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1.
Cancer Discov ; 12(4): 892-894, 2022 Apr 01.
Article in English | MEDLINE | ID: covidwho-1775023

ABSTRACT

SUMMARY: Fahrner and colleagues investigated the immune response of patients with cancer and cancer-free individuals to SARS-CoV-2 and found that a propensity toward an IL5-predominant Th2/Tc2 response was predictive of susceptibility to infection. The results of this study also suggest that a cellular response against the Spike 1 protein receptor binding domain (S1-RBD) region of the SARS-CoV-2 proteome contributes to protection and that mutations in this region may drive viral evolution and immune escape. See related article by Fahrner et al., p. 958 (8).


Subject(s)
COVID-19 , COVID-19/genetics , Humans , Membrane Glycoproteins/genetics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , T-Lymphocytes/metabolism , Viral Envelope Proteins/genetics , Viral Envelope Proteins/immunology , Viral Envelope Proteins/metabolism
2.
Euro Surveill ; 27(11)2022 03.
Article in English | MEDLINE | ID: covidwho-1753318

ABSTRACT

When SARS-CoV-2 Omicron emerged in 2021, S gene target failure enabled differentiation between Omicron and the dominant Delta variant. In England, where S gene target surveillance (SGTS) was already established, this led to rapid identification (within ca 3 days of sample collection) of possible Omicron cases, alongside real-time surveillance and modelling of Omicron growth. SGTS was key to public health action (including case identification and incident management), and we share applied insights on how and when to use SGTS.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/epidemiology , Humans , Membrane Glycoproteins/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Viral Envelope Proteins/genetics
3.
FASEB J ; 36(3): e22234, 2022 03.
Article in English | MEDLINE | ID: covidwho-1702985

ABSTRACT

The transmembrane protease angiotensin converting enzyme 2 (ACE2) is a protective regulator within the renin angiotensin system and additionally represents the cellular receptor for SARS-CoV. The release of soluble ACE2 (sACE2) from the cell surface is hence believed to be a crucial part of its (patho)physiological functions, as both, ACE2 protease activity and SARS-CoV binding ability, are transferred from the cell membrane to body fluids. Yet, the molecular sources of sACE2 are still not completely investigated. In this study, we show different sources and prerequisites for the release of sACE2 from the cell membrane. By using inhibitors as well as CRISPR/Cas9-derived cells, we demonstrated that, in addition to the metalloprotease ADAM17, also ADAM10 is an important novel shedding protease of ACE2. Moreover, we observed that ACE2 can also be released in extracellular vesicles. The degree of either ADAM10- or ADAM17-mediated ACE2 shedding is dependent on stimulatory conditions and on the expression level of the pro-inflammatory ADAM17 regulator iRhom2. Finally, by using structural analysis and in vitro verification, we determined for the first time that the susceptibility to ADAM10- and ADAM17-mediated shedding is mediated by the collectrin-like part of ACE2. Overall, our findings give novel insights into sACE2 release by several independent molecular mechanisms.


Subject(s)
ADAM10 Protein/metabolism , ADAM17 Protein/metabolism , Amyloid Precursor Protein Secretases/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Extracellular Vesicles/metabolism , Membrane Glycoproteins/metabolism , Membrane Proteins/metabolism , SARS Virus/metabolism , ADAM10 Protein/genetics , ADAM17 Protein/genetics , Amyloid Precursor Protein Secretases/genetics , Angiotensin-Converting Enzyme 2/genetics , Clustered Regularly Interspaced Short Palindromic Repeats , Extracellular Vesicles/genetics , HEK293 Cells , Humans , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Glycoproteins/genetics , Membrane Proteins/genetics , SARS Virus/genetics , SARS-CoV-2
4.
Arch Toxicol ; 96(3): 859-875, 2022 03.
Article in English | MEDLINE | ID: covidwho-1634984

ABSTRACT

rVSV-ΔG-SARS-CoV-2-S is a clinical stage (Phase 2) replication competent recombinant vaccine against SARS-CoV-2. To evaluate the safety profile of the vaccine, a series of non-clinical safety, immunogenicity and efficacy studies were conducted in four animal species, using multiple doses (up to 108 Plaque Forming Units/animal) and dosing regimens. There were no treatment-related mortalities or any noticeable clinical signs in any of the studies. Compared to unvaccinated controls, hematology and biochemistry parameters were unremarkable and no adverse histopathological findings. There was no detectable viral shedding in urine, nor viral RNA detected in whole blood or serum samples seven days post vaccination. The rVSV-ΔG-SARS-CoV-2-S vaccination gave rise to neutralizing antibodies, cellular immune responses, and increased lymphocytic cellularity in the spleen germinal centers and regional lymph nodes. No evidence for neurovirulence was found in C57BL/6 immune competent mice or in highly sensitive type I interferon knock-out mice. Vaccine virus replication and distribution in K18-human Angiotensin-converting enzyme 2-transgenic mice showed a gradual clearance from the vaccination site with no vaccine virus recovered from the lungs. The nonclinical data suggest that the rVSV-ΔG-SARS-CoV-2-S vaccine is safe and immunogenic. These results supported the initiation of clinical trials, currently in Phase 2.


Subject(s)
COVID-19 Vaccines/toxicity , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19 Vaccines/immunology , Cricetinae , Female , Membrane Glycoproteins/genetics , Mesocricetus , Mice , Mice, Inbred C57BL , Rabbits , Swine , Vaccination , Vaccines, Synthetic/toxicity , Viral Envelope Proteins/genetics
5.
PLoS One ; 17(1): e0260897, 2022.
Article in English | MEDLINE | ID: covidwho-1613343

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can manifest with varying disease severity and mortality. Genetic predisposition influences the clinical course of infectious diseases. We investigated whether genetic polymorphisms in candidate genes ACE2, TIRAP, and factor X are associated with clinical outcomes in COVID-19. METHODS: We conducted a single-centre retrospective cohort study. All patients who visited the emergency department with SARS-CoV-2 infection proven by polymerase chain reaction were included. Single nucleotide polymorphisms in ACE2 (rs2285666), TIRAP (rs8177374) and factor X (rs3211783) were assessed. The outcomes were mortality, respiratory failure and venous thromboembolism. Respiratory failure was defined as the necessity of >5 litres/minute oxygen, high flow nasal oxygen suppletion or mechanical ventilation. RESULTS: Between March and April 2020, 116 patients (35% female, median age 65 [inter quartile range 55-75] years) were included and treated according to the then applicable guidelines. Sixteen patients (14%) died, 44 patients (38%) had respiratory failure of whom 23 required endotracheal intubation for mechanical ventilation, and 20 patients (17%) developed venous thromboembolism. The percentage of TIRAP polymorphism carriers in the survivor group was 28% as compared to 0% in the non-survivor group (p = 0.01, Bonferroni corrected p = 0.02). Genotype distribution of ACE2 and factor X did not differ between survivors and non-survivors. CONCLUSION: This study shows that carriage of TIRAP polymorphism rs8177374 could be associated with a significantly lower mortality in COVID-19. This TIRAP polymorphism may be an important predictor in the outcome of COVID-19.


Subject(s)
COVID-19/genetics , COVID-19/mortality , Membrane Glycoproteins/genetics , Receptors, Interleukin-1/genetics , Aged , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/epidemiology , Cohort Studies , Factor X/genetics , Factor X/metabolism , Female , Genetic Predisposition to Disease/genetics , Genotype , Humans , Male , Membrane Glycoproteins/metabolism , Middle Aged , Netherlands/epidemiology , Polymorphism, Single Nucleotide/genetics , Receptors, Interleukin-1/metabolism , Retrospective Studies , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Severity of Illness Index , Treatment Outcome
7.
Infect Genet Evol ; 96: 105140, 2021 12.
Article in English | MEDLINE | ID: covidwho-1565617

ABSTRACT

Classical swine fever virus (CSFV) is an RNA virus that incurs severe economic costs to swine industries worldwide. This study was conducted to investigate the genetic diversity among CSFV strains circulating in Vietnam, with a focus on their genetic variants relative to four vaccine strains. Samples from clinical cases were collected from different provinces of Central and Southern Vietnam from 2017 to 2019. 21 CSFV-positive samples were selected for amplification and sequencing of the full-length Erns and E2 genes. Phylogenetic analyses of these two genes showed that most CSFV strains circulating in Central and Southern Vietnam from 2017 to 2019 belong to subgroup 2.1c, whereas the remaining strains cluster into subgroup 2.2. All CSFV field strains in this study were genetically distant from group 1 strains. Analysis of the E2 and Erns genes indicated that all CSFV field strains have low sequence identity with the vaccine strains (80-83.5% and 82.3-86% sequence identity for E2 and Erns, respectively). Likewise, amino acid-level sequence analysis showed 87.3-91.1% and 87.6-91.6% sequence identity for E2 and Erns, respectively. Together, our findings indicate that CSFV strains circulating in Vietnam belong to subtypes 2.2 and 2.1c, and we also provide novel insights into the epidemiology, molecular characteristics, genetic diversity, and evolution of these circulating CSFV strains.


Subject(s)
Classical Swine Fever Virus/genetics , Genetic Variation , Membrane Glycoproteins/genetics , Viral Envelope Proteins/genetics , Animals , Classical Swine Fever/virology , Phylogeny , Sus scrofa , Swine , Vietnam
8.
Nat Commun ; 12(1): 4502, 2021 07 23.
Article in English | MEDLINE | ID: covidwho-1550282

ABSTRACT

Cells in many tissues, such as bone, muscle, and placenta, fuse into syncytia to acquire new functions and transcriptional programs. While it is known that fused cells are specialized, it is unclear whether cell-fusion itself contributes to programmatic-changes that generate the new cellular state. Here, we address this by employing a fusogen-mediated, cell-fusion system to create syncytia from undifferentiated cells. RNA-Seq analysis reveals VSV-G-induced cell fusion precedes transcriptional changes. To gain mechanistic insights, we measure the plasma membrane surface area after cell-fusion and observe it diminishes through increases in endocytosis. Consequently, glucose transporters internalize, and cytoplasmic glucose and ATP transiently decrease. This reduced energetic state activates AMPK, which inhibits YAP1, causing transcriptional-reprogramming and cell-cycle arrest. Impairing either endocytosis or AMPK activity prevents YAP1 inhibition and cell-cycle arrest after fusion. Together, these data demonstrate plasma membrane diminishment upon cell-fusion causes transient nutrient stress that may promote transcriptional-reprogramming independent from extrinsic cues.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Cell Membrane/metabolism , Cell Nucleus/metabolism , Membrane Glycoproteins/metabolism , Transcription Factors/metabolism , Transcription, Genetic/genetics , Viral Envelope Proteins/metabolism , AMP-Activated Protein Kinases/genetics , AMP-Activated Protein Kinases/metabolism , Adaptor Proteins, Signal Transducing/genetics , Animals , Biological Transport , Cell Fusion , Cell Line , Cell Line, Tumor , Cells, Cultured , Giant Cells/metabolism , HEK293 Cells , Humans , Membrane Glycoproteins/genetics , Mice , RNA-Seq/methods , Signal Transduction/genetics , Transcription Factors/genetics , Viral Envelope Proteins/genetics
9.
Biochem Biophys Res Commun ; 586: 137-142, 2022 01 01.
Article in English | MEDLINE | ID: covidwho-1520712

ABSTRACT

Nuclear pore complexes (NPC) regulate molecular traffics on nuclear envelope, which plays crucial roles during cell fate specification and diseases. The viral accessory protein NSP9 of SARS-CoV-2 is reported to interact with nucleoporin 62 (NUP62), a structural component of the NPC, but its biological impact on the host cell remain obscure. Here, we established new cell line models with ectopic NSP9 expression and determined the subcellular destination and biological functions of NSP9. Confocal imaging identified NSP9 to be largely localized in close proximity to the endoplasmic reticulum. In agreement with the subcellular distribution of NSP9, association of NSP9 with NUP62 was observed in cytoplasm. Furthermore, the overexpression of NSP9 correlated with a reduction of NUP62 expression on the nuclear envelope, suggesting that attenuating NUP62 expression might have contributed to defective NPC formation. Importantly, the loss of NUP62 impaired translocation of p65, a subunit of NF-κB, upon TNF-α stimulation. Concordantly, NSP9 over-expression blocked p65 nuclear transport. Taken together, these data shed light on the molecular mechanisms underlying the modulation of host cells during SARS-CoV-2 infection.


Subject(s)
COVID-19/metabolism , COVID-19/virology , Host Microbial Interactions/physiology , Membrane Glycoproteins/metabolism , Nuclear Pore Complex Proteins/metabolism , RNA-Binding Proteins/metabolism , SARS-CoV-2/metabolism , Viral Nonstructural Proteins/metabolism , Active Transport, Cell Nucleus , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum/virology , Gene Knockdown Techniques , HeLa Cells , Humans , Membrane Glycoproteins/antagonists & inhibitors , Membrane Glycoproteins/genetics , Models, Biological , Nuclear Envelope/metabolism , Nuclear Envelope/virology , Nuclear Pore Complex Proteins/antagonists & inhibitors , Nuclear Pore Complex Proteins/genetics , RNA-Binding Proteins/genetics , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Transcription Factor RelA/metabolism , Viral Nonstructural Proteins/genetics
10.
Eur J Neurol ; 28(8): 2603-2613, 2021 08.
Article in English | MEDLINE | ID: covidwho-1518029

ABSTRACT

BACKGROUND AND PURPOSE: Nasu-Hakola disease (NHD) is a rare, autosomal recessive disorder characterized by skeletal and neurological symptoms. Behavioral symptoms with cognitive impairment may mimic the behavioral variant of frontotemporal dementia (bvFTD) and other early-onset dementias. Our patients were analyzed and the literature was reviewed to delineate neurological and neuroimaging findings suggestive of NHD. METHOD: Fourteen patients carrying a pathogenic mutation in the TREM2 gene were found in our database. Demographic, clinical, laboratory and radiological data were retrieved and analyzed. RESULTS: The presenting clinical picture was behavioral changes with cognitive decline resembling bvFTD in all patients. The mean age was 37.1 ± 4.97 years and the mean duration of the disease was 8.9 ± 3.51 years. Only two patients had typical bone cysts. Seven patients had bilateral calcification of the basal ganglia in computed tomography of the brain. Magnetic resonance imaging of the brain revealed severe atrophy of the corpus callosum, enlargement of the ventricles, atrophy of the caudate nuclei and periventricular white matter changes in all patients. Symmetrical global atrophy of the brain mainly affecting frontoparietal and lateral temporal regions were observed in all cases, and 13 patients had atrophy of the hippocampus. Cerebrospinal fluid examination of 10 patients showed elevated protein levels in six and the presence of oligoclonal bands in four patients. CONCLUSION: A combination of white matter changes, enlarged ventricles, atrophy of the caudate nuclei and thinning of the corpus callosum in magnetic resonance imaging strongly suggests NHD in patients with FTD syndrome. Molecular genetic analysis should be performed in suspected cases, and families should receive genetic counseling.


Subject(s)
Frontotemporal Dementia , Lipodystrophy , Membrane Glycoproteins/genetics , Osteochondrodysplasias , Receptors, Immunologic/genetics , Subacute Sclerosing Panencephalitis , Adult , Brain/diagnostic imaging , Frontotemporal Dementia/diagnostic imaging , Frontotemporal Dementia/genetics , Humans , Magnetic Resonance Imaging , Neuroimaging
11.
Viruses ; 13(10)2021 09 26.
Article in English | MEDLINE | ID: covidwho-1485180

ABSTRACT

Nascent HIV-1 particles incorporate the viral envelope glycoprotein and multiple host transmembrane proteins during assembly at the plasma membrane. At least some of these host transmembrane proteins on the surface of virions are reported as pro-viral factors that enhance virus attachment to target cells or facilitate trans-infection of CD4+ T cells via interactions with non-T cells. In addition to the pro-viral factors, anti-viral transmembrane proteins are incorporated into progeny virions. These virion-incorporated transmembrane proteins inhibit HIV-1 entry at the point of attachment and fusion. In infected polarized CD4+ T cells, HIV-1 Gag localizes to a rear-end protrusion known as the uropod. Regardless of cell polarization, Gag colocalizes with and promotes the virion incorporation of a subset of uropod-directed host transmembrane proteins, including CD162, CD43, and CD44. Until recently, the functions of these virion-incorporated proteins had not been clear. Here, we review the recent findings about the roles played by virion-incorporated CD162, CD43, and CD44 in HIV-1 spread to CD4+ T cells.


Subject(s)
HIV Infections/metabolism , Hyaluronan Receptors/metabolism , Leukosialin/metabolism , Membrane Glycoproteins/metabolism , Cell Membrane/metabolism , HIV Infections/genetics , HIV-1/genetics , HIV-1/metabolism , HIV-1/pathogenicity , Host-Pathogen Interactions , Humans , Hyaluronan Receptors/genetics , Leukosialin/genetics , Membrane Glycoproteins/genetics , Membrane Proteins/metabolism , T-Lymphocytes/metabolism , T-Lymphocytes/virology , Virion/metabolism , Virus Assembly , Virus Attachment , gag Gene Products, Human Immunodeficiency Virus/metabolism
12.
Physiol Rev ; 101(4): 1457-1486, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1443666

ABSTRACT

This medical review addresses the hypothesis that CD38/NADase is at the center of a functional axis (i.e., intracellular Ca2+ mobilization/IFNγ response/reactive oxygen species burst) driven by severe acute respiratory syndrome coronavirus 2 infection, as already verified in respiratory syncytial virus pathology and CD38 activity in other cellular settings. Key features of the hypothesis are that 1) the substrates of CD38 (e.g., NAD+ and NADP+) are depleted by viral-induced metabolic changes; 2) the products of the enzymatic activity of CD38 [e.g., cyclic adenosine diphosphate-ribose (ADPR)/ADPR/nicotinic acid adenine dinucleotide phosphate] and related enzymes [e.g., poly(ADP-ribose)polymerase, Sirtuins, and ADP-ribosyl hydrolase] are involved in the anti-viral and proinflammatory response that favors the onset of lung immunopathology (e.g., cytokine storm and organ fibrosis); and 3) the pathological changes induced by this kinetic mechanism may be reduced by distinct modulators of the CD38/NAD+ axis (e.g., CD38 blockers, NAD+ suppliers, among others). This view is supported by arrays of associative basic and applied research data that are herein discussed and integrated with conclusions reported by others in the field of inflammatory, immune, tumor, and viral diseases.


Subject(s)
ADP-ribosyl Cyclase 1/metabolism , COVID-19/metabolism , Membrane Glycoproteins/metabolism , SARS-CoV-2 , ADP-ribosyl Cyclase 1/genetics , COVID-19/pathology , COVID-19/virology , Gene Expression Regulation, Enzymologic , Humans , Membrane Glycoproteins/genetics
13.
Physiol Rev ; 102(1): 339-341, 2022 01 01.
Article in English | MEDLINE | ID: covidwho-1398740

ABSTRACT

During the COVID-19 pandemic, efforts have been made worldwide to develop effective therapies to address the devastating immune-mediated effects of SARS-CoV-2. With the exception of monoclonal antibody-mediated therapeutics and preventive approaches such as mass immunization, most experimental or repurposed drugs have failed in large randomized clinical trials (https://www.who.int/publications/i/item/therapeutics-and-covid-19-living-guideline). The worldwide spread of SARS-CoV-2 virus revealed specific susceptibilities to the virus among the elderly and individuals with age-related syndromes. These populations were more likely to experience a hyperimmune response characterized by a treatment-resistant acute lung pathology accompanied by multiple organ failure. These observations underscore the interplay between the virus, the biology of aging, and outcomes observed in the most severe cases of SARS-CoV-2 infection. The ectoenzyme CD38 has been implicated in the process of "inflammaging" in aged tissues. In a current publication, Horenstein et al. present evidence to support the hypothesis that CD38 plays a central role in altered immunometabolism resulting from COVID-19 infection. The authors discuss a critical but underappreciated trifecta of CD38-mediated NAD+ metabolism, aging, and COVID-19 immune response and speculate that the CD38/NAD+ axis is a promising therapeutic target for this disease.


Subject(s)
ADP-ribosyl Cyclase 1/metabolism , COVID-19/physiopathology , Membrane Glycoproteins/metabolism , SARS-CoV-2 , ADP-ribosyl Cyclase 1/genetics , Aging , Gene Expression Regulation, Enzymologic , Humans , Membrane Glycoproteins/genetics , NAD/metabolism
14.
Cell Chem Biol ; 29(2): 239-248.e4, 2022 02 17.
Article in English | MEDLINE | ID: covidwho-1347527

ABSTRACT

Triggering receptor expressed on myeloid cells-2 (TREM2) is a cell surface receptor on macrophages and microglia that senses and responds to disease-associated signals to regulate the phenotype of these innate immune cells. The TREM2 signaling pathway has been implicated in a variety of diseases ranging from neurodegeneration in the central nervous system to metabolic disease in the periphery. Here, we report that TREM2 is a thyroid hormone-regulated gene and its expression in macrophages and microglia is stimulated by thyroid hormone and synthetic thyroid hormone agonists (thyromimetics). Our findings report the endocrine regulation of TREM2 by thyroid hormone, and provide a unique opportunity to drug the TREM2 signaling pathway with orally active small-molecule therapeutic agents.


Subject(s)
Acetates/pharmacology , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Membrane Glycoproteins/genetics , Microglia/drug effects , Phenols/pharmacology , Receptors, Immunologic/genetics , Retinoid X Receptors/genetics , Thyroid Hormones/pharmacology , Acetates/chemical synthesis , Animals , Binding Sites , Brain/drug effects , Brain/immunology , Brain/pathology , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Gene Expression Regulation , Humans , Immunity, Innate , Macrophages/drug effects , Macrophages/immunology , Macrophages/pathology , Membrane Glycoproteins/antagonists & inhibitors , Membrane Glycoproteins/immunology , Mice , Mice, Inbred C57BL , Microglia/immunology , Microglia/pathology , Models, Molecular , Phenols/chemical synthesis , Phenoxyacetates/pharmacology , Promoter Regions, Genetic , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , RNA, Messenger/antagonists & inhibitors , RNA, Messenger/genetics , RNA, Messenger/immunology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Immunologic/immunology , Response Elements , Retinoid X Receptors/chemistry , Retinoid X Receptors/metabolism , Signal Transduction
15.
PLoS Pathog ; 17(6): e1009687, 2021 06.
Article in English | MEDLINE | ID: covidwho-1285204

ABSTRACT

COVID-19 outbreak is the biggest threat to human health in recent history. Currently, there are over 1.5 million related deaths and 75 million people infected around the world (as of 22/12/2020). The identification of virulence factors which determine disease susceptibility and severity in different cell types remains an essential challenge. The serine protease TMPRSS2 has been shown to be important for S protein priming and viral entry, however, little is known about its regulation. SPINT2 is a member of the family of Kunitz type serine protease inhibitors and has been shown to inhibit TMPRSS2. Here, we explored the existence of a co-regulation between SPINT2/TMPRSS2 and found a tightly regulated protease/inhibitor expression balance across tissues. We found that SPINT2 negatively correlates with SARS-CoV-2 expression in Calu-3 and Caco-2 cell lines and was down-regulated in secretory cells from COVID-19 patients. We validated our findings using Calu-3 cell lines and observed a strong increase in viral load after SPINT2 knockdown, while overexpression lead to a drastic reduction of the viral load. Additionally, we evaluated the expression of SPINT2 in datasets from comorbid diseases using bulk and scRNA-seq data. We observed its down-regulation in colon, kidney and liver tumors as well as in alpha pancreatic islets cells from diabetes Type 2 patients, which could have implications for the observed comorbidities in COVID-19 patients suffering from chronic diseases.


Subject(s)
COVID-19/metabolism , Membrane Glycoproteins/metabolism , SARS-CoV-2/metabolism , Virus Internalization , A549 Cells , COVID-19/genetics , Caco-2 Cells , Humans , Membrane Glycoproteins/genetics , SARS-CoV-2/genetics , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Severity of Illness Index
16.
Eur J Clin Invest ; 51(12): e13626, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1273086

ABSTRACT

BACKGROUND: Fever-7 is a test evaluating host mRNA expression levels of IFI27, JUP, LAX, HK3, TNIP1, GPAA1 and CTSB in blood able to detect viral infections. This test has been validated mostly in hospital settings. Here we have evaluated Fever-7 to identify the presence of respiratory viral infections in a Community Health Center. METHODS: A prospective study was conducted in the "Servicio de Urgencias de Atención Primaria" in Salamanca, Spain. Patients with clinical signs of respiratory infection and at least one point in the National Early Warning Score were recruited. Fever-7 mRNAs were profiled on a Nanostring nCounter® SPRINT instrument from blood collected upon patient enrolment. Viral diagnosis was performed on nasopharyngeal aspirates (NPAs) using the Biofire-RP2 panel. RESULTS: A respiratory virus was detected in the NPAs of 66 of the 100 patients enrolled. Median National Early Warning Score was 7 in the group with no virus detected and 6.5 in the group with a respiratory viral infection (P > .05). The Fever-7 score yielded an overall AUC of 0.81 to predict a positive viral syndromic test. The optimal operating point for the Fever-7 score yielded a sensitivity of 82% with a specificity of 71%. Multivariate analysis showed that Fever-7 was a robust marker of viral infection independently of age, sex, major comorbidities and disease severity at presentation (OR [CI95%], 3.73 [2.14-6.51], P < .001). CONCLUSIONS: Fever-7 is a promising host immune mRNA signature for the early identification of a respiratory viral infection in the community.


Subject(s)
RNA, Messenger/blood , Respiratory Tract Infections/diagnosis , Virus Diseases/diagnosis , Adaptor Proteins, Vesicular Transport/genetics , Aged , Aged, 80 and over , Cathepsin B/genetics , DNA-Binding Proteins/genetics , Early Warning Score , Female , Gene Expression Profiling , Humans , Male , Membrane Glycoproteins/genetics , Membrane Proteins/genetics , Nasopharynx/virology , Respiratory Tract Infections/blood , Respiratory Tract Infections/genetics , Transcriptome , Virus Diseases/blood , Virus Diseases/genetics , gamma Catenin/genetics
17.
Sci Rep ; 11(1): 9803, 2021 05 07.
Article in English | MEDLINE | ID: covidwho-1262011

ABSTRACT

Angiotensin converting enzyme 2 (ACE2) is a key regulator of the renin-angiotensin system, but also the functional receptor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on structural similarity with other γ-secretase (γS) targets, we hypothesized that ACE2 may be affected by γS proteolytic activity. We found that after ectodomain shedding, ACE2 is targeted for intramembrane proteolysis by γS, releasing a soluble ACE2 C-terminal fragment. Consistently, chemical or genetic inhibition of γS results in the accumulation of a membrane-bound fragment of ectodomain-deficient ACE2. Although chemical inhibition of γS does not alter SARS-CoV-2 cell entry, these data point to a novel pathway for cellular ACE2 trafficking.


Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Membrane Glycoproteins/metabolism , Presenilin-1/metabolism , Presenilin-2/metabolism , SARS-CoV-2/physiology , Amyloid Precursor Protein Secretases/genetics , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/genetics , Caco-2 Cells , Cell Line , Chlorocebus aethiops , Gene Knockout Techniques , HEK293 Cells , Humans , Membrane Glycoproteins/genetics , Mice , Presenilin-1/genetics , Presenilin-2/genetics , Proteolysis , Vero Cells , Virus Internalization
19.
Sci Rep ; 11(1): 9803, 2021 05 07.
Article in English | MEDLINE | ID: covidwho-1218960

ABSTRACT

Angiotensin converting enzyme 2 (ACE2) is a key regulator of the renin-angiotensin system, but also the functional receptor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on structural similarity with other γ-secretase (γS) targets, we hypothesized that ACE2 may be affected by γS proteolytic activity. We found that after ectodomain shedding, ACE2 is targeted for intramembrane proteolysis by γS, releasing a soluble ACE2 C-terminal fragment. Consistently, chemical or genetic inhibition of γS results in the accumulation of a membrane-bound fragment of ectodomain-deficient ACE2. Although chemical inhibition of γS does not alter SARS-CoV-2 cell entry, these data point to a novel pathway for cellular ACE2 trafficking.


Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Membrane Glycoproteins/metabolism , Presenilin-1/metabolism , Presenilin-2/metabolism , SARS-CoV-2/physiology , Amyloid Precursor Protein Secretases/genetics , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/genetics , Caco-2 Cells , Cell Line , Chlorocebus aethiops , Gene Knockout Techniques , HEK293 Cells , Humans , Membrane Glycoproteins/genetics , Mice , Presenilin-1/genetics , Presenilin-2/genetics , Proteolysis , Vero Cells , Virus Internalization
20.
Physiol Rev ; 101(4): 1457-1486, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1159738

ABSTRACT

This medical review addresses the hypothesis that CD38/NADase is at the center of a functional axis (i.e., intracellular Ca2+ mobilization/IFNγ response/reactive oxygen species burst) driven by severe acute respiratory syndrome coronavirus 2 infection, as already verified in respiratory syncytial virus pathology and CD38 activity in other cellular settings. Key features of the hypothesis are that 1) the substrates of CD38 (e.g., NAD+ and NADP+) are depleted by viral-induced metabolic changes; 2) the products of the enzymatic activity of CD38 [e.g., cyclic adenosine diphosphate-ribose (ADPR)/ADPR/nicotinic acid adenine dinucleotide phosphate] and related enzymes [e.g., poly(ADP-ribose)polymerase, Sirtuins, and ADP-ribosyl hydrolase] are involved in the anti-viral and proinflammatory response that favors the onset of lung immunopathology (e.g., cytokine storm and organ fibrosis); and 3) the pathological changes induced by this kinetic mechanism may be reduced by distinct modulators of the CD38/NAD+ axis (e.g., CD38 blockers, NAD+ suppliers, among others). This view is supported by arrays of associative basic and applied research data that are herein discussed and integrated with conclusions reported by others in the field of inflammatory, immune, tumor, and viral diseases.


Subject(s)
ADP-ribosyl Cyclase 1/metabolism , COVID-19/metabolism , Membrane Glycoproteins/metabolism , SARS-CoV-2 , ADP-ribosyl Cyclase 1/genetics , COVID-19/pathology , COVID-19/virology , Gene Expression Regulation, Enzymologic , Humans , Membrane Glycoproteins/genetics
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