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Differential neurovirulence of Usutu virus lineages in mice and neuronal cells

  • Clé, Marion1
  • Constant, Orianne1
  • Barthelemy, Jonathan1
  • Desmetz, Caroline2
  • Martin, Marie France3
  • Lapeyre, Lina3
  • Cadar, Daniel4
  • Savini, Giovanni5
  • Teodori, Liana5
  • Monaco, Federica5
  • Schmidt-Chanasit, Jonas4, 6
  • Saiz, Juan-Carlos7
  • Gonzales, Gaëlle8
  • Lecollinet, Sylvie8
  • Beck, Cécile8
  • Gosselet, Fabien9
  • Van de Perre, Philippe1, 10
  • Foulongne, Vincent1, 10
  • Salinas, Sara1
  • Simonin, Yannick1
  • 1 Université de Montpellier, INSERM, EFS, Montpellier, France , Montpellier (France)
  • 2 Montpellier University, Montpellier, France , Montpellier (France)
  • 3 Université de Montpellier, CNRS, Viral Trafficking, Restriction and Innate Signaling, Montpellier, France , Montpellier (France)
  • 4 Bernhard Nocht Institute for Tropical Medicine, WHO Collaborating Centre for Arbovirus and Haemorrhagic Fever Reference and Research, Hamburg, 20359, Germany , Hamburg (Germany)
  • 5 OIE Reference Centre for West Nile Disease, Istituto Zooprofilattico Sperimentale “G. Caporale”, Teramo, 46100, Italy , Teramo (Italy)
  • 6 Universität Hamburg, Hamburg, 20148, Germany , Hamburg (Germany)
  • 7 INIA, Madrid, Spain , Madrid (Spain)
  • 8 UPE, Anses Animal Health Laboratory, UMR1161 Virology, INRA, Anses, ENVA, Maisons-Alfort, France , Maisons-Alfort (France)
  • 9 University of Artois, UR2465, Lens, F-62300, France , Lens (France)
  • 10 Centre Hospitalier Universitaire de Montpellier, Montpellier, France , Montpellier (France)
Published Article
Journal of Neuroinflammation
Springer (Biomed Central Ltd.)
Publication Date
Jan 06, 2021
DOI: 10.1186/s12974-020-02060-4
Springer Nature


BackgroundUsutu 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.MethodsThe 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).ResultsOur 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.ConclusionsAltogether, 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.

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