be involved in COVID-19 severity and may help explain fatal outcomes in young and middle-aged patients. Our aim was to report the presence of rare genetic variants in certain genes, by using whole exome sequencing, in a selected group of COVID-19 patients under 65 years who required intubation or resulting in death (n = 44). To this end, different etiopathogenic mechanisms were explored using gene prioritization-based analysis in which genes involved in immune response, immunodeficiencies or blood coagulation were studied. We detected 44 different variants of interest, in 29 different patients (66%). Some of these variants were previously described as pathogenic and were located in genes mainly involved in immune response. A network analysis, including the 42 genes with candidate variants, showed three main components, consisting of 25 highly interconnected genes related to immune response and two additional networks composed by genes enriched in carbohydrate metabolism and in DNA metabolism and repair processes. In conclusion, we have detected candidate variants that may potentially influence COVID-19 outcome in our cohort of patients. Further studies are needed to confirm the ultimate role of the genetic variants described in the present study on COVID-19 severity.


Subject(s)
COVID-19 , Immunologic Deficiency Syndromes , Aged , COVID-19/genetics , Cohort Studies , Genetic Predisposition to Disease , Humans , Middle Aged , Whole Exome Sequencing
4.
Genet Med ; 24(8): 1653-1663, 2022 08.
Article in English | MEDLINE | ID: covidwho-1819495

ABSTRACT

PURPOSE: Emerging evidence suggest that infection-dependent hyperactivation of complement system (CS) may worsen COVID-19 outcome. We investigated the role of predicted high impact rare variants - referred as qualifying variants (QVs) - of CS genes in predisposing asymptomatic COVID-19 in elderly individuals, known to be more susceptible to severe disease. METHODS: Exploiting exome sequencing data and 56 CS genes, we performed a gene-based collapsing test between 164 asymptomatic subjects (aged ≥60 years) and 56,885 European individuals from the Genome Aggregation Database. We replicated this test comparing the same asymptomatic individuals with 147 hospitalized patients with COVID-19. RESULTS: We found an enrichment of QVs in 3 genes (MASP1, COLEC11, and COLEC10), which belong to the lectin pathway, in the asymptomatic cohort. Analyses of complement activity in serum showed decreased activity of lectin pathway in asymptomatic individuals with QVs. Finally, we found allelic variants associated with asymptomatic COVID-19 phenotype and with a decreased expression of MASP1, COLEC11, and COLEC10 in lung tissue. CONCLUSION: This study suggests that genetic rare variants can protect from severe COVID-19 by mitigating the activity of lectin pathway and prothrombin. The genetic data obtained through ES of 786 asymptomatic and 147 hospitalized individuals are publicly available at http://espocovid.ceinge.unina.it/.


Subject(s)
COVID-19 , Aged , COVID-19/genetics , Collectins/genetics , Collectins/metabolism , Germ Cells , Humans , Lectins/genetics , SARS-CoV-2 , Whole Exome Sequencing
5.
Per Med ; 19(3): 229-250, 2022 05.
Article in English | MEDLINE | ID: covidwho-1736673

ABSTRACT

Aim: A human immunogenetics variation study was conducted in samples collected from diverse COVID-19 populations. Materials & methods: Whole-genome and whole-exome sequencing (WGS/WES), data processing, analysis and visualization pipeline were applied to identify variants associated with genes of interest. Results: A total of 2886 mutations were found across the entire set of 13 genomes. Functional annotation of the gene variants revealed mutation type and protein change. Many variants were found to be biologically implicated in COVID-19. The involvement of these genes was also found in multiple other diseases. Conclusion: The analysis determined that ACE2, TMPRSS4, TMPRSS2, SLC6A20 and FYCOI had functional implications and TMPRSS4 was the gene most altered in virally infected patients.


The quest to establish an understanding of the genetics underlying COVID-19 is a central focus of life sciences today. COVID-19 is triggered by SARS-CoV-2, a single-stranded RNA respiratory virus. Several clinical-genomics studies have emerged positing different human gene mutations occurring due to COVID-19. A global analysis of these genes was conducted targeting major components of the immune system to identify possible variations likely to be involved in COVID-19 predisposition. Gene-variant analysis was performed on whole-genome sequencing samples collected from diverse populations. ACE2, TMPRSS4, TMPRSS2, SLC6A20 and FYCOI were found to have functional implications and TMPRSS4 may have a role in the severity of clinical manifestations of COVID-19.


Subject(s)
COVID-19 , Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Genome , Humans , Membrane Transport Proteins/genetics , SARS-CoV-2/genetics , Whole Exome Sequencing
6.
Nat Biotechnol ; 40(5): 681-691, 2022 05.
Article in English | MEDLINE | ID: covidwho-1713197

ABSTRACT

As the biomedical community produces datasets that are increasingly complex and high dimensional, there is a need for more sophisticated computational tools to extract biological insights. We present Multiscale PHATE, a method that sweeps through all levels of data granularity to learn abstracted biological features directly predictive of disease outcome. Built on a coarse-graining process called diffusion condensation, Multiscale PHATE learns a data topology that can be analyzed at coarse resolutions for high-level summarizations of data and at fine resolutions for detailed representations of subsets. We apply Multiscale PHATE to a coronavirus disease 2019 (COVID-19) dataset with 54 million cells from 168 hospitalized patients and find that patients who die show CD16hiCD66blo neutrophil and IFN-γ+ granzyme B+ Th17 cell responses. We also show that population groupings from Multiscale PHATE directly fed into a classifier predict disease outcome more accurately than naive featurizations of the data. Multiscale PHATE is broadly generalizable to different data types, including flow cytometry, single-cell RNA sequencing (scRNA-seq), single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq), and clinical variables.


Subject(s)
COVID-19 , Single-Cell Analysis , Chromatin , Humans , Single-Cell Analysis/methods , Transposases , Whole Exome Sequencing
7.
Genome Biol ; 23(1): 33, 2022 01 24.
Article in English | MEDLINE | ID: covidwho-1649470

ABSTRACT

We consider an increasingly popular study design where single-cell RNA-seq data are collected from multiple individuals and the question of interest is to find genes that are differentially expressed between two groups of individuals. Towards this end, we propose a statistical method named IDEAS (individual level differential expression analysis for scRNA-seq). For each gene, IDEAS summarizes its expression in each individual by a distribution and then assesses whether these individual-specific distributions are different between two groups of individuals. We apply IDEAS to assess gene expression differences of autism patients versus controls and COVID-19 patients with mild versus severe symptoms.


Subject(s)
Autistic Disorder/genetics , COVID-19/genetics , Sequence Analysis, RNA/methods , Single-Cell Analysis/methods , Software , Autistic Disorder/metabolism , Autistic Disorder/pathology , COVID-19/metabolism , COVID-19/pathology , COVID-19/virology , Case-Control Studies , Gene Expression Profiling , Gene Expression Regulation , Humans , Microglia/metabolism , Microglia/pathology , Nerve Tissue Proteins/classification , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , SARS-CoV-2/pathogenicity , Severity of Illness Index , Whole Exome Sequencing
8.
Hum Genet ; 141(1): 147-173, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1565371

ABSTRACT

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management.


Subject(s)
COVID-19/genetics , COVID-19/physiopathology , Genetic Predisposition to Disease , Phenotype , Severity of Illness Index , Whole Exome Sequencing , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , Germany , Humans , Italy , Male , Middle Aged , Polymorphism, Single Nucleotide , Quebec , SARS-CoV-2 , Sweden , United Kingdom
9.
Genes (Basel) ; 12(11)2021 11 22.
Article in English | MEDLINE | ID: covidwho-1533885

ABSTRACT

Host genomic information, specifically genomic variations, may characterize susceptibility to disease and identify people with a higher risk of harm, leading to better targeting of care and vaccination. Italy was the epicentre for the spread of COVID-19 in Europe, the first country to go into a national lockdown and has one of the highest COVID-19 associated mortality rates. Qatar, on the other hand has a very low mortality rate. In this study, we compared whole-genome sequencing data of 14398 adults and Qatari-national to 925 Italian individuals. We also included in the comparison whole-exome sequence data from 189 Italian laboratory-confirmed COVID-19 cases. We focused our study on a curated list of 3619 candidate genes involved in innate immunity and host-pathogen interaction. Two population-gene metric scores, the Delta Singleton-Cohort variant score (DSC) and Sum Singleton-Cohort variant score (SSC), were applied to estimate the presence of selective constraints in the Qatari population and in the Italian cohorts. Results based on DSC and SSC metrics demonstrated a different selective pressure on three genes (MUC5AC, ABCA7, FLNA) between Qatari and Italian populations. This study highlighted the genetic differences between Qatari and Italian populations and identified a subset of genes involved in innate immunity and host-pathogen interaction.


Subject(s)
COVID-19/genetics , Genetic Predisposition to Disease/genetics , Host Microbial Interactions/genetics , Adult , Alleles , COVID-19/epidemiology , Communicable Disease Control , Disease Susceptibility/metabolism , Exome/genetics , Female , Gene Frequency/genetics , Genetic Predisposition to Disease/epidemiology , Genetics, Population , Genomics/methods , Humans , Immunity, Innate/immunology , Italy/epidemiology , Male , Qatar/epidemiology , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Whole Exome Sequencing/methods , Whole Genome Sequencing/methods
10.
J Am Soc Nephrol ; 32(1): 41-51, 2021 01.
Article in English | MEDLINE | ID: covidwho-1496668

ABSTRACT

BACKGROUND: Mutations in PKD1 and PKD2, which encode the transmembrane proteins polycystin-1 and polycystin-2, respectively, cause autosomal dominant polycystic kidney disease (ADPKD). Polycystins are expressed in the primary cilium, and disrupting cilia structure significantly slows ADPKD progression following inactivation of polycystins. The cellular mechanisms of polycystin- and cilia-dependent cyst progression in ADPKD remain incompletely understood. METHODS: Unbiased transcriptional profiling in an adult-onset Pkd2 mouse model before cysts formed revealed significant differentially expressed genes (DEGs) in Pkd2 single-knockout kidneys, which were used to identify candidate pathways dysregulated in kidneys destined to form cysts. In vivo studies validated the role of the candidate pathway in the progression of ADPKD. Wild-type and Pkd2/Ift88 double-knockout mice that are protected from cyst growth served as controls. RESULTS: The RNASeq data identified cell proliferation as the most dysregulated pathway, with 15 of 241 DEGs related to cell cycle functions. Cdk1 appeared as a central component in this analysis. Cdk1 expression was similarly dysregulated in Pkd1 models of ADPKD, and conditional inactivation of Cdk1 with Pkd1 markedly improved the cystic phenotype and kidney function compared with inactivation of Pkd1 alone. The Pkd1/Cdk1 double knockout blocked cyst cell proliferation that otherwise accompanied Pkd1 inactivation alone. CONCLUSIONS: Dysregulation of Cdk1 is an early driver of cyst cell proliferation in ADPKD due to Pkd1 inactivation. Selective targeting of cyst cell proliferation is an effective means of slowing ADPKD progression caused by inactivation of Pkd1.


Subject(s)
CDC2 Protein Kinase/metabolism , Polycystic Kidney, Autosomal Dominant/genetics , Polycystic Kidney, Autosomal Dominant/metabolism , TRPP Cation Channels/metabolism , Animals , Apoptosis , CDC2 Protein Kinase/genetics , Catalytic Domain , Cell Proliferation , Crosses, Genetic , DNA Replication , Female , Gene Expression Profiling , Gene Expression Regulation , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mutation , Phenotype , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/genetics , RNA-Seq , TRPP Cation Channels/genetics , Transcription, Genetic , Whole Exome Sequencing
11.
Nucleic Acids Res ; 50(D1): D1115-D1122, 2022 01 07.
Article in English | MEDLINE | ID: covidwho-1493885

ABSTRACT

The UCSC Genome Browser, https://genome.ucsc.edu, is a graphical viewer for exploring genome annotations. The website provides integrated tools for visualizing, comparing, analyzing, and sharing both publicly available and user-generated genomic datasets. Data highlights this year include a collection of easily accessible public hub assemblies on new organisms, now featuring BLAT alignment and PCR capabilities, and new and updated clinical tracks (gnomAD, DECIPHER, CADD, REVEL). We introduced a new Track Sets feature and enhanced variant displays to aid in the interpretation of clinical data. We also added a tool to rapidly place new SARS-CoV-2 genomes in a global phylogenetic tree enabling researchers to view the context of emerging mutations in our SARS-CoV-2 Genome Browser. Other new software focuses on usability features, including more informative mouseover displays and new fonts.


Subject(s)
Databases, Genetic , Web Browser , Animals , Genome, Human , Humans , Phylogeny , Polymerase Chain Reaction , SARS-CoV-2/genetics , User-Computer Interface , Whole Exome Sequencing
12.
Urology ; 159: 83-86, 2022 01.
Article in English | MEDLINE | ID: covidwho-1472193

ABSTRACT

COVID orchitis (testicular pain) is reported in 10-15% of men with long COVID. We identified 2 siblings with COVID orchitis and hypothesized that genetic mutations are associated with susceptibility. Blood samples from 5 COVID-19 (+) men, three of whom had orchitis were evaluated by whole-exome-sequencing. A rare deletion on chromosome 7 was found in NACAD among the 3 men with orchitis. Interestingly, circulating ACE2 levels was decreased in men with COVID orchitis. This pilot study generated the hypothesis that men who develop COVID orchitis could have underlying genetic variants and altered levels in circulating ACE2 that may increase their risk.


Subject(s)
COVID-19/complications , Chromosome Deletion , Chromosomes, Human, Pair 7 , Orchitis/virology , Whole Exome Sequencing , Adult , Angiotensin-Converting Enzyme 2/blood , Frameshift Mutation , Humans , Male , Siblings
13.
Front Immunol ; 12: 742881, 2021.
Article in English | MEDLINE | ID: covidwho-1470759

ABSTRACT

Despite the high number of individuals infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who develop coronavirus disease 2019 (COVID-19) symptoms worldwide, many exposed individuals remain asymptomatic and/or uninfected and seronegative. This could be explained by a combination of environmental (exposure), immunological (previous infection), epigenetic, and genetic factors. Aiming to identify genetic factors involved in immune response in symptomatic COVID-19 as compared to asymptomatic exposed individuals, we analyzed 83 Brazilian couples where one individual was infected and symptomatic while the partner remained asymptomatic and serum-negative for at least 6 months despite sharing the same bedroom during the infection. We refer to these as "discordant couples". We performed whole-exome sequencing followed by a state-of-the-art method to call genotypes and haplotypes across the highly polymorphic major histocompatibility complex (MHC) region. The discordant partners had comparable ages and genetic ancestry, but women were overrepresented (65%) in the asymptomatic group. In the antigen-presentation pathway, we observed an association between HLA-DRB1 alleles encoding Lys at residue 71 (mostly DRB1*03:01 and DRB1*04:01) and DOB*01:02 with symptomatic infections and HLA-A alleles encoding 144Q/151R with asymptomatic seronegative women. Among the genes related to immune modulation, we detected variants in MICA and MICB associated with symptomatic infections. These variants are related to higher expression of soluble MICA and low expression of MICB. Thus, quantitative differences in these molecules that modulate natural killer (NK) activity could contribute to susceptibility to COVID-19 by downregulating NK cell cytotoxic activity in infected individuals but not in the asymptomatic partners.


Subject(s)
Asymptomatic Infections , COVID-19 , Histocompatibility Antigens , Major Histocompatibility Complex , SARS-CoV-2 , Adult , Aged , Brazil , COVID-19/genetics , COVID-19/immunology , Female , Genetic Predisposition to Disease , Genotype , Histocompatibility Antigens/genetics , Histocompatibility Antigens/immunology , Humans , Major Histocompatibility Complex/genetics , Major Histocompatibility Complex/immunology , Male , Middle Aged , Whole Exome Sequencing
14.
Front Immunol ; 12: 718744, 2021.
Article in English | MEDLINE | ID: covidwho-1417083

ABSTRACT

COVID-19 associated multisystem inflammatory syndrome (MIS) is a rare condition mostly affecting children but also adults (MIS-A). Although severe systemic inflammation and multiorgan dysfunction are hallmarks of the syndrome, the underlying pathogenesis is unclear. We aimed to provide novel immunological and genetic descriptions of MIS-A patients. Cytokine responses (IL-6, IL-1ß, TNFα, CXCL10, type I, II and III interferons) following SARS-CoV-2 infection of peripheral blood mononuclear cells in vitro were analyzed as well as antibodies against IFNα and IFNω (by ELISA) in patients and healthy controls. We also performed whole exome sequencing (WES) of patient DNA. A total of five patients (ages 19, 23, 33, 38, 50 years) were included. The patients shared characteristic features, although organ involvement and the time course of disease varied slightly. SARS-CoV-2 in vitro infection of patient PBMCs revealed impaired type I and III interferon responses and reduced CXCL10 expression, whereas production of proinflammatory cytokines were less affected, compared to healthy controls. Presence of interferon autoantibodies was not detected. Whole exome sequencing analysis of patient DNA revealed 12 rare potentially disease-causing variants in genes related to autophagy, classical Kawasaki disease, restriction factors and immune responses. In conclusion, we observed an impaired production of type I and III interferons in response to SARS-CoV-2 infection and detected several rare potentially disease-causing gene variants potentially contributing to MIS-A.


Subject(s)
COVID-19/pathology , Cytokines/blood , Interferon-alpha/biosynthesis , Interferons/biosynthesis , Systemic Inflammatory Response Syndrome/pathology , Adult , Autoantibodies/blood , Chemokine CXCL10/biosynthesis , Comorbidity , Exome/genetics , Female , Humans , Interferon-alpha/immunology , Interferons/immunology , Leukocytes, Mononuclear/immunology , Male , Middle Aged , SARS-CoV-2/immunology , Whole Exome Sequencing , Young Adult
15.
Eur J Med Genet ; 64(10): 104268, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1401450

ABSTRACT

Pathogenic variants in phosphatidylinositol glycan anchor biosynthesis class B (PIGB) gene have been first described as the cause of early infantile epileptic encephalopathy 80 (EIEE-80) in 2019. This disorder, an inherited glycosylphosphatidylinositol deficiency, is associated with a complex neurologic phenotype, including developmental delay, early-onset epilepsy and peripheral neuropathy. We report on a 5 year-old girl born from consanguineous parents, manifesting severe global developmental delay with absent speech, mixed peripheral polyneuropathy, hypotonia, bilateral equino-varo-supinated-cavus foot, early-onset scoliosis, elevated serum alkaline phosphatase and a single episode of febrile status epilepticus. Hypomyelination was documented on brain MRI. Whole-exome sequencing (WES) disclosed the likely pathogenic biallelic PIGB NM_004855.4: c.463G > C, p.(Asp155His) missense variant. In our patient, while other characteristic clinical, neuroimaging and laboratory findings (as described in the first research paper) were present, seizures were not a major clinical issue, thus contributing to our knowledge on this ultra-rare disorder.


Subject(s)
Brain/physiopathology , Developmental Disabilities/genetics , Epilepsy/genetics , Mannosyltransferases/genetics , Peripheral Nervous System Diseases/genetics , Brain/diagnostic imaging , Child , Developmental Disabilities/diagnosis , Electroencephalography , Epilepsy/diagnosis , Female , Humans , Mannosyltransferases/deficiency , Peripheral Nervous System Diseases/diagnosis , Whole Exome Sequencing
16.
J Clin Immunol ; 41(6): 1146-1153, 2021 08.
Article in English | MEDLINE | ID: covidwho-1384523

ABSTRACT

Immunocompromised patients, including those with inborn errors of immunity (IEI), may be at increased risk for severe or prolonged infections with SARS-CoV-2 (Zhu et al. N Engl J Med. 382:727-33, 2020; Guan et al. 2020; Minotti et al. J Infect. 81:e61-6, 2020). While antibody and T cell responses to SARS-CoV-2 structural proteins are well described in healthy convalescent donors, adaptive humoral and cellular immunity has not yet been characterized in patients with antibody deficiency (Grifoni et al. Cell. 181:1489-1501 e1415, 2020; Burbelo et al. 2020; Long et al. Nat Med. 26:845-8, 2020; Braun et al. 2020). Herein, we describe the clinical course, antibody, and T cell responses to SARS-CoV-2 structural proteins in a cohort of adult and pediatric patients with antibody deficiencies (n = 5) and controls (related and unrelated) infected with SARS-CoV-2. Five patients within the same family (3 with antibody deficiency, 2 immunocompetent controls) showed antibody responses to nucleocapsid and spike proteins, as well as SARS-CoV-2 specific T cell immunity at days 65-84 from onset of symptoms. No significant difference was identified between immunocompromised patients and controls. Two additional unrelated, adult patients with common variable immune deficiency were assessed. One did not show antibody response, but both demonstrated SARS-CoV-2-specific T cell immunity when evaluated 33 and 76 days, respectively, following SARS-CoV-2 diagnosis. This report is the first to show robust T cell activity and humoral immunity against SARS-CoV-2 structural proteins in some patients with antibody deficiency. Given the reliance on spike protein in most candidate vaccines (Folegatti et al. Lancet. 396:467-78, 2020; Jackson et al. N Engl J Med. 383:1920-31, 2020), the responses are encouraging. Additional studies will be needed to further define the timing of onset of immunity, longevity of the immune response, and variability of response in immunocompromised patients.


Subject(s)
Antibodies, Viral/blood , COVID-19/immunology , Common Variable Immunodeficiency/immunology , SARS-CoV-2/physiology , T-Lymphocytes/immunology , Adolescent , Adult , Carrier State , Cells, Cultured , Child , Female , Humans , Immunity, Humoral , Lymphocyte Activation , Male , Middle Aged , Mutation/genetics , Pedigree , Transmembrane Activator and CAML Interactor Protein/genetics , Whole Exome Sequencing , Young Adult
17.
FEBS Open Bio ; 11(9): 2441-2452, 2021 09.
Article in English | MEDLINE | ID: covidwho-1380363

ABSTRACT

Whole genome and exome sequencing (WGS/WES) are the most popular next-generation sequencing (NGS) methodologies and are at present often used to detect rare and common genetic variants of clinical significance. We emphasize that automated sequence data processing, management, and visualization should be an indispensable component of modern WGS and WES data analysis for sequence assembly, variant detection (SNPs, SVs), imputation, and resolution of haplotypes. In this manuscript, we present a newly developed findable, accessible, interoperable, and reusable (FAIR) bioinformatics-genomics pipeline Java based Whole Genome/Exome Sequence Data Processing Pipeline (JWES) for efficient variant discovery and interpretation, and big data modeling and visualization. JWES is a cross-platform, user-friendly, product line application, that entails three modules: (a) data processing, (b) storage, and (c) visualization. The data processing module performs a series of different tasks for variant calling, the data storage module efficiently manages high-volume gene-variant data, and the data visualization module supports variant data interpretation with Circos graphs. The performance of JWES was tested and validated in-house with different experiments, using Microsoft Windows, macOS Big Sur, and UNIX operating systems. JWES is an open-source and freely available pipeline, allowing scientists to take full advantage of all the computing resources available, without requiring much computer science knowledge. We have successfully applied JWES for processing, management, and gene-variant discovery, annotation, prediction, and genotyping of WGS and WES data to analyze variable complex disorders. In summary, we report the performance of JWES with some reproducible case studies, using open access and in-house generated, high-quality datasets.


Subject(s)
Computational Biology/methods , Exome , Genome , Genomics/methods , Sequence Analysis, DNA/methods , Software , Data Management , Databases, Genetic , Genetic Variation , Humans , Molecular Sequence Annotation , Reproducibility of Results , Whole Exome Sequencing , Whole Genome Sequencing , Workflow
18.
J Clin Invest ; 131(14)2021 07 15.
Article in English | MEDLINE | ID: covidwho-1365266

ABSTRACT

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,864 COVID-19 cases (713 with severe and 1,151 with mild disease) and 15,033 ancestry-matched population controls across 4 independent COVID-19 biobanks. We tested whether rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only 1 rare pLOF mutation across these genes among 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We found no evidence of association of rare LOF variants in the 13 candidate genes with severe COVID-19 outcomes.


Subject(s)
COVID-19/genetics , COVID-19/immunology , Interferon Type I/genetics , Interferon Type I/immunology , Loss of Function Mutation , SARS-CoV-2 , Adolescent , Adult , Aged , Aged, 80 and over , Case-Control Studies , Child , Child, Preschool , Cohort Studies , Female , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Infant , Infant, Newborn , Interferon Regulatory Factor-7/genetics , Male , Middle Aged , Severity of Illness Index , Toll-Like Receptor 3/genetics , Whole Exome Sequencing , Whole Genome Sequencing , Young Adult
19.
Cells ; 10(8)2021 08 05.
Article in English | MEDLINE | ID: covidwho-1348605

ABSTRACT

Sarcoidosis is a multisystem disease characterized by the development and accumulation of granulomas, the hallmark of an inflammatory process induced by environmental and/or infectious and or genetic factors. This auto-inflammatory disease mainly affects the lungs, the gateway to environmental aggressions and viral infections. We have shown previously that genetic predisposition to sarcoidosis occurring in familial cases is related to a large spectrum of pathogenic variants with, however, a clustering around mTOR (mammalian Target Of Rapamycin)-related pathways and autophagy regulation. The context of the COVID-19 pandemic led us to evaluate whether such genetic defects may increase the risk of a severe course of SARS-CoV2 infection in patients with sarcoidosis. We extended a whole exome screening to 13 families predisposed to sarcoidosis and crossed the genes sharing mutations with the list of genes involved in the SARS-CoV2 host-pathogen protein-protein interactome. A similar analysis protocol was applied to a series of 100 healthy individuals. Using ENRICH.R, a comprehensive gene set enrichment web server, we identified the functional pathways represented in the set of genes carrying deleterious mutations and confirmed the overrepresentation of autophagy- and mitophagy-related functions in familial cases of sarcoidosis. The same protocol was applied to the set of genes common to sarcoidosis and the SARS-CoV2-host interactome and found a significant enrichment of genes related to mitochondrial factors involved in autophagy, mitophagy, and RIG-I-like (Retinoic Acid Inducible Gene 1) Receptor antiviral response signaling. From these results, we discuss the hypothesis according to which sarcoidosis is a model for studying genetic abnormalities associated with host response to viral infections as a consequence of defects in autophagy and mitophagy processes.


Subject(s)
Autophagy , COVID-19/physiopathology , Sarcoidosis/physiopathology , COVID-19/enzymology , Genomics , Humans , Mitophagy , Sarcoidosis/enzymology , Whole Exome Sequencing
20.
Brief Bioinform ; 22(6)2021 11 05.
Article in English | MEDLINE | ID: covidwho-1324576

ABSTRACT

In single cell analyses, cell types are conventionally identified based on expressions of known marker genes, whose identifications are time-consuming and irreproducible. To solve this issue, many supervised approaches have been developed to identify cell types based on the rapid accumulation of public datasets. However, these approaches are sensitive to batch effects or biological variations since the data distributions are different in cross-platforms or species predictions. In this study, we developed scAdapt, a virtual adversarial domain adaptation network, to transfer cell labels between datasets with batch effects. scAdapt used both the labeled source and unlabeled target data to train an enhanced classifier and aligned the labeled source centroids and pseudo-labeled target centroids to generate a joint embedding. The scAdapt was demonstrated to outperform existing methods for classification in simulated, cross-platforms, cross-species, spatial transcriptomic and COVID-19 immune datasets. Further quantitative evaluations and visualizations for the aligned embeddings confirm the superiority in cell mixing and the ability to preserve discriminative cluster structure present in the original datasets.


Subject(s)
COVID-19/genetics , SARS-CoV-2/genetics , Single-Cell Analysis , Transcriptome/genetics , COVID-19/virology , Humans , RNA-Seq , SARS-CoV-2/isolation & purification , Species Specificity , Whole Exome Sequencing
SELECTION OF CITATIONS
SEARCH DETAIL