Marion Clé1, Orianne Constant1, Jonathan Barthelemy1, Caroline Desmetz2, Marie France Martin3, Lina Lapeyre3, Daniel Cadar4, Giovanni Savini5, Liana Teodori5, Federica Monaco5, Jonas Schmidt-Chanasit4,6, Juan-Carlos Saiz7, Gaëlle Gonzales8, Sylvie Lecollinet8, Cécile Beck8, Fabien Gosselet9, Philippe Van de Perre1,10, Vincent Foulongne1,10, Sara Salinas1, Yannick Simonin11. 1. Pathogenesis and Control of Chronic Infections, Université de Montpellier, INSERM, EFS, Montpellier, France. 2. BioCommunication en CardioMétabolique (BC2M), Montpellier University, Montpellier, France. 3. Université de Montpellier, CNRS, Viral Trafficking, Restriction and Innate Signaling, Montpellier, France. 4. Bernhard Nocht Institute for Tropical Medicine, WHO Collaborating Centre for Arbovirus and Haemorrhagic Fever Reference and Research, 20359, Hamburg, Germany. 5. OIE Reference Centre for West Nile Disease, Istituto Zooprofilattico Sperimentale "G. Caporale", 46100, Teramo, Italy. 6. Faculty of Mathematics, Informatics and Natural Sciences, Universität Hamburg, 20148, Hamburg, Germany. 7. Department of Biotechnology, INIA, Madrid, Spain. 8. UPE, Anses Animal Health Laboratory, UMR1161 Virology, INRA, Anses, ENVA, Maisons-Alfort, France. 9. Blood-Brain Barrier Laboratory (BBB Lab), University of Artois, UR2465, F-62300, Lens, France. 10. Centre Hospitalier Universitaire de Montpellier, Montpellier, France. 11. Pathogenesis and Control of Chronic Infections, Université de Montpellier, INSERM, EFS, Montpellier, France. yannick.simonin@umontpellier.fr.
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.
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, humansinfected 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.
Entities:
Keywords:
Arbovirus; Central nervous system; Flavivirus; Neurotropism; Usutu virus
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