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


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.

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
J Extracell Vesicles ; 10(2): e12050, 2020 12.
Article in English | MEDLINE | ID: covidwho-1064378


SARS-CoV-2 entry is mediated by binding of the spike protein (S) to the surface receptor ACE2 and subsequent priming by host TMPRSS2 allowing membrane fusion. Here, we produced extracellular vesicles (EVs) exposing ACE2 and demonstrate that ACE2-EVs are efficient decoys for SARS-CoV-2 S protein-containing lentivirus. Reduction of infectivity positively correlates with the level of ACE2, is much more efficient than with soluble ACE2 and further enhanced by the inclusion of TMPRSS2.

Angiotensin-Converting Enzyme 2/chemistry , COVID-19/prevention & control , COVID-19/virology , Angiotensin-Converting Enzyme 2/physiology , Caco-2 Cells/virology , Cell Line/virology , Extracellular Vesicles/metabolism , Humans , Lentivirus , Receptors, Virus/metabolism , SARS-CoV-2 , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus , Virus Internalization
Virus Res ; 287: 198094, 2020 10 02.
Article in English | MEDLINE | ID: covidwho-680841


The past century has witnessed major advances in the control of many infectious diseases, yet outbreaks and epidemics caused by (re-) emerging RNA viruses continue to pose a global threat to human health. As illustrated by the global COVID19 pandemic, high healthcare costs, economic disruption and loss of productivity reinforce the unmet medical need to develop new antiviral strategies to combat not only the current pandemic but also future viral outbreaks. Pivotal for effective anti-viral defense is the innate immune system, a first line host response that senses and responds to virus infection. While molecular details of the innate immune response are well characterized, this research field is now being revolutionized with the recognition that cell metabolism has a major impact on the antiviral and inflammatory responses to virus infections. A detailed understanding of the role of metabolic regulation with respect to antiviral and inflammatory responses, together with knowledge of the strategies used by viruses to exploit immunometabolic pathways, will ultimately change our understanding and treatment of pathogenic viral diseases. INITIATE is a Marie Sklodowska-Curie Actions Innovative Training Network (MSCA-ITN), with the goal to train 15 early stage PhD researchers (ESRs) to become experts in antiviral immunometabolism ( To this end, INITIATE brings together a highly complementary international team of academic and corporate leaders from 7 European countries, with outstanding track records in the historically distinct research fields of virology, immunology and metabolism. The ESRs of INITIATE are trained in these interdisciplinary research fields through individual investigator-driven research projects, specialized scientific training events, workshops on academia-industry interactions, outreach & communication. INITIATE will deliver a new generation of creative and entrepreneurial researchers who will be able to face the inevitable future challenges in combating viral diseases.

Betacoronavirus/immunology , Biomedical Research/methods , Coronavirus Infections/drug therapy , Education, Medical/methods , Immunity, Innate/immunology , Pneumonia, Viral/drug therapy , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , COVID-19 , Coronavirus Infections/economics , Delivery of Health Care/economics , Delivery of Health Care/methods , Host-Pathogen Interactions/physiology , Humans , Pandemics/economics , Pneumonia, Viral/economics , SARS-CoV-2