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1.
J Mol Biol ; 434(6): 167277, 2022 03 30.
Article in English | MEDLINE | ID: covidwho-2061566

ABSTRACT

Establishment of the interferon (IFN)-mediated antiviral state provides a crucial initial line of defense against viral infection. Numerous genes that contribute to this antiviral state remain to be identified. Using a loss-of-function strategy, we screened an original library of 1156 siRNAs targeting 386 individual curated human genes in stimulated microglial cells infected with Zika virus (ZIKV), an emerging RNA virus that belongs to the flavivirus genus. The screen recovered twenty-one potential host proteins that modulate ZIKV replication in an IFN-dependent manner, including the previously known IFITM3 and LY6E. Further characterization contributed to delineate the spectrum of action of these genes towards other pathogenic RNA viruses, including Hepatitis C virus and SARS-CoV-2. Our data revealed that APOL3 acts as a proviral factor for ZIKV and several other related and unrelated RNA viruses. In addition, we showed that MTA2, a chromatin remodeling factor, possesses potent flavivirus-specific antiviral functions induced by IFN. Our work identified previously unrecognized genes that modulate the replication of RNA viruses in an IFN-dependent manner, opening new perspectives to target weakness points in the life cycle of these viruses.


Subject(s)
Flavivirus , Interferons , Virus Replication , Apolipoproteins L/genetics , Apolipoproteins L/metabolism , Flavivirus/physiology , Histone Deacetylases/genetics , Histone Deacetylases/metabolism , Humans , Interferons/genetics , Membrane Proteins/genetics , Membrane Proteins/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Repressor Proteins/genetics , Repressor Proteins/metabolism , SARS-CoV-2/physiology , Zika Virus/physiology
2.
Nat Commun ; 12(1): 7193, 2021 12 10.
Article in English | MEDLINE | ID: covidwho-1565717

ABSTRACT

Programmed ribosomal frameshifting (PRF) is a fundamental gene expression event in many viruses, including SARS-CoV-2. It allows production of essential viral, structural and replicative enzymes that are encoded in an alternative reading frame. Despite the importance of PRF for the viral life cycle, it is still largely unknown how and to what extent cellular factors alter mechanical properties of frameshift elements and thereby impact virulence. This prompted us to comprehensively dissect the interplay between the SARS-CoV-2 frameshift element and the host proteome. We reveal that the short isoform of the zinc-finger antiviral protein (ZAP-S) is a direct regulator of PRF in SARS-CoV-2 infected cells. ZAP-S overexpression strongly impairs frameshifting and inhibits viral replication. Using in vitro ensemble and single-molecule techniques, we further demonstrate that ZAP-S directly interacts with the SARS-CoV-2 RNA and interferes with the folding of the frameshift RNA element. Together, these data identify ZAP-S as a host-encoded inhibitor of SARS-CoV-2 frameshifting and expand our understanding of RNA-based gene regulation.


Subject(s)
Frameshifting, Ribosomal , RNA-Binding Proteins/metabolism , Repressor Proteins/metabolism , SARS-CoV-2/genetics , COVID-19 , HEK293 Cells , Host-Pathogen Interactions , Humans , Nucleic Acid Conformation , Protein Isoforms , Proteome , RNA, Viral/genetics , SARS-CoV-2/physiology , Virus Replication
3.
BMJ Case Rep ; 14(10)2021 Oct 13.
Article in English | MEDLINE | ID: covidwho-1467679

ABSTRACT

Solitary fibrous tumours (SFTs) are rare mesenchymal tumours that are mostly seen in the pleura. Lately, they have also been described in other locations. Recent discovery of the NAB2-STAT6 fusion gene which is specific for SFTs has led to an accurate diagnosis of SFTs. The occurrence of SFTs in the mesentery is very rarely reported in the literature. We report a case of a 63-year-old female who presented with abdominal pain, rectal bleeding and Fusobacterium bacteraemia, who was ultimately found to have a mesenteric SFT.


Subject(s)
Sepsis , Solitary Fibrous Tumors , Biomarkers, Tumor , Female , Fusobacterium , Humans , Immunohistochemistry , Mesentery , Middle Aged , Repressor Proteins/metabolism , STAT6 Transcription Factor/metabolism , Solitary Fibrous Tumors/complications , Solitary Fibrous Tumors/diagnostic imaging , Solitary Fibrous Tumors/surgery
4.
Am J Respir Cell Mol Biol ; 65(4): 403-412, 2021 10.
Article in English | MEDLINE | ID: covidwho-1237350

ABSTRACT

Mechanical ventilation is a known risk factor for delirium, a cognitive impairment characterized by dysfunction of the frontal cortex and hippocampus. Although IL-6 is upregulated in mechanical ventilation-induced lung injury (VILI) and may contribute to delirium, it is not known whether the inhibition of systemic IL-6 mitigates delirium-relevant neuropathology. To histologically define neuropathological effects of IL-6 inhibition in an experimental VILI model, VILI was simulated in anesthetized adult mice using a 35 cc/kg tidal volume mechanical ventilation model. There were two control groups, as follow: 1) spontaneously breathing or 2) anesthetized and mechanically ventilated with 10 cc/kg tidal volume to distinguish effects of anesthesia from VILI. Two hours before inducing VILI, mice were treated with either anti-IL-6 antibody, anti-IL-6 receptor antibody, or saline. Neuronal injury, stress, and inflammation were assessed using immunohistochemistry. CC3 (cleaved caspase-3), a neuronal apoptosis marker, was significantly increased in the frontal (P < 0.001) and hippocampal (P < 0.0001) brain regions and accompanied by significant increases in c-Fos and heat shock protein-90 in the frontal cortices of VILI mice compared with control mice (P < 0.001). These findings were not related to cerebral hypoxia, and there was no evidence of irreversible neuronal death. Frontal and hippocampal neuronal CC3 were significantly reduced with anti-IL-6 antibody (P < 0.01 and P < 0.0001, respectively) and anti-IL-6 receptor antibody (P < 0.05 and P < 0.0001, respectively) compared with saline VILI mice. In summary, VILI induces potentially reversible neuronal injury and inflammation in the frontal cortex and hippocampus, which is mitigated with systemic IL-6 inhibition. These data suggest a potentially novel neuroprotective role of systemic IL-6 inhibition that justifies further investigation.


Subject(s)
Antibodies/pharmacology , Apoptosis/drug effects , Delirium/metabolism , Interleukin-6/antagonists & inhibitors , Neurons/metabolism , Ventilator-Induced Lung Injury/metabolism , Animals , Delirium/drug therapy , Delirium/pathology , Disease Models, Animal , Female , Frontal Lobe/injuries , Frontal Lobe/metabolism , Frontal Lobe/pathology , HSP90 Heat-Shock Proteins/metabolism , Hippocampus/injuries , Hippocampus/metabolism , Hippocampus/pathology , Inflammation/drug therapy , Inflammation/metabolism , Inflammation/pathology , Interleukin-6/metabolism , Mice , Neurons/pathology , Proto-Oncogene Proteins c-fos/metabolism , Repressor Proteins/metabolism , Tumor Suppressor Proteins/metabolism , Ventilator-Induced Lung Injury/drug therapy , Ventilator-Induced Lung Injury/pathology
5.
Mol Biol Cell ; 32(14): 1273-1282, 2021 07 01.
Article in English | MEDLINE | ID: covidwho-1233836

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that has triggered global health and economic crises. Here we report the effects of SARS-CoV-2 infection on peroxisomes of human cell lines Huh-7 and SK-N-SH. Peroxisomes undergo dramatic changes in morphology in SARS-CoV-2-infected cells. Rearrangement of peroxisomal membranes is followed by redistribution of peroxisomal matrix proteins to the cytosol, resulting in a dramatic decrease in the number of mature peroxisomes. The SARS-CoV-2 ORF14 protein was shown to interact physically with human PEX14, a peroxisomal membrane protein required for matrix protein import and peroxisome biogenesis. Given the important roles of peroxisomes in innate immunity, SARS-CoV-2 may directly target peroxisomes, resulting in loss of peroxisome structural integrity, matrix protein content and ability to function in antiviral signaling.


Subject(s)
Peroxisomes/virology , Animals , Cell Line , Cell Membrane/pathology , Chlorocebus aethiops , Coronavirus Nucleocapsid Proteins/metabolism , Extracellular Matrix Proteins/metabolism , Humans , Membrane Proteins/metabolism , Peroxisomes/metabolism , Peroxisomes/pathology , Phosphoproteins/metabolism , Repressor Proteins/metabolism , SARS-CoV-2/metabolism , Vero Cells
6.
Viruses ; 12(11)2020 10 25.
Article in English | MEDLINE | ID: covidwho-896046

ABSTRACT

The ability to detect and respond to varying oxygen tension is an essential prerequisite to life. Several mechanisms regulate the cellular response to oxygen including the prolyl hydroxylase domain (PHD)/factor inhibiting HIF (FIH)-hypoxia inducible factor (HIF) pathway, cysteamine (2-aminoethanethiol) dioxygenase (ADO) system, and the lysine-specific demethylases (KDM) 5A and KDM6A. Using a systems-based approach we discuss the literature on oxygen sensing pathways in the context of virus replication in different tissues that experience variable oxygen tension. Current information supports a model where the PHD-HIF pathway enhances the replication of viruses infecting tissues under low oxygen, however, the reverse is true for viruses with a selective tropism for higher oxygen environments. Differences in oxygen tension and associated HIF signaling may play an important role in viral tropism and pathogenesis. Thus, pharmaceutical agents that modulate HIF activity could provide novel treatment options for viral infections and associated pathological conditions.


Subject(s)
Oxygen/metabolism , Signal Transduction , Viral Tropism , Virus Replication , Viruses/pathogenicity , Animals , Humans , Hypoxia , Hypoxia-Inducible Factor 1/metabolism , Mice , Repressor Proteins/metabolism , Viruses/classification , Viruses/metabolism
7.
Mol Cell Endocrinol ; 515: 110917, 2020 09 15.
Article in English | MEDLINE | ID: covidwho-661768

ABSTRACT

Obesity patients are more susceptible to develop COVID-19 severe outcome due to the role of angiotensin-converting enzyme 2 (ACE2) in the viral infection. ACE2 is regulated in the human cells by different genes associated with increased (TLR3, HAT1, HDAC2, KDM5B, SIRT1, RAB1A, FURIN and ADAM10) or decreased (TRIB3) virus replication. RNA-seq data revealed 14857 genes expressed in human subcutaneous adipocytes, including genes mentioned above. Irisin treatment increased by 3-fold the levels of TRIB3 transcript and decreased the levels of other genes. The decrease in FURIN and ADAM10 expression enriched diverse biological processes, including extracellular structure organization. Our results, in human subcutaneous adipocytes cell culture, indicate a positive effect of irisin on the expression of multiple genes related to viral infection by SARS-CoV-2; furthermore, translatable for other tissues and organs targeted by the novel coronavirus and present, thus, promising approaches for the treatment of COVID-19 infection as therapeutic strategy to decrease ACE2 regulatory genes.


Subject(s)
Adipocytes/drug effects , Fibronectins/pharmacology , Gene Expression Regulation/drug effects , ADAM10 Protein/genetics , ADAM10 Protein/metabolism , Adipocytes/cytology , Adipocytes/metabolism , Amyloid Precursor Protein Secretases/genetics , Amyloid Precursor Protein Secretases/metabolism , Angiotensin-Converting Enzyme 2 , Betacoronavirus/genetics , Betacoronavirus/metabolism , COVID-19 , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cells, Cultured , Coronavirus Infections/virology , Fibronectins/genetics , Fibronectins/metabolism , Furin/genetics , Furin/metabolism , Gene Ontology , Histone Acetyltransferases/genetics , Histone Acetyltransferases/metabolism , Histone Deacetylase 2/genetics , Histone Deacetylase 2/metabolism , Humans , Jumonji Domain-Containing Histone Demethylases/genetics , Jumonji Domain-Containing Histone Demethylases/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Models, Biological , Molecular Sequence Annotation , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Obesity/virology , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , /genetics , Repressor Proteins/genetics , Repressor Proteins/metabolism , SARS-CoV-2 , Signal Transduction , Sirtuin 1/genetics , Sirtuin 1/metabolism , Toll-Like Receptor 3/genetics , Toll-Like Receptor 3/metabolism , rab1 GTP-Binding Proteins/genetics , rab1 GTP-Binding Proteins/metabolism
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