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Schmallenberg Virus Pathogenesis, Tropism and Interaction with the Innate Immune System of the Host

26 February 2013

In an effort to reduce the effects of the schmallenberg virus, researchers have engineered the genome of the virus in a form that can be easily introduced and replicated in cultured cells.

Author Summary

In vitro phenotypic characterization of SBV and sSBV.
A. Comparison of plaques produced by wild type SBV and sSBV rescued using BSR-T7/5 and 293T cells. B. Growth kinetics of SBV and sSBV. CPT-Tert and BFAE cells were infected at a MOI of 0.05 for 90 min.

Supernatants were collected at the indicated times post-infection and virus titer was measured using standard plaque assays in CPT-Tert cells. C. The presence of SBV in CPT-Tert and BFAE cells infected with wild type and rescued virus was confirmed by western blotting using antibodies against the SBV N (nucleocapsid) protein. doi:10.1371/journal.ppat.1003133.g003

Schmallenberg virus (SBV) was discovered in Germany (near the town of Schmallenberg) in November 2011 and since then has been found to be the cause of malformations and stillbirths in ruminants. SBV has spread very rapidly to many European countries including the Netherlands, Belgium, France and the United Kingdom. Very little is known about the biological properties of this virus and there is no vaccine available. In this study (i) we developed an approach (called reverse genetics) that allows the recovery of “synthetic” SBV under laboratory conditions; (ii) we developed a mouse model of infection for SBV; (iii) we showed that SBV replicates in neurons of experimentally infected mice similar to naturally infected lambs and calves; (iv) we developed viral mutants that are not as pathogenic as the original virus due to the inability to counteract the host cell defenses; and v) we identified mutations that are associated with increased virulence. This work provides the experimental tools to understand how this newly emerged virus causes disease in ruminants. In addition, it will now be possible to manipulate the SBV genome in order to develop highly effective vaccines.

A. Left panel: survival plots of 2-day old NIH-Swiss mice inoculated intracerebrally using the indicated viruses or cell culture media as a control. Right panel: survival plots of 10 and 18-day old NIH-Swiss mice inoculated as described in A. B–E histopathology of brain sections from SBV-infected infected mice stained with hematoxylin. B and C. brain sections from SBV-infected mice at 72 h post-infection.

Arrows indicate areas of malacia and hemorrhage. D and E brain sections from SBV infected mice at 120 h post-infection, showing areas of vacuolation in low and high magnification respectively.

F–K immunohistochemistry of brain sections of mock-infected mice (F–G), or SBV infected mice at 48 h (H–I) or 72 h (J–K) post-infection using an SBV N antiserum as described in Materials and Methods. Bars = 2 mm in B, F, H, J; 200 µm in C; 500 µm in D; 100 µm in E, G, I, K. doi:10.1371/journal.ppat.1003133.g005


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 (SBV?NSs) is less virulent in mice than wild type SBV. Attenuation of SBV virulence depends on the inability of SBV?NSs 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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February 2013

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