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2.
Nature ; 607(7917): 97-103, 2022 07.
Article in English | MEDLINE | ID: covidwho-1730298

ABSTRACT

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2-4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.


Subject(s)
COVID-19 , Critical Illness , Genome, Human , Host-Pathogen Interactions , Whole Genome Sequencing , ATP-Binding Cassette Transporters , COVID-19/genetics , COVID-19/mortality , COVID-19/pathology , COVID-19/virology , Cell Adhesion Molecules , Critical Care , Critical Illness/mortality , E-Selectin , Factor VIII , Fucosyltransferases , Genome, Human/genetics , Genome-Wide Association Study , Host-Pathogen Interactions/genetics , Humans , Interleukin-10 Receptor beta Subunit , Lectins, C-Type , Mucin-1 , Nerve Tissue Proteins , Phospholipid Transfer Proteins , Receptors, Cell Surface , Repressor Proteins , SARS-CoV-2/pathogenicity
3.
Cells ; 10(11)2021 11 13.
Article in English | MEDLINE | ID: covidwho-1512139

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the recently emerged virus responsible for the COVID-19 pandemic. Clinical presentation can range from asymptomatic disease and mild respiratory tract infection to severe disease with lung injury, multiorgan failure, and death. SARS-CoV-2 is the third animal coronavirus to emerge in humans in the 21st century, and coronaviruses appear to possess a unique ability to cross borders between species and infect a wide range of organisms. This is somewhat surprising as, except for the requirement of host cell receptors, cell-pathogen interactions are usually species-specific. Insights into these host-virus interactions will provide a deeper understanding of the process of SARS-CoV-2 infection and provide a means for the design and development of antiviral agents. In this study, we describe a complex analysis of SARS-CoV-2 infection using a genome-wide CRISPR-Cas9 knock-out system in HeLa cells overexpressing entry receptor angiotensin-converting enzyme 2 (ACE2). This platform allows for the identification of factors required for viral replication. This study was designed to include a high number of replicates (48 replicates; 16 biological repeats with 3 technical replicates each) to prevent data instability, remove sources of bias, and allow multifactorial bioinformatic analyses in order to study the resulting interaction network. The results obtained provide an interesting insight into the replication mechanisms of SARS-CoV-2.


Subject(s)
SARS-CoV-2/physiology , Virus Replication , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , CRISPR-Cas Systems , Computational Biology , Genome, Human/genetics , HeLa Cells , Host-Pathogen Interactions , Humans , SARS-CoV-2/pathogenicity
4.
J Med Virol ; 93(7): 4576-4584, 2021 07.
Article in English | MEDLINE | ID: covidwho-1384233

ABSTRACT

Effective countermeasures against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) demand a better understanding of the pathogen-host interactions. However, such information about the targets, responses, and effects in the host due to the virus is limited, especially so in the case of newly emerged pathogens. The peptide domains that form the interfaces of host and pathogen interacting proteins being evolutionarily conserved, it may be hypothesized that such interactions can be inferred from the similarities in the nucleotide sequences between the host and the pathogen. This communication reports the results of a study based on a parsimonious approach for the identification of the host-virus interactions, where sequence complementarity between the human and SARS-Cov-2 genomes was used to predict several interactions between the host and SARS-CoV-2 at different levels of biological organization. In particular, the findings are suggestive of a direct effect of SARS-CoV-2 on cardiac health. The existing literature on host responses to SARS-CoV-2 and other viruses attest to many of these predicted interactions, supporting the utility of the proposed approach for the identification of host interactions with other novel pathogens.


Subject(s)
Genome, Human/genetics , Genome, Viral/genetics , Host-Pathogen Interactions/genetics , SARS-CoV-2/metabolism , Viral Proteins/metabolism , Amino Acid Sequence/genetics , COVID-19/diagnosis , Cardiomyopathies/virology , Computational Biology/methods , Humans , SARS-CoV-2/isolation & purification , Viral Proteins/genetics
7.
Curr Biol ; 31(16): 3504-3514.e9, 2021 08 23.
Article in English | MEDLINE | ID: covidwho-1281407

ABSTRACT

The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has emphasized the vulnerability of human populations to novel viral pressures, despite the vast array of epidemiological and biomedical tools now available. Notably, modern human genomes contain evolutionary information tracing back tens of thousands of years, which may help identify the viruses that have impacted our ancestors-pointing to which viruses have future pandemic potential. Here, we apply evolutionary analyses to human genomic datasets to recover selection events involving tens of human genes that interact with coronaviruses, including SARS-CoV-2, that likely started more than 20,000 years ago. These adaptive events were limited to the population ancestral to East Asian populations. Multiple lines of functional evidence support an ancient viral selective pressure, and East Asia is the geographical origin of several modern coronavirus epidemics. An arms race with an ancient coronavirus, or with a different virus that happened to use similar interactions as coronaviruses with human hosts, may thus have taken place in ancestral East Asian populations. By learning more about our ancient viral foes, our study highlights the promise of evolutionary information to better predict the pandemics of the future. Importantly, adaptation to ancient viral epidemics in specific human populations does not necessarily imply any difference in genetic susceptibility between different human populations, and the current evidence points toward an overwhelming impact of socioeconomic factors in the case of coronavirus disease 2019 (COVID-19).


Subject(s)
Coronavirus Infections/history , Coronavirus/genetics , Genome, Human/genetics , Host Microbial Interactions/genetics , Pandemics/history , Coronavirus Infections/virology , Datasets as Topic , Evolution, Molecular , Far East/epidemiology , Gene Frequency , Genetic Predisposition to Disease , Genome, Viral/genetics , Genome-Wide Association Study , History, Ancient , Human Genome Project , Humans , Mutation , Phylogeny , Selection, Genetic
8.
Trends Genet ; 37(7): 625-630, 2021 07.
Article in English | MEDLINE | ID: covidwho-1187872

ABSTRACT

Comprehensively characterizing the cellular composition and organization of tissues has been a long-term scientific challenge that has limited our ability to study fundamental and clinical aspects of human physiology. The Human Cell Atlas (HCA) is a global collaborative effort to create a reference map of all human cells as a basis for both understanding human health and diagnosing, monitoring, and treating disease. Many aspects of the HCA are analogous to the Human Genome Project (HGP), whose completion presents a major milestone in modern biology. To commemorate the HGP's 20-year anniversary of completion, we discuss the launch of the HCA in light of the HGP, and highlight recent progress by the HCA consortium.


Subject(s)
Cell Lineage/genetics , Cell Physiological Phenomena/genetics , Cells/classification , Genome, Human/genetics , Human Genome Project , Humans
9.
Virus Res ; 302: 198466, 2021 09.
Article in English | MEDLINE | ID: covidwho-1253729

ABSTRACT

Vigorous vaccination programs against SARS-CoV-2-causing Covid-19 are the major chance to fight this dreadful pandemic. The currently administered vaccines depend on adenovirus DNA vectors or on SARS-CoV-2 mRNA that might become reverse transcribed into DNA, however infrequently. In some societies, people have become sensitized against the potential short- or long-term side effects of foreign DNA being injected into humans. In my laboratory, the fate of foreign DNA in mammalian (human) cells and organisms has been investigated for many years. In this review, a summary of the results obtained will be presented. This synopsis has been put in the evolutionary context of retrotransposon insertions into pre-human genomes millions of years ago. In addition, studies on adenovirus vector-based DNA, on the fate of food-ingested DNA as well as the long-term persistence of SARS-CoV-2 RNA/DNA will be described. Actual integration of viral DNA molecules and of adenovirus vector DNA will likely be chance events whose frequency and epigenetic consequences cannot with certainty be assessed. The review also addresses problems of remaining adenoviral gene expression in adenoviral-based vectors and their role in side effects of vaccines. Eventually, it will come down to weighing the possible risks of genomic insertions of vaccine-associated foreign DNA and unknown levels of vector-carried adenoviral gene expression versus protection against the dangers of Covid-19. A decision in favor of vaccination against life-threatening disease appears prudent. Informing the public about the complexities of biology will be a reliable guide when having to reach personal decisions about vaccinations.


Subject(s)
Adenoviridae/genetics , COVID-19 Vaccines/genetics , COVID-19/prevention & control , Genome, Human/genetics , Pandemics , SARS-CoV-2/immunology , Vaccination , COVID-19/epidemiology , COVID-19/virology , DNA, Viral/genetics , Gene Expression , Genetic Vectors/genetics , Humans , RNA, Messenger/genetics , RNA, Viral/genetics , SARS-CoV-2/genetics
10.
Nat Genet ; 53(4): 435-444, 2021 04.
Article in English | MEDLINE | ID: covidwho-1123140

ABSTRACT

The ongoing COVID-19 pandemic has caused a global economic and health crisis. To identify host factors essential for coronavirus infection, we performed genome-wide functional genetic screens with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human coronavirus 229E. These screens uncovered virus-specific as well as shared host factors, including TMEM41B and PI3K type 3. We discovered that SARS-CoV-2 requires the lysosomal protein TMEM106B to infect human cell lines and primary lung cells. TMEM106B overexpression enhanced SARS-CoV-2 infection as well as pseudovirus infection, suggesting a role in viral entry. Furthermore, single-cell RNA-sequencing of airway cells from patients with COVID-19 demonstrated that TMEM106B expression correlates with SARS-CoV-2 infection. The present study uncovered a collection of coronavirus host factors that may be exploited to develop drugs against SARS-CoV-2 infection or future zoonotic coronavirus outbreaks.


Subject(s)
COVID-19/genetics , CRISPR-Cas Systems , Genome, Human/genetics , Genome-Wide Association Study/methods , Membrane Proteins/genetics , Nerve Tissue Proteins/genetics , Bronchoalveolar Lavage Fluid/cytology , COVID-19/epidemiology , COVID-19/virology , Cell Line, Tumor , Cells, Cultured , Coronavirus 229E, Human/genetics , Epidemics , Epithelial Cells/virology , Gene Expression , Host-Pathogen Interactions , Humans , Proviruses/physiology , SARS-CoV-2/physiology , Virus Internalization
11.
EBioMedicine ; 65: 103246, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1108220

ABSTRACT

BACKGROUND: While SARS-CoV-2 similarly infects men and women, COVID-19 outcome is less favorable in men. Variability in COVID-19 severity may be explained by differences in the host genome. METHODS: We compared poly-amino acids variability from WES data in severely affected COVID-19 patients versus SARS-CoV-2 PCR-positive oligo-asymptomatic subjects. FINDINGS: Shorter polyQ alleles (≤22) in the androgen receptor (AR) conferred protection against severe outcome in COVID-19 in the first tested cohort (both males and females) of 638 Italian subjects. The association between long polyQ alleles (≥23) and severe clinical outcome (p = 0.024) was also validated in an independent cohort of Spanish men <60 years of age (p = 0.014). Testosterone was higher in subjects with AR long-polyQ, possibly indicating receptor resistance (p = 0.042 Mann-Whitney U test). Inappropriately low serum testosterone level among carriers of the long-polyQ alleles (p = 0.0004 Mann-Whitney U test) predicted the need for intensive care in COVID-19 infected men. In agreement with the known anti-inflammatory action of testosterone, patients with long-polyQ and age ≥60 years had increased levels of CRP (p = 0.018, not accounting for multiple testing). INTERPRETATION: We identify the first genetic polymorphism that appears to predispose some men to develop more severe disease. Failure of the endocrine feedback to overcome AR signaling defects by increasing testosterone levels during the infection leads to the polyQ tract becoming dominant to serum testosterone levels for the clinical outcome. These results may contribute to designing reliable clinical and public health measures and provide a rationale to test testosterone as adjuvant therapy in men with COVID-19 expressing long AR polyQ repeats. FUNDING: MIUR project "Dipartimenti di Eccellenza 2018-2020" to Department of Medical Biotechnologies University of Siena, Italy (Italian D.L. n.18 March 17, 2020) and "Bando Ricerca COVID-19 Toscana" project to Azienda Ospedaliero-Universitaria Senese. Private donors for COVID-19 research and charity funds from Intesa San Paolo.


Subject(s)
COVID-19/pathology , Peptides/genetics , Receptors, Androgen/genetics , Aged , Case-Control Studies , Critical Care/statistics & numerical data , Female , Genome, Human/genetics , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Risk Factors , SARS-CoV-2 , Severity of Illness Index , Spain , Testosterone/blood
13.
Pharmacogenomics J ; 21(3): 275-284, 2021 06.
Article in English | MEDLINE | ID: covidwho-1065847

ABSTRACT

The outbreak of Coronavirus disease 2019 (COVID-19) has evolved into an emergent global pandemic. Many drugs without established efficacy are being used to treat COVID-19 patients either as an offlabel/compassionate use or as a clinical trial. Although drug repurposing is an attractive approach with reduced time and cost, there is a need to make predictions on success before the start of therapy. For the optimum use of these repurposed drugs, many factors should be considered such as drug-gene or dug-drug interactions, drug toxicity, and patient co-morbidity. There is limited data on the pharmacogenomics of these agents and this may constitute an obstacle for successful COVID-19 therapy. This article reviewed the available human genome interactions with some promising repurposed drugs for COVID-19 management. These drugs include chloroquine (CQ), hydroxychloroquine (HCQ), azithromycin, lopinavir/ritonavir (LPV/r), atazanavir (ATV), favipiravir (FVP), nevirapine (NVP), efavirenz (EFV), oseltamivir, remdesivir, anakinra, tocilizumab (TCZ), eculizumab, heme oxygenase 1 (HO-1) regulators, renin-angiotensin-aldosterone system (RAAS) inhibitors, ivermectin, and nitazoxanide. Drug-gene variant pairs that may alter the therapeutic outcomes in COVID-19 patients are presented. The major drug variant pairs that associated with variations in clinical efficacy include CQ/HCQ (CYP2C8, CYP2D6, ACE2, and HO-1); azithromycin (ABCB1); LPV/r (SLCO1B1, ABCB1, ABCC2 and CYP3A); NVP (ABCC10); oseltamivir (CES1 and ABCB1); remdesivir (CYP2C8, CYP2D6, CYP3A4, and OATP1B1); anakinra (IL-1a); and TCZ (IL6R and FCGR3A). The major drug variant pairs that associated with variations in adverse effects include CQ/HCQ (G6PD; hemolysis and ABCA4; retinopathy), ATV (MDR1 and UGT1A1*28; hyperbilirubinemia; and APOA5; dyslipidemia), NVP (HLA-DRB1*01, HLA-B*3505 and CYP2B6; skin rash and MDR1; hepatotoxicity), and EFV (CYP2B6; depression and suicidal tendencies).


Subject(s)
Antiviral Agents/administration & dosage , COVID-19/drug therapy , COVID-19/genetics , Drug Repositioning/methods , Genome, Human/genetics , Pharmacogenetics/methods , Drug Repositioning/trends , Humans , Pharmacogenetics/trends
14.
J Med Virol ; 93(7): 4576-4584, 2021 07.
Article in English | MEDLINE | ID: covidwho-1051312

ABSTRACT

Effective countermeasures against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) demand a better understanding of the pathogen-host interactions. However, such information about the targets, responses, and effects in the host due to the virus is limited, especially so in the case of newly emerged pathogens. The peptide domains that form the interfaces of host and pathogen interacting proteins being evolutionarily conserved, it may be hypothesized that such interactions can be inferred from the similarities in the nucleotide sequences between the host and the pathogen. This communication reports the results of a study based on a parsimonious approach for the identification of the host-virus interactions, where sequence complementarity between the human and SARS-Cov-2 genomes was used to predict several interactions between the host and SARS-CoV-2 at different levels of biological organization. In particular, the findings are suggestive of a direct effect of SARS-CoV-2 on cardiac health. The existing literature on host responses to SARS-CoV-2 and other viruses attest to many of these predicted interactions, supporting the utility of the proposed approach for the identification of host interactions with other novel pathogens.


Subject(s)
Genome, Human/genetics , Genome, Viral/genetics , Host-Pathogen Interactions/genetics , SARS-CoV-2/metabolism , Viral Proteins/metabolism , Amino Acid Sequence/genetics , COVID-19/diagnosis , Cardiomyopathies/virology , Computational Biology/methods , Humans , SARS-CoV-2/isolation & purification , Viral Proteins/genetics
15.
Nature ; 586(7831): 683-692, 2020 10.
Article in English | MEDLINE | ID: covidwho-1028698

ABSTRACT

Starting with the launch of the Human Genome Project three decades ago, and continuing after its completion in 2003, genomics has progressively come to have a central and catalytic role in basic and translational research. In addition, studies increasingly demonstrate how genomic information can be effectively used in clinical care. In the future, the anticipated advances in technology development, biological insights, and clinical applications (among others) will lead to more widespread integration of genomics into almost all areas of biomedical research, the adoption of genomics into mainstream medical and public-health practices, and an increasing relevance of genomics for everyday life. On behalf of the research community, the National Human Genome Research Institute recently completed a multi-year process of strategic engagement to identify future research priorities and opportunities in human genomics, with an emphasis on health applications. Here we describe the highest-priority elements envisioned for the cutting-edge of human genomics going forward-that is, at 'The Forefront of Genomics'.


Subject(s)
Biomedical Research/trends , Genome, Human/genetics , Genomics/trends , Public Health/standards , /trends , Biomedical Research/economics , COVID-19/genetics , Genomics/economics , Humans , National Human Genome Research Institute (U.S.)/economics , Social Change , United States
16.
Elife ; 92020 11 24.
Article in English | MEDLINE | ID: covidwho-1024779

ABSTRACT

It is known that research into human genes is heavily skewed towards genes that have been widely studied for decades, including many genes that were being studied before the productive phase of the Human Genome Project. This means that the genes most frequently investigated by the research community tend to be only marginally more important to human physiology and disease than a random selection of genes. Based on an analysis of 10,395 research publications about SARS-CoV-2 that mention at least one human gene, we report here that the COVID-19 literature up to mid-October 2020 follows a similar pattern. This means that a large number of host genes that have been implicated in SARS-CoV-2 infection by four genome-wide studies remain unstudied. While quantifying the consequences of this neglect is not possible, they could be significant.


Subject(s)
COVID-19/genetics , Genome, Human/genetics , Host Microbial Interactions/genetics , COVID-19/metabolism , COVID-19/virology , Gene Ontology , Genome-Wide Association Study , Humans , Pandemics , Publications , SARS-CoV-2/pathogenicity
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