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1. Zika Virus Infection Promotes Local Inflammation, Cell Adhesion Molecule Upregulation, and Leukocyte Recruitment at the Blood-Brain Barrier.

Author

Clé M, Desmetz C, Barthelemy J, Martin MF, Constant O, Maarifi G, Foulongne V, Bolloré K, Glasson Y, De Bock F, Blaquiere M, Dehouck L, Pirot N, Tuaillon E, Nisole S, Najioullah F, Van de Perre P, Cabié A, Marchi N, Gosselet F, Simonin Y, and Salinas S

Subjects
Animals, Brain immunology, Brain virology, Cell Adhesion genetics, Cells, Cultured, Chlorocebus aethiops, Disease Models, Animal, Hematopoietic Stem Cells, Humans, Mice, Up-Regulation, Vero Cells, Zika Virus, Zika Virus Infection pathology, Blood-Brain Barrier immunology, Cell Adhesion Molecules genetics, Inflammation virology, Leukocytes immunology, Zika Virus Infection immunology
Abstract

The blood-brain barrier (BBB) largely prevents toxins and pathogens from accessing the brain. Some viruses have the ability to cross this barrier and replicate in the central nervous system (CNS). Zika virus (ZIKV) was responsible in 2015 to 2016 for a major epidemic in South America and was associated in some cases with neurological impairments. Here, we characterized some of the mechanisms behind its neuroinvasion using an innovative in vitro human BBB model. ZIKV efficiently replicated, was released on the BBB parenchyma side, and triggered subtle modulation of BBB integrity as well as an upregulation of inflammatory and cell adhesion molecules (CAMs), which in turn favored leukocyte recruitment. Finally, we showed that ZIKV-infected mouse models displayed similar CAM upregulation and that soluble CAMs were increased in plasma samples from ZIKV-infected patients. Our observations suggest a complex interplay between ZIKV and the BBB, which may trigger local inflammation, leukocyte recruitment, and possible cerebral vasculature impairment. IMPORTANCE Zika virus (ZIKV) can be associated with neurological impairment in children and adults. To reach the central nervous system, viruses have to cross the blood-brain barrier (BBB), a multicellular system allowing a tight separation between the bloodstream and the brain. Here, we show that ZIKV infects cells of the BBB and triggers a subtle change in its permeability. Moreover, ZIKV infection leads to the production of inflammatory molecules known to modulate BBB integrity and participate in immune cell attraction. The virus also led to the upregulation of cellular adhesion molecules (CAMs), which in turn favored immune cell binding to the BBB and potentially increased infiltration into the brain. These results were also observed in a mouse model of ZIKV infection. Furthermore, plasma samples from ZIKV-infected patients displayed an increase in CAMs, suggesting that this mechanism could be involved in neuroinflammation triggered by ZIKV., (Copyright © 2020 Clé et al.)

Published
2020
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2. Etude du neurotropisme de deux arbovirus émergents : les virus Zika et Usutu

Author

Clé, Marion, Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Université Montpellier, Sara Salinas, and Yannick Simonin

Subjects
Arbovirus, [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Barrière hémato-encéphalique, Systeme nerveux, Blood-Brain barrier, Nervous System
Abstract

Emerging viruses are defined as viruses gaining new territories or as known viruses that have mutated or recombined and become more pathogenic and contagious in the population. These viruses represent major public health problems as they can sometimes cause unknown and potentially serious disorders, particularly neuroinvasive diseases. This is the case, for example, with the recent emergence of two neurotropic viruses: Zika virus (ZIKV) and Usutu virus (USUV). ZIKV is responsible for epidemics mainly in French Polynesia in 2013 and Latin America in 2015-2016, where it was also responsible for neurological disorders (encephalitis, meningoencephalitis, Guillain-Barré syndrome, microcephaly, and others) in some patients. USUV has recently emerged in Europe, where it has been implicated in significant avian mortality, mainly in blackbirds, but also in neuroinvasive infections in humans (encephalitis, meningoencephalitis, and others). Despite this, the pathogenesis of these two emerging viruses remained poorly explored. The objective of this thesis was to characterize the effects of ZIKV infection on the blood-brain barrier (BBB) structure and homeostasis and to evaluate and compare the neuropathogenicity of different USUV lineages by combining in vivo and in vitro approaches. Our results first suggest a complex interaction between ZIKV and the BBB that could trigger local inflammation, leukocyte recruitment, and possible long-term cerebrovascular impairment. Secondly, regarding USUV, our data suggest that the virus can reach the brain and cause massive inflammation leading to the recruitment of immune cells, which correlates with human brain inflammatory pathologies such as encephalitis. Also, following the analysis of circulating USUV lineages, our results suggest that some USUV lineages may have a higher degree of neurovirulence, notably the Europe 2 lineage. The emergence and rapid spread of new viruses constitute a complex and constant challenge for human health. Today, many factors such as ecological changes, increased animal movements, world population density, and improved means of transport are contributing to emerging virus appearance and facilitating their transmission. For these reasons, it is necessary to study in greater detail mechanisms of viral infection (entry of the virus into cells, transmission, multiplication, and etc.) to develop appropriate antiviral treatments or specific vaccines.Key Words: Zika Virus, Usutu Virus, flavivirus, central nervous system, neurovirulence and neurotropism; Les virus émergents sont définis comme étant des virus gagnant de nouveaux territoires ou comme des virus connus mais ayant muté ou recombiné au point de devenir beaucoup plus transmissibles et contagieux dans la population. Ces virus posent des problèmes majeurs pour la santé publique car ils peuvent être à l’origine de maladies parfois inconnues et potentiellement graves notamment neuroinvasives. C’est le cas, par exemple, avec l’émergence récente de deux virus neurotropes : Zika (ZIKV) et Usutu (USUV). ZIKV a été responsable d’épidémies principalement en Polynésie Française en 2013 et en Amérique Latine en 2015-2016 où il a été la cause chez certains patients d’atteintes neurologiques (encéphalite, méningo-encéphalite, syndrome de Guillain-Barré, microcéphalie, etc.). USUV, quant à lui, a émergé récemment en Europe, où il a été impliqué dans une importante mortalité aviaire (principalement chez le merle noir) mais aussi dans des infections neuroinvasives chez l’Homme (encéphalite, méningo-encéphalite, etc.). Malgré cela, la pathogenèse de ces deux virus reste peu explorée. L'objectif de cette thèse était de caractériser l’effet de l’infection du ZIKV sur la structure et l’homéostasie de la barrière hémato-encéphalique (BHE) ainsi que d'évaluer et de comparer la neuropathogénicité de différentes lignées d’USUV en combinant des approches in vivo et in vitro. Nos résultats suggèrent premièrement une interaction complexe entre le ZIKV et la BHE qui pourrait déclencher une inflammation locale, le recrutement de leucocytes et une éventuelle perturbation vasculaire cérébrale sur du long terme. Deuxièmement, pour USUV, nos résultats corrèlent avec les pathologies inflammatoires cérébrales engendrées chez l’Homme comme l’encéphalite. De plus, suite à l’analyse des lignées circulantes d’USUV, nos résultats suggèrent que certaines lignées d’USUV peuvent avoir une neurovirulence plus importante, notamment la lignée Europe 2. L'émergence et la propagation rapide des nouveaux virus illustrent le défi complexe et constant pour la santé humaine. Aujourd’hui, de nombreux facteurs tels que les modifications écologiques, l’augmentation des déplacements animaliers et de la densité de la population mondiale ainsi que l’amélioration des moyens de transport favorisent l’apparition des virus émergents et facilitent leur transmission. Pour ces raisons, il est nécessaire d’étudier plus en détails les mécanismes impliqués dans l’infection virale (entrée du virus dans les cellules, sa transmission, sa multiplication et etc.) pour développer des traitements antiviraux adaptés ou des vaccins spécifiques.Mots clés : Virus Zika, Virus Usutu, flavivirus, système nerveux central, neurovirulence et neurotropisme

Published
2020

3. Study of neurotropism of two emerging arboviruses : Zika and Usutu viruses

Author

Clé, Marion, STAR, ABES, Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Université Montpellier, Sara Salinas, and Yannick Simonin

Subjects
Arbovirus, [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Barrière hémato-encéphalique, [SDV.SA] Life Sciences [q-bio]/Agricultural sciences, Systeme nerveux, Blood-Brain barrier, Nervous System
Abstract

Emerging viruses are defined as viruses gaining new territories or as known viruses that have mutated or recombined and become more pathogenic and contagious in the population. These viruses represent major public health problems as they can sometimes cause unknown and potentially serious disorders, particularly neuroinvasive diseases. This is the case, for example, with the recent emergence of two neurotropic viruses: Zika virus (ZIKV) and Usutu virus (USUV). ZIKV is responsible for epidemics mainly in French Polynesia in 2013 and Latin America in 2015-2016, where it was also responsible for neurological disorders (encephalitis, meningoencephalitis, Guillain-Barré syndrome, microcephaly, and others) in some patients. USUV has recently emerged in Europe, where it has been implicated in significant avian mortality, mainly in blackbirds, but also in neuroinvasive infections in humans (encephalitis, meningoencephalitis, and others). Despite this, the pathogenesis of these two emerging viruses remained poorly explored. The objective of this thesis was to characterize the effects of ZIKV infection on the blood-brain barrier (BBB) structure and homeostasis and to evaluate and compare the neuropathogenicity of different USUV lineages by combining in vivo and in vitro approaches. Our results first suggest a complex interaction between ZIKV and the BBB that could trigger local inflammation, leukocyte recruitment, and possible long-term cerebrovascular impairment. Secondly, regarding USUV, our data suggest that the virus can reach the brain and cause massive inflammation leading to the recruitment of immune cells, which correlates with human brain inflammatory pathologies such as encephalitis. Also, following the analysis of circulating USUV lineages, our results suggest that some USUV lineages may have a higher degree of neurovirulence, notably the Europe 2 lineage. The emergence and rapid spread of new viruses constitute a complex and constant challenge for human health. Today, many factors such as ecological changes, increased animal movements, world population density, and improved means of transport are contributing to emerging virus appearance and facilitating their transmission. For these reasons, it is necessary to study in greater detail mechanisms of viral infection (entry of the virus into cells, transmission, multiplication, and etc.) to develop appropriate antiviral treatments or specific vaccines.Key Words: Zika Virus, Usutu Virus, flavivirus, central nervous system, neurovirulence and neurotropism, Les virus émergents sont définis comme étant des virus gagnant de nouveaux territoires ou comme des virus connus mais ayant muté ou recombiné au point de devenir beaucoup plus transmissibles et contagieux dans la population. Ces virus posent des problèmes majeurs pour la santé publique car ils peuvent être à l’origine de maladies parfois inconnues et potentiellement graves notamment neuroinvasives. C’est le cas, par exemple, avec l’émergence récente de deux virus neurotropes : Zika (ZIKV) et Usutu (USUV). ZIKV a été responsable d’épidémies principalement en Polynésie Française en 2013 et en Amérique Latine en 2015-2016 où il a été la cause chez certains patients d’atteintes neurologiques (encéphalite, méningo-encéphalite, syndrome de Guillain-Barré, microcéphalie, etc.). USUV, quant à lui, a émergé récemment en Europe, où il a été impliqué dans une importante mortalité aviaire (principalement chez le merle noir) mais aussi dans des infections neuroinvasives chez l’Homme (encéphalite, méningo-encéphalite, etc.). Malgré cela, la pathogenèse de ces deux virus reste peu explorée. L'objectif de cette thèse était de caractériser l’effet de l’infection du ZIKV sur la structure et l’homéostasie de la barrière hémato-encéphalique (BHE) ainsi que d'évaluer et de comparer la neuropathogénicité de différentes lignées d’USUV en combinant des approches in vivo et in vitro. Nos résultats suggèrent premièrement une interaction complexe entre le ZIKV et la BHE qui pourrait déclencher une inflammation locale, le recrutement de leucocytes et une éventuelle perturbation vasculaire cérébrale sur du long terme. Deuxièmement, pour USUV, nos résultats corrèlent avec les pathologies inflammatoires cérébrales engendrées chez l’Homme comme l’encéphalite. De plus, suite à l’analyse des lignées circulantes d’USUV, nos résultats suggèrent que certaines lignées d’USUV peuvent avoir une neurovirulence plus importante, notamment la lignée Europe 2. L'émergence et la propagation rapide des nouveaux virus illustrent le défi complexe et constant pour la santé humaine. Aujourd’hui, de nombreux facteurs tels que les modifications écologiques, l’augmentation des déplacements animaliers et de la densité de la population mondiale ainsi que l’amélioration des moyens de transport favorisent l’apparition des virus émergents et facilitent leur transmission. Pour ces raisons, il est nécessaire d’étudier plus en détails les mécanismes impliqués dans l’infection virale (entrée du virus dans les cellules, sa transmission, sa multiplication et etc.) pour développer des traitements antiviraux adaptés ou des vaccins spécifiques.Mots clés : Virus Zika, Virus Usutu, flavivirus, système nerveux central, neurovirulence et neurotropisme

Published
2020

4. Differential neurovirulence of Usutu virus lineages in mice and neuronal cells.

Author

Clé, Marion, Constant, Orianne, Barthelemy, Jonathan, Desmetz, Caroline, Martin, Marie France, Lapeyre, Lina, Cadar, Daniel, Savini, Giovanni, Teodori, Liana, Monaco, Federica, Schmidt-Chanasit, Jonas, Saiz, Juan-Carlos, Gonzales, Gaëlle, Lecollinet, Sylvie, Beck, Cécile, Gosselet, Fabien, Van de Perre, Philippe, Foulongne, Vincent, Salinas, Sara, and Simonin, Yannick

Subjects
*ARBOVIRUSES, *RNA replicase, *WEST Nile virus, *CENTRAL nervous system, *ENDOTHELIAL cells, *BLOOD-brain barrier
Abstract

Background: Usutu virus (USUV) is an emerging neurotropic arthropod-borne virus recently involved in massive die offs of wild birds predominantly reported in Europe. Although primarily asymptomatic or presenting mild clinical signs, humans infected by USUV can develop neuroinvasive pathologies (including encephalitis and meningoencephalitis). Similar to other flaviviruses, such as West Nile virus, USUV is capable of reaching the central nervous system. However, the neuropathogenesis of USUV is still poorly understood, and the virulence of the specific USUV lineages is currently unknown. One of the major complexities of the study of USUV pathogenesis is the presence of a great diversity of lineages circulating at the same time and in the same location. Methods: The aim of this work was to determine the neurovirulence of isolates from the six main lineages circulating in Europe using mouse model and several neuronal cell lines (neurons, microglia, pericytes, brain endothelial cells, astrocytes, and in vitro Blood-Brain Barrier model). Results: Our results indicate that all strains are neurotropic but have different virulence profiles. The Europe 2 strain, previously described as being involved in several clinical cases, induced the shortest survival time and highest mortality in vivo and appeared to be more virulent and persistent in microglial, astrocytes, and brain endothelial cells, while also inducing an atypical cytopathic effect. Moreover, an amino acid substitution (D3425E) was specifically identified in the RNA-dependent RNA polymerase domain of the NS5 protein of this lineage. Conclusions: Altogether, these data show a broad neurotropism for USUV in the central nervous system with lineage-dependent virulence. Our results will help to better understand the biological and epidemiological diversity of USUV infection. [ABSTRACT FROM AUTHOR]

Published
2021
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5. Study of Usutu virus neuropathogenicity in mice and human cellular models.

Author

Clé, Marion, Barthelemy, Jonathan, Desmetz, Caroline, Foulongne, Vincent, Lapeyre, Lina, Bolloré, Karine, Tuaillon, Edouard, Erkilic, Nejla, Kalatzis, Vasiliki, Lecollinet, Sylvie, Beck, Cécile, Pirot, Nelly, Glasson, Yaël, Gosselet, Fabien, Alvarez Martinez, Maria Teresa, Van de Perre, Philippe, Salinas, Sara, and Simonin, Yannick

Subjects
*BLOOD-brain barrier, *NEUROLOGICAL disorders, *WEST Nile virus, *CENTRAL nervous system, *SYMPTOMS, *RHODOPSIN, *ANTI-NMDA receptor encephalitis
Abstract

Usutu virus (USUV), an African mosquito-borne flavivirus closely related to West Nile virus, was first isolated in South Africa in 1959. USUV emerged in Europe two decades ago, causing notably massive mortality in Eurasian blackbirds. USUV is attracting increasing attention due to its potential for emergence and its rapid spread in Europe in recent years. Although mainly asymptomatic or responsible for mild clinical signs, USUV was recently described as being associated with neurological disorders in humans such as encephalitis and meningoencephalitis, highlighting the potential health threat posed by the virus. Despite this, USUV pathogenesis remains largely unexplored. The aim of this study was to evaluate USUV neuropathogenicity using in vivo and in vitro approaches. Our results indicate that USUV efficiently replicates in the murine central nervous system. Replication in the spinal cord and brain is associated with recruitment of inflammatory cells and the release of inflammatory molecules as well as induction of antiviral-responses without major modulation of blood-brain barrier integrity. Endothelial cells integrity is also maintained in a human model of the blood-brain barrier despite USUV replication and release of pro-inflammatory cytokines. Furthermore, USUV-inoculated mice developed major ocular defects associated with inflammation. Moreover, USUV efficiently replicates in human retinal pigment epithelium. Our results will help to better characterize the physiopathology related to USUV infection in order to anticipate the potential threat of USUV emergence. Author summary: Number of emerging arboviruses involved in human infections has increased considerably in the past years. Among them, Usutu virus (USUV) is an African mosquito-borne virus first isolated in South Africa that recently emerged. USUV infection in humans is considered to be most often asymptomatic or to cause mild clinical signs. Nonetheless, increased cases of neurological complications such as encephalitis or meningoencephalitis have been reported in Europe but the mechanisms behind this neuropathogenesis remain largely unclear. In this study we showed that USUV can infect efficiently several organs and cells of the central nervous system associated with a drastic inflammation and various deleterious effects. Our results contribute to the characterization of the neurotropism related to USUV infection. [ABSTRACT FROM AUTHOR]

Published
2020
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