Abstract
Schmallenberg virus (SBV) is the cause of severe fetal malformations when immunologically naïve pregnant ruminants are infected. In those malformed fetuses, a “hot-spot”-region of high genetic variability within the N-terminal region of the viral envelope protein Gc has been observed previously, and this region co-localizes with a known key immunogenic domain. We studied a series of M-segments of those SBV variants from malformed fetuses with point mutations, insertions or large in-frame deletions of up to 612 nucleotides. Furthermore, a unique cell-culture isolate from a malformed fetus with large in-frame deletions within the M-segment was analyzed.Each Gc-protein with amino acid deletions within the “hot spot” of mutations failed to react with any neutralizing anti-SBV monoclonal antibodies or a domain specific antiserum. In addition, in vitro virus replication of the natural deletion variant could not be markedly reduced by neutralizing monoclonal antibodies or antisera from the field. The large-deletion variant of SBV that could be isolated in cell culture was highly attenuated with an impaired in vivo replication following the inoculation of sheep.In conclusion, the observed amino acid sequence mutations within the N-terminal main immunogenic domain of glycoprotein Gc result in an efficient immune evasion from neutralizing antibodies in the special environment of a developing fetus. These SBV-variants were never detected as circulating viruses, and therefore should be considered to be dead-end virus variants, which are not able to spread further. The observations described here may be transferred to other orthobunyaviruses, particularly those of the Simbu serogroup that have been shown to infect fetuses. Importantly, such mutant strains should not be included in attempts to trace the spatial-temporal evolution of orthobunyaviruses in molecular-epidemiolocal approaches during outbreak investigations.
Highlights
Schmallenberg virus (SBV), which emerged in 2011 in Central Europe, is transmitted by Culicoides biting midges and causes no or only mild non-specific and short-lived clinical signs in adult ruminants [1], but can induce premature birth, stillbirth, or severe malformations in the offspring when immunologically naïve animals are infected during a vulnerable period of pregnancy [2]
SBV Gc deletion mutant viruses occur naturally In January 2015, different tissue samples of a malformed lamb were submitted to the Friedrich-Loeffler-Institut to be analyzed for the presence of SBV-genome
The deletion found in the brain and unidentifiable organ sample was located in a genomic region which has been previously described as a mutation hot spot [14,28], and affected the M-segment based SBV realtime RT-PCR
Summary
Schmallenberg virus (SBV), which emerged in 2011 in Central Europe, is transmitted by Culicoides biting midges and causes no or only mild non-specific and short-lived clinical signs in adult ruminants [1], but can induce premature birth, stillbirth, or severe malformations in the offspring when immunologically naïve animals are infected during a vulnerable period of pregnancy [2]. Within the insect vector season, in which the virus was detected for the first time (year 2011), SBV spread very rapidly across the European ruminant population. SBV circulated further in Germany, albeit at a much lower level. In summer and autumn 2014, the virus circulated again widely in continental Europe [7] and in the following winter the frequency of offspring displaying SBV-induced malformation increased. In 2016 and in 2019 the virus circulated again on a larger scale in the European ruminant population and in the following winters (2016/17 and 2019/2020) an increasing number of malformed calves and lambs were born [8,9,10,11]
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