Schmallenberg virus pathogenesis, tropism and interaction with the innate immune system of the host

Marianna Varela, Esther Schnettler, Marco Caporale, Claudio Murgia, Gerald Barry, Melanie McFarlane, Eva McGregor, Ilaria M. Piras, Andrew Shaw, Catherine Lamm, Anna Janowicz, Martin Beer, Mandy Glass, Vanessa Herder, Kerstin Hann, Wolfgang Baumgaertner, Alain Kohl, Massimo Palmarini

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)1-13
Number of pages13
JournalPLOS Pathogens
Volume9
Issue number1
DOIs
Publication statusPublished - 10 Jan 2013
Externally publishedYes

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Tropism
Immune System
Viruses
Virulence
Viral Tropism
Cell Culture Techniques
Orthobunyavirus
Synthetic Biology
Neurons
Reverse Genetics

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Varela, M., Schnettler, E., Caporale, M., Murgia, C., Barry, G., McFarlane, M., ... Palmarini, M. (2013). Schmallenberg virus pathogenesis, tropism and interaction with the innate immune system of the host. PLOS Pathogens, 9(1), 1-13. https://doi.org/10.1371/journal.ppat.1003133
Varela, Marianna ; Schnettler, Esther ; Caporale, Marco ; Murgia, Claudio ; Barry, Gerald ; McFarlane, Melanie ; McGregor, Eva ; Piras, Ilaria M. ; Shaw, Andrew ; Lamm, Catherine ; Janowicz, Anna ; Beer, Martin ; Glass, Mandy ; Herder, Vanessa ; Hann, Kerstin ; Baumgaertner, Wolfgang ; Kohl, Alain ; Palmarini, Massimo. / Schmallenberg virus pathogenesis, tropism and interaction with the innate immune system of the host. In: PLOS Pathogens. 2013 ; Vol. 9, No. 1. pp. 1-13.
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Varela, M, Schnettler, E, Caporale, M, Murgia, C, Barry, G, McFarlane, M, McGregor, E, Piras, IM, Shaw, A, Lamm, C, Janowicz, A, Beer, M, Glass, M, Herder, V, Hann, K, Baumgaertner, W, Kohl, A & Palmarini, M 2013, 'Schmallenberg virus pathogenesis, tropism and interaction with the innate immune system of the host' PLOS Pathogens, vol. 9, no. 1, pp. 1-13. https://doi.org/10.1371/journal.ppat.1003133

Schmallenberg virus pathogenesis, tropism and interaction with the innate immune system of the host. / Varela, Marianna; Schnettler, Esther; Caporale, Marco ; Murgia, Claudio; Barry, Gerald ; McFarlane, Melanie; McGregor, Eva; Piras, Ilaria M.; Shaw, Andrew; Lamm, Catherine; Janowicz, Anna; Beer, Martin; Glass, Mandy; Herder, Vanessa; Hann, Kerstin; Baumgaertner, Wolfgang; Kohl, Alain; Palmarini, Massimo.

In: PLOS Pathogens, Vol. 9, No. 1, 10.01.2013, p. 1-13.

Research output: Contribution to journalArticle

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AU - Varela, Marianna

AU - Schnettler, Esther

AU - Caporale, Marco

AU - Murgia, Claudio

AU - Barry, Gerald

AU - McFarlane, Melanie

AU - McGregor, Eva

AU - Piras, Ilaria M.

AU - Shaw, Andrew

AU - Lamm, Catherine

AU - Janowicz, Anna

AU - Beer, Martin

AU - Glass, Mandy

AU - Herder, Vanessa

AU - Hann, Kerstin

AU - Baumgaertner, Wolfgang

AU - Kohl, Alain

AU - Palmarini, Massimo

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N2 - 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.

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DO - 10.1371/journal.ppat.1003133

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