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1.
Hum Genomics ; 16(1): 19, 2022 Jun 01.
Article in English | MEDLINE | ID: covidwho-1869105

ABSTRACT

COVID-19, which is caused by the SARS-CoV-2, has ravaged the world for the past 2 years. Here, we review the current state of research into the disease with focus on its history, human genetics and genomics and the transition from the pandemic to the endemic phase. We are particularly concerned by the lack of solid information from the initial phases of the pandemic that highlighted the necessity for better preparation to face similar future threats. On the other hand, we are gratified by the progress into human genetic susceptibility investigations and we believe now is the time to explore the transition from the pandemic to the endemic phase. The latter will require worldwide vigilance and cooperation, especially in emerging countries. In the transition to the endemic phase, vaccination rates have lagged and developed countries should assist, as warranted, in bolstering vaccination rates worldwide. We also discuss the current status of vaccines and the outlook for COVID-19.


Subject(s)
COVID-19 , Influenza, Human , Humans , Pandemics/prevention & control , SARS-CoV-2
2.
Cell Rep ; 39(9): 110905, 2022 May 31.
Article in English | MEDLINE | ID: covidwho-1850802

ABSTRACT

Neutralizing antibodies (nAbs) that target the SARS-CoV-2 spike protein have received emergency use approval for treatment of COVID-19. However, with the emergence of variants of concern, there is a need for new treatment options. We report a format that enables modular assembly of bi-paratopic tetravalent nAbs with antigen-binding sites from two distinct nAbs. The tetravalent nAb purifies in high yield and exhibits biophysical characteristics that are comparable to those of clinically used therapeutic antibodies. The tetravalent nAb binds to the spike protein trimer at least 100-fold more tightly than bivalent IgGs (apparent KD < 1 pM) and neutralizes a broad array of SARS-CoV-2 pseudoviruses, chimeric viruses, and authentic viral variants with high potency. Together, these results establish the tetravalent diabody-Fc-Fab as a robust, modular platform for rapid production of drug-grade nAbs with potencies and breadth of coverage that greatly exceed those of conventional bivalent IgGs.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , Humans , Neutralization Tests , Spike Glycoprotein, Coronavirus
3.
Genes (Basel) ; 13(4)2022 04 12.
Article in English | MEDLINE | ID: covidwho-1785608

ABSTRACT

Since early December 2019, the COVID-19 pandemic has impacted global society: over 400 million people have been infected with SARS-CoV-2, and there have been nearly 6 million deaths worldwide (1 [...].


Subject(s)
COVID-19 , COVID-19/genetics , Humans , Molecular Biology , Pandemics , SARS-CoV-2
4.
Cells ; 11(7)2022 04 05.
Article in English | MEDLINE | ID: covidwho-1776139

ABSTRACT

The global health emergency for SARS-CoV-2 (COVID-19) created an urgent need to develop new treatments and therapeutic drugs. In this study, we tested, for the first time on human cells, a new tetravalent neutralizing antibody (15033-7) targeting Spike protein and a synthetic peptide homologous to dipeptidyl peptidase-4 (DPP4) receptor on host cells. Both could represent powerful immunotherapeutic candidates for COVID-19 treatment. The infection begins in the proximal airways, namely the alveolar type 2 (AT2) cells of the distal lung, which express both ACE2 and DPP4 receptors. Thus, to evaluate the efficacy of both approaches, we developed three-dimensional (3D) complex lung organoid structures (hLORGs) derived from human-induced pluripotent stem cells (iPSCs) and resembling the in vivo organ. Afterward, hLORGs were infected by different SARS-CoV-2 S pseudovirus variants and treated by the Ab15033-7 or DPP4 peptide. Using both approaches, we observed a significant reduction of viral entry and a modulation of the expression of genes implicated in innate immunity and inflammatory response. These data demonstrate the efficacy of such approaches in strongly reducing the infection efficiency in vitro and, importantly, provide proof-of-principle evidence that hiPSC-derived hLORGs represent an ideal in vitro system for testing both therapeutic and preventive modalities against COVID-19.


Subject(s)
COVID-19 , Induced Pluripotent Stem Cells , COVID-19/drug therapy , Dipeptidyl Peptidase 4/metabolism , Humans , Induced Pluripotent Stem Cells/metabolism , Lung/metabolism , Organoids/metabolism , SARS-CoV-2
6.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-318110

ABSTRACT

Background: Coronaviruses (CoV) are a large family of viruses that are common in humans and many animal species. Animal coronaviruses rarely infect humans with the exceptions of the Middle East Respiratory Syndrome (MERS-CoV), the Severe Acute Respiratory Syndrome CoronaVirus (SARS-CoV), and now SARS-CoV-2, which is the cause of the ongoing pandemic of coronavirus disease 2019 (COVID-19). Several studies suggested that genetic variants in the ACE2 gene may influence the host susceptibility or resistance to SARS-CoV-2 infection according to the functional role of ACE2 in human pathophysiology. However, many of these studies have been conducted in silico based on epidemiological and population data. We therefore investigated the occurrence of ACE2 variants in a cohort of 131 Italian unrelated individuals clinically diagnosed with COVID-19 and in an Italian control population, to evaluate a possible allelic association with COVID-19, by direct DNA analysis. Methods: : As a pilot study, we analyzed, by whole-exome sequencing, genetic variants of ACE2 gene in 131 DNA samples of COVID-19 patients hospitalized at Tor Vergata University Hospital and at Bambino Gesù Children’s Hospital, Rome. We used a large control group consisting of 1,000 individuals (500 males and 500 females). Results: : We identified three different germline variants: one intronic c.439+4G>A and two missense c.1888G>C p.(Asp630His) and c.2158A>G p.(Asn720Asp) in a total of 131 patients with a similar frequency in male and female. Thus far, only the c.1888G>C p.(Asp630His) variant shows a statistically different frequency compared to the ethnically matched populations. Therefore, further studies are needed in larger cohorts, since it was found only in one heterozygous COVID-19 patient. Conclusions: : Our results suggest that there is no strong evidence, in our cohort, of consistent association of ACE2 variants with COVID-19 severity. We might speculate that rare susceptibility/resistant alleles could be located in the non-coding regions of the ACE2 gene, known to play a role in regulation of the gene activity.

7.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-310419

ABSTRACT

Takotsubo syndrome (TTS), recognized as stress’s cardiomyopathy, or better as left ventricular apical balloon syndrome in the recent years, is a rare pathology, described for the first time by Japanese researchers in 1990. TTS is characterized by an interindividual heterogeneity in onset and progression, and by the strong predominance in postmenopausal women. The clear causes of these TTS features are uncertain, given the reduced understanding of this intriguing syndrome until now. However, the increasing frequency of TTS cases in the last years, and particularly correlated to SARS-CoV-2 pandemic, leads us to imperative necessity both of a complete knowledge of TTS pathophysiology for identifying biomarkers facilitating its management, and targets for specific and effective treatments. The suspect of a genetic basis in TTS pathogenesis has been evidenced. Accordingly, familial form of TTS has been described. But a systematic and comprehensive characterization of the genetic or epigenetic factors significantly associated with TTS is lacking. Thus, we, here, conducted a systematic review of literature before June 2021, to contribute to identify potential genetic and epigenetic factors associated with TTS. Interesting data were evidenced, but of reduced number and with diverse limitations. Consequently, we concluded further work is needed to address the gaps discussed, and probably a clear evidence may arrive using multi-omics investigations.

8.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-322118

ABSTRACT

The Angiotensin-converting enzyme 2 (ACE2) has been recently recognized as the entry receptor of the novel pathogenic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2). The presence of structural and sequence variants in ACE2 gene may affect its expression in different tissues and determine a differential response to SARS-Cov-2 infection and COVID19-related phenotype. The present study investigated the genetic variability of ACE2 in terms of Single Nucleotide Variants (SNVs), Copy Number Variations (CNVs) and expression Quantitative Loci (eQTLs) in a cohort of 268 individuals representative of the Italian general population. The analysis identified 5 SNVs (rs35803318, rs41303171, rs774469453, rs773676270, rs2285666) which displayed a significantly different frequency distribution in the Italian cohort compared to the worldwide populations. The analysis of eQTLs located in and targeting ACE2, revealed a high distribution of eQTL variants in different brain tissues, suggesting a possible link between the genetic variability of ACE2 and the neurological complications in patients with COVID19. Further research is needed to clarify the possible relationship between ACE2 expression and the susceptibility to neurological complications in patients with COVID19. In fact, patients at higher risk of neurological involvement may need different monitoring and treatment strategies in order to prevent severe, permanent brain injury.

10.
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
11.
J Clin Invest ; 131(23)2021 12 01.
Article in English | MEDLINE | ID: covidwho-1484167

ABSTRACT

GWAS involve testing genetic variants across the genomes of many individuals to identify genotype-phenotype associations. GWAS have enabled the identification of numerous genomic biomarkers in various complex human diseases, including infectious ones. However, few of these studies are relevant for clinical practice or at the bedside. In this issue of the JCI, Nakanishi et al. characterized the clinical implications of a major genetic risk factor for COVID-19 severity and its age-dependent effect, using individual-level data in a large international multicenter consortium. This study indicates that a common COVID-19 genetic risk factor (rs10490770) associates with increased risks of morbidity and mortality, suggesting potential implications for future clinical risk management. How can the genomic biomarkers identified by GWAS be associated with the clinical outcomes of an infectious disease? In this Commentary, we evaluate the advantages and limitations of this approach.


Subject(s)
COVID-19 , Genome-Wide Association Study , Biomarkers, Tumor , Genomics , Humans , SARS-CoV-2
12.
Nat Immunol ; 23(2): 159-164, 2022 02.
Article in English | MEDLINE | ID: covidwho-1475313

ABSTRACT

SARS-CoV-2 infections display tremendous interindividual variability, ranging from asymptomatic infections to life-threatening disease. Inborn errors of, and autoantibodies directed against, type I interferons (IFNs) account for about 20% of critical COVID-19 cases among SARS-CoV-2-infected individuals. By contrast, the genetic and immunological determinants of resistance to infection per se remain unknown. Following the discovery that autosomal recessive deficiency in the DARC chemokine receptor confers resistance to Plasmodium vivax, autosomal recessive deficiencies of chemokine receptor 5 (CCR5) and the enzyme FUT2 were shown to underlie resistance to HIV-1 and noroviruses, respectively. Along the same lines, we propose a strategy for identifying, recruiting, and genetically analyzing individuals who are naturally resistant to SARS-CoV-2 infection.


Subject(s)
COVID-19/genetics , Disease Resistance/genetics , Genetic Predisposition to Disease , SARS-CoV-2/pathogenicity , Animals , COVID-19/immunology , COVID-19/virology , Genetic Heterogeneity , Host-Pathogen Interactions , Humans , Phenotype , Protective Factors , Risk Assessment , Risk Factors , SARS-CoV-2/immunology
13.
Sci Immunol ; 6(62)2021 08 19.
Article in English | MEDLINE | ID: covidwho-1434876

ABSTRACT

Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.


Subject(s)
COVID-19/complications , Genetic Diseases, X-Linked/complications , Immune System Diseases/complications , Toll-Like Receptor 7/deficiency , Adolescent , Adult , Aged , Aged, 80 and over , Alleles , Child , Child, Preschool , Humans , Infant , Male , Middle Aged , Pedigree , Penetrance , Toll-Like Receptor 7/genetics , Young Adult
15.
Int J Mol Sci ; 22(18)2021 Sep 13.
Article in English | MEDLINE | ID: covidwho-1409701

ABSTRACT

Takotsubo syndrome (TTS), recognized as stress's cardiomyopathy, or as left ventricular apical balloon syndrome in recent years, is a rare pathology, described for the first time by Japanese researchers in 1990. TTS is characterized by an interindividual heterogeneity in onset and progression, and by strong predominance in postmenopausal women. The clear causes of these TTS features are uncertain, given the limited understanding of this intriguing syndrome until now. However, the increasing frequency of TTS cases in recent years, and particularly correlated to the SARS-CoV-2 pandemic, leads us to the imperative necessity both of a complete knowledge of TTS pathophysiology for identifying biomarkers facilitating its management, and of targets for specific and effective treatments. The suspect of a genetic basis in TTS pathogenesis has been evidenced. Accordingly, familial forms of TTS have been described. However, a systematic and comprehensive characterization of the genetic or epigenetic factors significantly associated with TTS is lacking. Thus, we here conducted a systematic review of the literature before June 2021, to contribute to the identification of potential genetic and epigenetic factors associated with TTS. Interesting data were evidenced, but few in number and with diverse limitations. Consequently, we concluded that further work is needed to address the gaps discussed, and clear evidence may arrive by using multi-omics investigations.


Subject(s)
COVID-19/complications , Epigenesis, Genetic/immunology , Genetic Heterogeneity , Genetic Predisposition to Disease , Takotsubo Cardiomyopathy/genetics , Biomarkers/analysis , COVID-19/immunology , COVID-19/virology , DNA Copy Number Variations/immunology , Genetic Loci/immunology , Heart Ventricles/immunology , Heart Ventricles/pathology , Humans , Medical History Taking , Polymorphism, Single Nucleotide/immunology , SARS-CoV-2/immunology , Takotsubo Cardiomyopathy/diagnosis , Takotsubo Cardiomyopathy/immunology , Takotsubo Cardiomyopathy/pathology
16.
COVID ; 1(1):335-336, 2021.
Article in English | MDPI | ID: covidwho-1390553

ABSTRACT

The COVID-19 pandemic, a global health, economic, and social tsunami, has profoundly changed the relationship between science and public opinion [...]

18.
Viruses ; 13(8)2021 08 23.
Article in English | MEDLINE | ID: covidwho-1367926

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a global pandemic causing over 195 million infections and more than 4 million fatalities as of July 2021.To date, it has been demonstrated that a number of mutations in the spike glycoprotein (S protein) of SARS-CoV-2 variants of concern abrogate or reduce the neutralization potency of several therapeutic antibodies and vaccine-elicited antibodies. Therefore, the development of additional vaccine platforms with improved supply and logistic profile remains a pressing need. In this work, we have validated the applicability of a peptide-based strategy focused on a preventive as well as a therapeutic purpose. On the basis of the involvement of the dipeptidyl peptidase 4 (DPP4), in addition to the angiotensin converting enzyme 2 (ACE2) receptor in the mechanism of virus entry, we analyzed peptides bearing DPP4 sequences by protein-protein docking and assessed their ability to block pseudovirus infection in vitro. In parallel, we have selected and synthetized peptide sequences located within the highly conserved receptor-binding domain (RBD) of the S protein, and we found that RBD-based vaccines could better promote elicitation of high titers of neutralizing antibodies specific against the regions of interest, as confirmed by immunoinformatic methodologies and in vivo studies. These findings unveil a key antigenic site targeted by broadly neutralizing antibodies and pave the way to the design of pan-coronavirus vaccines.


Subject(s)
Dipeptidyl Peptidase 4/chemistry , Peptide Fragments/immunology , Peptide Fragments/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Broadly Neutralizing Antibodies/immunology , COVID-19/drug therapy , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Chlorocebus aethiops , Dipeptidyl Peptidase 4/metabolism , Epitopes, T-Lymphocyte/immunology , Humans , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Protein Binding , Protein Domains , Receptors, Coronavirus/chemistry , Receptors, Coronavirus/metabolism , SARS-CoV-2/chemistry , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells , Virus Internalization
19.
Sci Immunol ; 6(62)2021 08 19.
Article in English | MEDLINE | ID: covidwho-1367380

ABSTRACT

Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.


Subject(s)
COVID-19/complications , Genetic Diseases, X-Linked/complications , Immune System Diseases/complications , Toll-Like Receptor 7/deficiency , Adolescent , Adult , Aged , Aged, 80 and over , Alleles , Child , Child, Preschool , Humans , Infant , Male , Middle Aged , Pedigree , Penetrance , Toll-Like Receptor 7/genetics , Young Adult
20.
Cell Death Dis ; 12(8): 762, 2021 08 03.
Article in English | MEDLINE | ID: covidwho-1338531

ABSTRACT

While vaccination is the single most effective intervention to drastically reduce severe disease and death following SARS-CoV-2 infection, as shown in UK and Israel, some serious concerns have been raised for an unusual adverse drug reaction (ADR), including vaccine-induced immune thrombotic thrombocytopenia (VITT) with concurrent low platelets as well as capillary leak syndrome. In fact, the overall safety of the vaccine is highlighted by the low frequency of ADR considering that in UK, by the early June, 40 million first doses and 29 million second doses have been injected; nonetheless, 390 thrombotic events, including 71 fatal events have been reported. Interestingly, the cases reported low platelet counts with the presence of anti-platelet factor-4 (PF4) antibodies, indicating an abnormal clotting reaction. Here, out of three referred cases, we report a post-vaccine clinical case of fatal thrombosis with postmortem examination and whole exome sequencing (WES) analysis, whose pathogenesis appeared associated to a preexisting condition of thrombocytopenia due to myelodysplasia.


Subject(s)
COVID-19 Vaccines/adverse effects , Thrombocytopenia/complications , Thromboembolism/etiology , Bone Marrow/pathology , COVID-19/prevention & control , Fatal Outcome , Female , Humans , Lung/pathology , Middle Aged , Myelodysplastic Syndromes/complications , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/pathology , SARS-CoV-2/immunology , Thrombocytopenia/diagnosis , Thrombocytopenia/pathology
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