title: Schmallenberg virus pathogenesis, tropism and interaction with the innate immune system of the host.
abstract: Schmallenberg virus (SBV) is an emerging orthobunyavirus of ruminants associated with outbreaks of congenital malformations in aborted and stillborn animals. Since its discovery in November 2011, SBV has spread very rapidly to many European countries. Here, we developed molecular and serological tools, and an experimental in vivo model as a platform to study SBV pathogenesis, tropism and virus-host cell interactions. Using a synthetic biology approach, we developed a reverse genetics system for the rapid rescue and genetic manipulation of SBV. We showed that SBV has a wide tropism in cell culture and "synthetic" SBV replicates in vitro as efficiently as wild type virus. We developed an experimental mouse model to study SBV infection and showed that this virus replicates abundantly in neurons where it causes cerebral malacia and vacuolation of the cerebral cortex. These virus-induced acute lesions are useful in understanding the progression from vacuolation to porencephaly and extensive tissue destruction, often observed in aborted lambs and calves in naturally occurring Schmallenberg cases. Indeed, we detected high levels of SBV antigens in the neurons of the gray matter of brain and spinal cord of naturally affected lambs and calves, suggesting that muscular hypoplasia observed in SBV-infected lambs is mostly secondary to central nervous system damage. Finally, we investigated the molecular determinants of SBV virulence. Interestingly, we found a biological SBV clone that after passage in cell culture displays increased virulence in mice. We also found that a SBV deletion mutant of the non-structural NSs protein (SBVΔNSs) is less virulent in mice than wild type SBV. Attenuation of SBV virulence depends on the inability of SBVΔNSs to block IFN synthesis in virus infected cells. In conclusion, this work provides a useful experimental framework to study the biology and pathogenesis of SBV.
authors: MRC Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors: Mariana
authors: M
authors: Varela
authors: Esther
authors: E
authors: Schnettler
authors: Marco
authors: M
authors: Caporale
authors: Claudio
authors: C
authors: Murgia
authors: Gerald
authors: G
authors: Barry
authors: Melanie
authors: M
authors: McFarlane
authors: Eva
authors: E
authors: McGregor
authors: Ilaria M
authors: IM
authors: Piras
authors: Andrew
authors: A
authors: Shaw
authors: Catherine
authors: C
authors: Lamm
authors: Anna
authors: A
authors: Janowicz
authors: Martin
authors: M
authors: Beer
authors: Mandy
authors: M
authors: Glass
authors: Vanessa
authors: V
authors: Herder
authors: Kerstin
authors: K
authors: Hahn
authors: Wolfgang
authors: W
authors: Baumgärtner
authors: Alain
authors: A
authors: Kohl
authors: Massimo
authors: M
authors: Palmarini
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002044:Bunyaviridae Infections / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000821:virology*; D002417:Cattle; D002460:Cell Line; D002526:Cerebellar Diseases / Q000276:immunology / Q000473:pathology / Q000821:virology; D002540:Cerebral Cortex / Q000276:immunology / Q000473:pathology / Q000821:virology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology / Q000821:virology; D054884:Host-Pathogen Interactions / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000276:immunology / Q000473:pathology / Q000821:virology; D016851:Orthobunyavirus / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity*; D017384:Sequence Deletion; D012756:Sheep; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology / Q000821:virology; D015996:Survival Rate; D014617:Vacuoles; D056189:Viral Tropism; D014774:Virulence; D014776:Virus Cultivation; D014779:Virus Replication