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.

A review on Schmallenberg virus infection: a newly emerging disease of cattle, sheep and goats

“…Additional SBV pathogenesis studies in an experimental mouse model showed that SBV to replicate abundantly in neurons where it caused cerebral malacia and vacuolation of the cerebral cortex, thus reconfirming its strong neurotropism (Varela et al 2013). The SBV-induced acute lesions in experimental mice progressed from per-acute haemorrhages at 48 h post-infection to malacia at 72 h that extended to more widespread vacuolation of the white matter at 96-120 h post-inoculation.…”

“…The Gn and Gc proteins act as antigenic determinants and are recognised by neutralizing antibodies. The S RNA segment encodes the nucleocapsid protein (N) and non-structural protein (NSs) which plays a role in complement fixation (Elliott and Blakqori 2011;Goller et al 2012;Yanase et al 2012) and also in modulating the innate immune response of host cells Varela et al 2013). Of the three segments, the M RNA segment is the most variable among orthobunyaviruses.…”

“…A recent study on SBV pathogenesis revealed that the virus is neurotropic in naturally in utero-infected lambs and calves (Varela et al 2013). Analysing tissue sections of brain and spinal cord from a total of eight naturally infected lambs and calves presenting congenital malformations viz.…”

“…The malformations and deformities observed in SBV-infected lambs and calves are accompanied by muscle hypoplasia and demyelination. The muscular hypoplasia and muscular defects are mostly secondary to damage of the CNS (Varela et al 2013).…”

“…NSs acts as a virulence factor which antagonises interferon probably by globally inhibiting host cell metabolism. In this way the host innate immune response is overcome and efficient viral replication is permitted Varela et al 2013). Similar roles have been identified for the NSs proteins of Rift Valley fever virus (Bouloy et al 2001) and La Crosse virus (Blakqori et al 2007).…”