36 research outputs found
Regulation of ÎČ1 Integrin-Klf2-mediated angiogenesis by CCM proteins
International audienceGraphical Abstract Click here to download high resolution imag
Enhanced Zika virus susceptibility of globally invasive Aedes aegypti populations
The drivers and patterns of zoonotic virus emergence in the human population are poorly understood. The mosquito Aedes aegypti is a major arbovirus vector native to Africa that invaded most of the worldâs tropical belt over the past four centuries, after the evolution of a âdomesticâ form that specialized in biting humans and breeding in water storage containers. Here, we show that human specialization and subsequent spread of A. aegypti out of Africa were accompanied by an increase in its intrinsic ability to acquire and transmit the emerging human pathogen Zika virus. Thus, the recent evolution and global expansion of A. aegypti promoted arbovirus emergence not solely through increased vectorâhost contact but also as a result of enhanced vector susceptibility
Mammal responses to global changes in human activity vary by trophic group and landscape
Wildlife must adapt to human presence to survive in the Anthropocene, so it is critical to understand species responses to humans in different contexts. We used camera trapping as a lens to view mammal responses to changes in human activity during the COVID-19 pandemic. Across 163 species sampled in 102 projects around the world, changes in the amount and timing of animal activity varied widely. Under higher human activity, mammals were less active in undeveloped areas but unexpectedly more active in developed areas while exhibiting greater nocturnality. Carnivores were most sensitive, showing the strongest decreases in activity and greatest increases in nocturnality. Wildlife managers must consider how habituation and uneven sensitivity across species may cause fundamental differences in humanâwildlife interactions along gradients of human influence.Peer reviewe
Genetic control of susceptibility to Zika virus in the mouse using strains of the Collaborative Cross
Zika virus (ZIKV) is a mosquito-transmitted flavivirus responsible for worldwide epidemics and constitutes a major public health threat. The majority of ZIKV infections in humans are either asymptomatic or result in a mild febrile illness. However, some patients develop a more severe, sometimes life-threatening, form of the disease. Recent evidence showed that ZIKV infection can trigger Guillain-BarrĂ© syndrome and encephalitis in adults, as well as congenital malformations such as microcephaly. The severity of ZIKV disease in humans depends on many factors, likely including host genetic determinants.We investigated how genome-wide variants could impact the susceptibility to ZIKV infection in mice. To this end, we used mouse strains of the Collaborative Cross (CC), a new genetic reference population encompassing a genetic diversity as broad as that of human populations.First, we described that the susceptibility of Ifnar1 (receptor to type I interferon) knockout mice is largely influenced by their genetic background. We then showed that the genetic diversity of CC mice, which IFNAR was blocked by anti-IFNAR antibody, expressed phenotypes ranging from complete resistance to severe symptoms and death with large variations in the peak and rate of decrease of plasma viral load, in brain viral load, in brain histopathology and in viral replication rate in infected cells. Differences of susceptibility between CC strains were correlated between Zika, Dengue and West Nile viruses. We identified highly susceptible and resistant CC strains as new models to investigate the mechanisms of human ZIKV disease and other flavivirus infections. Genetic analyses revealed that phenotypic variations were driven by multiple genes with small effects, reflecting the complexity of ZIKV disease susceptibility in human population. Notably, our results also ruled out a role of the Oas1b gene in the susceptibility to ZIKV.In a second part, we searched for genes which modify the susceptibility of Ifnar1 knockout mice in an F2 cross between C57BL/6J and 129S2/SvPas mice harboring the mutation. Genetic analysis revealed two Quantitative Trait Locus (QTL) controlling either the peak viremia or the mouse survival. Although these QTLs critical intervals contained hundreds of genes, data mining led us to identify a few candidate causal genes.Then, we investigated how host genetic factors influence viral replication in infected cells using Mouse Embryonic Fibroblasts (MEFs) derived from a series of CC strains with contrasted phenotypes observed in response to ZIKV infection in vivo. MEFs from CC071 strain displayed unique features of increased viral replication rate in late infection. Using transcriptomic analysis, we demonstrated that the phenotype of CC071 infected MEFs resulted from a delayed induction of the type I interferon (IFN) response. Genetic analyses ruled out single gene deficiencies but rather suggested combined effects of multiple factors in the type I IFN induction signaling pathway.Finally, we characterized the ZIKV-induced type I IFN response in MEFs and primary neurons derived from C57BL/6J mouse strain. Primary neurons were less capable than MEFs to control the viral replication due to a delayed IFN response. We later showed that host genetic factors also play a critical role in this context as ZIKV-infected CC071 primary neurons displayed an extreme phenotype compared to neurons from strains that are more resistant.Altogether, our work has unraveled the role of host genes in the pathogeny of ZIKV infection and illustrates the potential of CC mouse strains for genetic studies and as new models of infectious diseases. Extensive analysis of CC strains with extreme phenotypes help us elucidate how genetic variants affect susceptibility as well as immune responses to flaviviral infection and will provide deeper understanding of the pathophysiology of human ZIKV disease.Zika est un Flavivirus Ă©mergent transmis Ă lâHomme par piqĂ»re de moustique. Il a rĂ©cemment Ă©tĂ© Ă lâorigine dâĂ©pidĂ©mies dâenvergure mondiale et reprĂ©sente une menace pour la santĂ© publique. Lâinfection Zika est souvent asymptomatique ou engendre un syndrome grippal bĂ©nin. Cependant, des complications sĂ©vĂšres ont Ă©tĂ© associĂ©es au virus Zika, telles quâun syndrome de Guillain-BarrĂ© ou des encĂ©phalites chez lâadulte, ainsi que des malformations congĂ©nitales comme la microcĂ©phalie. De nombreux facteurs sont susceptibles dâinfluencer la sensibilitĂ© dâun individu au virus Zika, y compris les variants gĂ©nĂ©tiques de lâhĂŽte.Nous avons Ă©tudiĂ© le rĂŽle des facteurs gĂ©nĂ©tiques de lâhĂŽte dans sa sensibilitĂ© Ă lâinfection par le virus Zika. Pour cela, nous avons utilisĂ© des lignĂ©es de souris du Collaborative Cross (CC), une population gĂ©nĂ©tique de rĂ©fĂ©rence caractĂ©risĂ©e par une diversitĂ© gĂ©nĂ©tique aussi vaste que celle des populations humaines.Nous avons dâabord montrĂ© que le fond gĂ©nĂ©tique de souris dĂ©ficientes pour le gĂšne du rĂ©cepteur Ă lâinterfĂ©ron de type I (Ifnar1) joue un rĂŽle drastique dans leur sensibilitĂ© au virus Zika. La diversitĂ© gĂ©nĂ©tique des souris CC, prĂ©alablement traitĂ©es par un anticorps bloquant le rĂ©cepteur IFNAR, sâexprime par des phĂ©notypes allant dâune rĂ©sistance complĂšte jusquâĂ des formes sĂ©vĂšres de la maladie. Lâinfluence des facteurs gĂ©nĂ©tiques de lâhĂŽte sâexerce sur de nombreux paramĂštres tels que la virĂ©mie, la charge virale et les lĂ©sions pathologiques dans le cerveau, et enfin le taux de rĂ©plication dans les cellules infectĂ©es. Les diffĂ©rences de sensibilitĂ© entre lignĂ©es CC sâavĂšrent corrĂ©lĂ©es entre les Flavivirus Zika, Dengue et West-Nile. Nos analyses gĂ©nĂ©tiques ont montrĂ© que de multiples gĂšnes Ă effets faibles sous-tendent ces variations phĂ©notypiques, reflĂ©tant la complexitĂ© de la sensibilitĂ© au virus Zika dans les populations humaines, et permettent dâexclure un rĂŽle majeur du facteur de rĂ©sistance Oas1b.Nous avons ensuite cherchĂ© des gĂšnes agissant comme modificateurs de la sensibilitĂ© chez des souris dĂ©ficientes pour le gĂšne Ifnar1 dans un croisement F2 entre des souris C57BL/6J et 129S2/SvPas portant la mutation. Lâanalyse gĂ©nĂ©tique a permis lâidentification de deux QTLs (Quantitative Trait Locus), lâun contrĂŽlant le pic de virĂ©mie et lâautre la survie. Une Ă©tude bio-informatique nous a permis dâidentifier quelques gĂšnes candidats.Nous avons Ă©galement Ă©tudiĂ© comment les facteurs gĂ©nĂ©tiques de lâhĂŽte impactent la rĂ©plication virale dans des fibroblastes embryonnaires murins (MEFs) dĂ©rivĂ©s dâune sĂ©rie de lignĂ©es de souris prĂ©sentant des phĂ©notypes contrastĂ©s en rĂ©ponse Ă lâinfection Zika. Nous avons identifiĂ© une augmentation de la rĂ©plication virale tardive dans les MEFs de la lignĂ©e CC071, rĂ©sultant dâun retard Ă lâactivation de la rĂ©ponse interfĂ©ron (IFN). Des analyses gĂ©nĂ©tique et transcriptomique ont exclus des dĂ©ficiences causĂ©es par des gĂšnes uniques et ont favorisĂ© lâhypothĂšse dâune combinatoire de gĂšnes exerçant des effets faibles dans la voie dâinduction de la rĂ©ponse IFN.Pour finir, nous avons caractĂ©risĂ© la rĂ©ponse IFN induite par le virus Zika dans des neurones primaires murins. Cette Ă©tude a montrĂ© que la capacitĂ© des neurones primaires Ă limiter la rĂ©plication virale est moindre que celle des MEFs en raison dâun retard Ă lâinduction de la rĂ©ponse IFN. Enfin, les facteurs gĂ©nĂ©tiques de lâhĂŽte exercent un rĂŽle critique dans ce contexte puisque les neurones primaires de CC071 prĂ©sentent un phĂ©notype extrĂȘme par comparaison avec des lignĂ©es plus rĂ©sistantes.Notre travail a mis en Ă©vidence le rĂŽle des facteurs gĂ©nĂ©tiques de lâhĂŽte dans la pathogĂ©nie de lâinfection Zika et illustre le potentiel des souris CC dans des Ă©tudes gĂ©nĂ©tiques aussi bien quâen tant que nouveaux modĂšles dâinfection. Une analyse poussĂ©e des lignĂ©es aux phĂ©notypes extrĂȘmes permettra dâĂ©lucider les mĂ©canismes gĂ©nĂ©tiques de la sensibilitĂ© au virus Zika et amĂ©liorera notre comprĂ©hension de la maladie chez lâHomme
Genetic control oContrÎle génétique de la sensibilité au virus Zika chez la souris à l'aide de lignées du Collaborative Cross
Zika est un Flavivirus Ă©mergent transmis Ă lâHomme par piqĂ»re de moustique. Il a rĂ©cemment Ă©tĂ© Ă lâorigine dâĂ©pidĂ©mies dâenvergure mondiale et reprĂ©sente une menace pour la santĂ© publique. Lâinfection Zika est souvent asymptomatique ou engendre un syndrome grippal bĂ©nin. Cependant, des complications sĂ©vĂšres ont Ă©tĂ© associĂ©es au virus Zika, telles quâun syndrome de Guillain-BarrĂ© ou des encĂ©phalites chez lâadulte, ainsi que des malformations congĂ©nitales comme la microcĂ©phalie. De nombreux facteurs sont susceptibles dâinfluencer la sensibilitĂ© dâun individu au virus Zika, y compris les variants gĂ©nĂ©tiques de lâhĂŽte.Nous avons Ă©tudiĂ© le rĂŽle des facteurs gĂ©nĂ©tiques de lâhĂŽte dans sa sensibilitĂ© Ă lâinfection par le virus Zika. Pour cela, nous avons utilisĂ© des lignĂ©es de souris du Collaborative Cross (CC), une population gĂ©nĂ©tique de rĂ©fĂ©rence caractĂ©risĂ©e par une diversitĂ© gĂ©nĂ©tique aussi vaste que celle des populations humaines.Nous avons dâabord montrĂ© que le fond gĂ©nĂ©tique de souris dĂ©ficientes pour le gĂšne du rĂ©cepteur Ă lâinterfĂ©ron de type I (Ifnar1) joue un rĂŽle drastique dans leur sensibilitĂ© au virus Zika. La diversitĂ© gĂ©nĂ©tique des souris CC, prĂ©alablement traitĂ©es par un anticorps bloquant le rĂ©cepteur IFNAR, sâexprime par des phĂ©notypes allant dâune rĂ©sistance complĂšte jusquâĂ des formes sĂ©vĂšres de la maladie. Lâinfluence des facteurs gĂ©nĂ©tiques de lâhĂŽte sâexerce sur de nombreux paramĂštres tels que la virĂ©mie, la charge virale et les lĂ©sions pathologiques dans le cerveau, et enfin le taux de rĂ©plication dans les cellules infectĂ©es. Les diffĂ©rences de sensibilitĂ© entre lignĂ©es CC sâavĂšrent corrĂ©lĂ©es entre les Flavivirus Zika, Dengue et West-Nile. Nos analyses gĂ©nĂ©tiques ont montrĂ© que de multiples gĂšnes Ă effets faibles sous-tendent ces variations phĂ©notypiques, reflĂ©tant la complexitĂ© de la sensibilitĂ© au virus Zika dans les populations humaines, et permettent dâexclure un rĂŽle majeur du facteur de rĂ©sistance Oas1b.Nous avons ensuite cherchĂ© des gĂšnes agissant comme modificateurs de la sensibilitĂ© chez des souris dĂ©ficientes pour le gĂšne Ifnar1 dans un croisement F2 entre des souris C57BL/6J et 129S2/SvPas portant la mutation. Lâanalyse gĂ©nĂ©tique a permis lâidentification de deux QTLs (Quantitative Trait Locus), lâun contrĂŽlant le pic de virĂ©mie et lâautre la survie. Une Ă©tude bio-informatique nous a permis dâidentifier quelques gĂšnes candidats.Nous avons Ă©galement Ă©tudiĂ© comment les facteurs gĂ©nĂ©tiques de lâhĂŽte impactent la rĂ©plication virale dans des fibroblastes embryonnaires murins (MEFs) dĂ©rivĂ©s dâune sĂ©rie de lignĂ©es de souris prĂ©sentant des phĂ©notypes contrastĂ©s en rĂ©ponse Ă lâinfection Zika. Nous avons identifiĂ© une augmentation de la rĂ©plication virale tardive dans les MEFs de la lignĂ©e CC071, rĂ©sultant dâun retard Ă lâactivation de la rĂ©ponse interfĂ©ron (IFN). Des analyses gĂ©nĂ©tique et transcriptomique ont exclus des dĂ©ficiences causĂ©es par des gĂšnes uniques et ont favorisĂ© lâhypothĂšse dâune combinatoire de gĂšnes exerçant des effets faibles dans la voie dâinduction de la rĂ©ponse IFN.Pour finir, nous avons caractĂ©risĂ© la rĂ©ponse IFN induite par le virus Zika dans des neurones primaires murins. Cette Ă©tude a montrĂ© que la capacitĂ© des neurones primaires Ă limiter la rĂ©plication virale est moindre que celle des MEFs en raison dâun retard Ă lâinduction de la rĂ©ponse IFN. Enfin, les facteurs gĂ©nĂ©tiques de lâhĂŽte exercent un rĂŽle critique dans ce contexte puisque les neurones primaires de CC071 prĂ©sentent un phĂ©notype extrĂȘme par comparaison avec des lignĂ©es plus rĂ©sistantes.Notre travail a mis en Ă©vidence le rĂŽle des facteurs gĂ©nĂ©tiques de lâhĂŽte dans la pathogĂ©nie de lâinfection Zika et illustre le potentiel des souris CC dans des Ă©tudes gĂ©nĂ©tiques aussi bien quâen tant que nouveaux modĂšles dâinfection. Une analyse poussĂ©e des lignĂ©es aux phĂ©notypes extrĂȘmes permettra dâĂ©lucider les mĂ©canismes gĂ©nĂ©tiques de la sensibilitĂ© au virus Zika et amĂ©liorera notre comprĂ©hension de la maladie chez lâHomme.Zika virus (ZIKV) is a mosquito-transmitted flavivirus responsible for worldwide epidemics and constitutes a major public health threat. The majority of ZIKV infections in humans are either asymptomatic or result in a mild febrile illness. However, some patients develop a more severe, sometimes life-threatening, form of the disease. Recent evidence showed that ZIKV infection can trigger Guillain-BarrĂ© syndrome and encephalitis in adults, as well as congenital malformations such as microcephaly. The severity of ZIKV disease in humans depends on many factors, likely including host genetic determinants.We investigated how genome-wide variants could impact the susceptibility to ZIKV infection in mice. To this end, we used mouse strains of the Collaborative Cross (CC), a new genetic reference population encompassing a genetic diversity as broad as that of human populations.First, we described that the susceptibility of Ifnar1 (receptor to type I interferon) knockout mice is largely influenced by their genetic background. We then showed that the genetic diversity of CC mice, which IFNAR was blocked by anti-IFNAR antibody, expressed phenotypes ranging from complete resistance to severe symptoms and death with large variations in the peak and rate of decrease of plasma viral load, in brain viral load, in brain histopathology and in viral replication rate in infected cells. Differences of susceptibility between CC strains were correlated between Zika, Dengue and West Nile viruses. We identified highly susceptible and resistant CC strains as new models to investigate the mechanisms of human ZIKV disease and other flavivirus infections. Genetic analyses revealed that phenotypic variations were driven by multiple genes with small effects, reflecting the complexity of ZIKV disease susceptibility in human population. Notably, our results also ruled out a role of the Oas1b gene in the susceptibility to ZIKV.In a second part, we searched for genes which modify the susceptibility of Ifnar1 knockout mice in an F2 cross between C57BL/6J and 129S2/SvPas mice harboring the mutation. Genetic analysis revealed two Quantitative Trait Locus (QTL) controlling either the peak viremia or the mouse survival. Although these QTLs critical intervals contained hundreds of genes, data mining led us to identify a few candidate causal genes.Then, we investigated how host genetic factors influence viral replication in infected cells using Mouse Embryonic Fibroblasts (MEFs) derived from a series of CC strains with contrasted phenotypes observed in response to ZIKV infection in vivo. MEFs from CC071 strain displayed unique features of increased viral replication rate in late infection. Using transcriptomic analysis, we demonstrated that the phenotype of CC071 infected MEFs resulted from a delayed induction of the type I interferon (IFN) response. Genetic analyses ruled out single gene deficiencies but rather suggested combined effects of multiple factors in the type I IFN induction signaling pathway.Finally, we characterized the ZIKV-induced type I IFN response in MEFs and primary neurons derived from C57BL/6J mouse strain. Primary neurons were less capable than MEFs to control the viral replication due to a delayed IFN response. We later showed that host genetic factors also play a critical role in this context as ZIKV-infected CC071 primary neurons displayed an extreme phenotype compared to neurons from strains that are more resistant.Altogether, our work has unraveled the role of host genes in the pathogeny of ZIKV infection and illustrates the potential of CC mouse strains for genetic studies and as new models of infectious diseases. Extensive analysis of CC strains with extreme phenotypes help us elucidate how genetic variants affect susceptibility as well as immune responses to flaviviral infection and will provide deeper understanding of the pathophysiology of human ZIKV disease
L'inaptitude mĂ©dicale au poste de travail (enquĂȘte Ă©pidĂ©miologique descriptive dans trois services de santĂ© au travail de Meurthe-et-Moselle en 2007)
L'intensification du travail, l'apparition de nouveaux facteurs de pĂ©nibilitĂ© au travail et le vieillissement de la population active sont Ă l'origine de l'augmentation du nombre des inaptitudes. Nous avons rĂ©alisĂ© une Ă©tude Ă©pidĂ©miologique descriptive transversale, afin de connaĂźtre les caractĂ©ristiques des salariĂ©s dĂ©clarĂ©s inaptes dĂ©finitifs Ă leur poste de travail dans trois services de santĂ© au travail de Meurthe-et-Moselle en 2007, incluant 408 salariĂ©s. L'inaptitude touche surtout les salariĂ©s de plus de 45 ans, peu qualifiĂ©s, appartenant Ă des petites entreprises de moins de 50 salariĂ©s. Les affections responsables sont majoritairement les pathologies ostĂ©o-articulaires et les psycho-pathologies. Elles sont liĂ©es Ă l'exercice professionnel dans plus de 80% des cas. Plus de neuf fois sur dix, l'inaptitude dĂ©bouchera sur un licenciement. L'intĂ©rĂȘt de cette Ă©tude rĂ©side dans le suivi des salariĂ©s : ils seront recontactĂ©s Ă un an de leur inaptitude afin de connaĂźtre leur devenir. Les chiffres de l'inaptitude et leurs lourdes consĂ©quences socio-professionnelles posent la question du recentrage de l'action des mĂ©decins du travail sur l'amĂ©lioration des conditions de travail et le maintien dans l'emploi.NANCY1-SCD Medecine (545472101) / SudocNANCY1-Bib. numĂ©rique (543959902) / SudocSudocFranceF
Host genetic susceptibility to viral infections: the role of type I interferon induction
International audienceThe innate immune response is the major front line of defense against viral infections. It involves hundreds of genes with antiviral properties which expression is induced by type I interferons (IFNs) and are therefore called interferon stimulated genes (ISGs). Type I IFNs are produced after viral recognition by pathogen recognition receptors, which trigger a cascade of activation events. Human and mouse studies have shown that defective type I IFNs induction may hamper the ability to control viral infections. In humans, moderate to high-effect variants have been identified in individuals with particularly severe complications following viral infection. In mice, functional studies using knock-out alleles have revealed the specific role of most genes of the IFN pathway. Here, we review the role of the molecular partners of the type I IFNs induction pathway and their implication in the control of viral infections and of their complications
Ebony Magazine: An Investigation of the black American community represented in magazines
Host genetic control of mosquito-borne Flavivirus infections
International audienceFlaviviruses are arthropod-borne viruses, several of which represent emerging or re-emerging pathogens responsible for widespread infections with consequences ranging from asymptomatic seroconversion to severe clinical diseases and congenital developmental deficits. This variability is due to multiple factors including host genetic determinants, the role of which has been investigated in mouse models and human genetic studies. In this review, we provide an overview of the host genes and variants which modify susceptibility or resistance to major mosquito-borne flaviviruses infections in mice and humans
Susceptibility to Zika virus in a Collaborative Cross mouse strain is induced by Irf3 deficiency in vitro but requires other variants in vivo
Zika virus (ZIKV) is a Flavivirus responsible for recent epidemics in Pacific Islands and in the Americas. In humans, the consequences of ZIKV infection range from asymptomatic infection to severe neurological disease such as Guillain-Barre ÂŽsyndrome or fetal neurodevelopmental defects, suggesting, among other factors, the influence of host genetic variants. We previously reported similar diverse outcomes of ZIKV infection in mice of the Collaborative Cross (CC), a collection of inbred strains with large genetic diversity. CC071/TauUnc (CC071) was the most susceptible CC strain with severe symptoms and lethality. Notably, CC071 has been recently reported to be also susceptible to other flaviviruses including dengue virus, Powassan virus, West Nile virus, and to Rift Valley fever virus. To identify the genetic origin of this broad susceptibility, we investigated ZIKV replication in mouse embryonic fibroblasts (MEFs) from CC071 and two resistant strains. CC071 showed uncontrolled ZIKV replication associated with delayed induction of type-I interferons (IFN-I). Genetic analysis identified a mutation in the Irf3 gene specific to the CC071 strain which prevents the protein phosphorylation required to activate interferon beta transcription. We demonstrated that this mutation induces the same defective IFN-I response and uncontrolled viral replication in MEFs as an Irf3 knockout allele. By contrast, we also showed that Irf3 deficiency did not induce the high plasma viral load and clinical severity observed in CC071 mice and that susceptibility alleles at other genes, not associated with the IFN-I response, are required. Our results provide new insight into the in vitro and in vivo roles of Irf3, and into the genetic complexity of host responses to flaviviruses