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Akabane virus (AKAV), Aino virus, Peaton virus, Sathuperi virus, and Shamonda virus are arthropod-borne viruses belonging to the order Elliovirales, family Peribunyaviridae, genus Orthobunyavirus. These viruses cause or may cause congenital malformations in ruminants, including hydranencephaly, poliomyelitis, and arthrogryposis, although their pathogenicity may vary among field cases. AKAV may cause relatively severe congenital lesions such as hydranencephaly in calves. Furthermore, strains of AKAV genogroups I and II exhibit different disease courses. Genogroup I strains predominantly cause postnatal viral encephalomyelitis, while genogroup II strains are primarily detected in cases of congenital malformation. However, the biological properties of AKAV and other orthobunyaviruses are insufficiently investigated in hosts in the field and in vitro. Here, we used an immortalized bovine brain cell line (FBBC-1) to investigate viral replication efficiency, cytopathogenicity, and host innate immune responses. AKAV genogroup II and Shamonda virus replicated to higher titers in FBBC-1 cells compared with the other viruses, and only AKAV caused cytopathic effects. These results may be associated with the severe congenital lesions in the brain caused by AKAV genogroup II. AKAV genogroup II strains replicated to higher titers in FBBC-1 cells than AKAV genogroup I strains, suggesting that genogroup II strains replicated more efficiently in fetal brain cells, accounting for the detection of the latter strains mainly in fetal infection cases. Therefore, FBBC-1 cells may serve as a valuable tool for investigating the virulence and tropism of the orthobunyaviruses for bovine neonatal brain tissues in vitro.

Background Akabane virus (AKAV) is divided into five genogroups (I to V), and strains of different genogroups exhibit marked differences in pathogenicity. We isolated a genogroup II AKAV strain, TJ2016, in China in 2016, but its virulence remains unknown. The pathogenic potential of other genogroup II strains isolated in China also remains uncharacterized. The objectives of this study were to determine the pathogenicity of TJ2016. Methods Kunming or Balb/c mice at 7 days or 8 weeks of age were inoculated with TJ2016 by intracerebral (IC), intraperitoneal (IP), subcutaneous (SC), or intramuscular (IM) routes. Clinical signs, pathological alterations, and AKAV distributions in the inoculated mice were monitored and analyzed. Results Virus inoculations by the IC route resulted in 75% ~ 100% mortality of the inoculated mice regardless of the mouse strains or ages. Virus inoculations by the IP route killed 75% to 100% of the suckling mice but killed no adult mice. All the mice inoculated via SC and IM routes survived until the end of the trial. AKAV was detected only in the brains of the mice that died or were euthanized before the end of the experiment. The AKAV antigens were only identifiable within neuronal cells. Brain lesions such as proliferation and infiltration of microglial cells, perivascular cuffing (PVC) of lymphocytes and macrophages, neuronal degeneration/necrosis, vascular dilatation and congestion, etc., were observed only in the mice that died or were euthanized before the end of the experiment. Conclusions We characterized the virulence of TJ2016 by inoculating suckling and adult mice via different routes and established experimental mouse models, which holds significant implications for vaccine/drug development and further research on viral pathogenesis.

Akabane virus (AKAV) is a Simbu serogroup virus that can cause congenital abnormalities in ruminants. In 2010, an AKAV-7 strain exhibiting different characteristics and belonging to a distinctive genogroup compared to previous AKAVs was isolated in South Korea. Although this novel pathogenic AKAV-7 has been discovered, in vivo studies on AKAV-7 are currently insufficient due to limitations of using large animals and suckling mice. Therefore, the development of a novel small animal model for AKAV studies is necessary. Type I interferon receptor knock out (IFNAR1 KO) mice are widely employed as an infection model for Bunyavirales viruses. Here, we evaluated the suitability of IFNAR1 KO mice as a small animal model for AKAV infection. IFNAR1 KO mice inoculated with AKAV-7 strain by intraperitoneal (IP) and subcutaneous (SC) routes showed 100% mortality with high viral loads in organs and histopathological changes in the spleen and liver. These findings suggest that IFNAR1 KO mouse is susceptible to AKAV-7 infection and suitable for use as a uniformly lethal mouse model of AKAV-7. Furthermore, IFNAR1 KO mice vaccinated with the AKAV vaccine showed full protection against AKAV-7 challenge, suggesting that IFNAR1 KO mice might be useful as an animal model for AKAV vaccine studies.

•A short fragment of the nucleoprotein of Schmallenberg virus has been identified as candidate subunit vaccine.•The candidate subunit vaccine reduces viraemia in infected mice.•The subunit vaccine shares high sequence homology with the nucleoproteins of the members of the Simbu serogroup. Schmallenberg Virus (SBV), an arbovirus from the Peribunyaviridae family and Orthobunyavirus genus, was discovered in late 2011 in Germany and has been circulating in Europe, Asia and Africa ever since. The virus causes a disease associated with ruminants that includes fever, fetal malformation, drop in milk production, diarrhoea and stillbirths, becoming a burden for small and large farms. Building on previous studies on SBV nucleoprotein (SBV-N) as a promising vaccine candidate, we have investigated the possible protein regions responsible for protection. Based on selective truncation of domains designed from the available crystal structure of the SBV-N, we identified both the N-terminal domain (N-term; Met1 – Thr133) and a smaller fragment within (C4; Met1 – Ala58) as vaccine prototypes. Two injections of the N-term and C4 polypeptides protected mice knockout for type I interferon (IFN) receptors (IFNAR-/-) challenged with virulent SBV, opposite to control groups that presented severe signs of morbidity and weight loss. Viremia analyses along with the presence of IFN-γ secreted from splenocytes re-stimulated with the N-terminal region of the protein corroborate that these two portions of SBV-N can be employed as subunit vaccines. Apart from both proteinaceous fragments being easily produced in bacterial cells, the C4 polypeptide shares a high sequence homology (∼87.1 %) with the corresponding region of nucleoproteins of several viruses of the Simbu serogroup, a group of Orthobunyaviruses that comprises SBV and veterinary pathogens like Akabane virus and human infecting viruses like Oropouche. Thus, we propose that this smaller fragment is better suited for vaccine nanoparticle formulation, and it paves the way to further research with other related Orthobunyaviruses.

Akabane virus infection can cause abortion, stillbirth in pregnant ruminants, and congenital malformations in newborns. It is prevalent in most regions of Asia, as well as parts of Africa and Europe, causing severe impacts on the livestock industry. Inactivated vaccines are one of the effective means of disease prevention. In this study, an AKAV strain (CH-JL-01-2022) belonging to genetic group I was isolated, and based on this strain, an inactivated vaccine was developed, with screening conducted for the inactivating agent and adjuvant. Formaldehyde can completely inactivate AKAV, and mixed with the Imject ® Alum adjuvant can induce the high differentiation of CD4 + and CD8 + T-cells and produce high levels of TNF-α. High titers of neutralizing antibodies can be detected 21 days post-vaccination with inactivated virus and adjuvant mixture The viral load and lesions in some organs after virus challenge can be reduced. It was found that formaldehyde is the optimal Inactivating agent and Imject ® Alum is the best adjuvant, laying a foundation for the development of AKAV vaccines.

Background Akabane virus (AKAV) is an arthropod-borne virus that causes congenital malformations and neuropathology in cattle and sheep. In South Korea, AKAVs are classified into two main genogroups: K0505 and AKAV-7 strains. The K0505 strain infects pregnant cattle, leading to fetal abnormalities, while the AKAV-7 strain induces encephalomyelitis in post-natal cattle. The pathogenicities of K0505 and AKAV-7 strains differ significantly; however, the specific gene in the AKAV-7 strain that drives its pathogenicity remains unidentified. In this study, changes in viral replication and pathogenicity were investigated, particularly when the S segment of AKAV-7 was mutated using a T7 RNA polymerase-based reverse genetics (RG) system. Results The rAKAV-7ΔNSs virus, with a deletion in the NSs protein of the wild-type AKAV-7 virus (wtAKAV-7), and the rAKAV-7(S-K0505) virus, where the S segment of wtAKAV-7 was reassorted with that from the wild type K0505 strain (wtK0505), were successfully rescued. The rAKAV-7ΔNSs virus demonstrated impaired replication in Vero cells and exhibited reduced mortality and RNA viral load in the organs of suckling mice compared to the wtAKAV-7. The rAKAV-7(S-K0505) virus displayed similar growth kinetics in Vero cells and showed no significant reduction in mortality rate in suckling mice compared to wtAKAV-7. Conclusions These observations suggest that the S segment, especially the NS protein, is associated with the pathogenicity of AKAV-7. Also, the results imply that the L and M segments might explain the differences in pathogenicity between the AKAV-7 and K0505 strains. Moreover, our findings indicate the potential for reassortment between distinct genogroups of AKAVs.

Akabane virus (AKAV) is a member of the genus Orthobunyavirus, family Peribunyaviridae. In addition to AKAV strains that cause fetal Akabane disease, which is characterized by abortion in ruminants, some AKAV strains cause postnatal infection characterized by nonsuppurative encephalomyelitis in ruminants. Here, we focused on the NSs protein, a virulence factor for most viruses belonging to the genus Orthobunyavirus, and we hypothesized that this protein would act as a neurovirulence factor in AKAV strains causing postnatal encephalomyelitis. We generated AKAV strains that were unable to produce the NSs protein, derived from two different genogroups, genogroups I and II, and then examined the role of their NSs proteins by inoculating mice intracerebrally with these modified viruses. Our results revealed that the neurovirulence of genogroup II strains is dependent on the NSs protein, whereas that of genogroup I strains is independent of this protein. Notably, infection of primary cultured bovine cells with these viruses suggested that the NSs proteins of both genogroups suppress innate immune-related gene expression with equal efficiency. These results indicate differences in the determinants of virulence of orthobunyaviruses.

Background Akabane virus (AKAV) is the causative agent of an economically significant disease in ruminants, manifested notably by outbreaks of abortion and congenital abnormalities. Vaccination stands as the primary defense against this disease. However, the development of safer, more stable, and efficient AKAV vaccines, including epitope-based designs, remains unexplored. Prior work by our group has pinpointed a neutralizing epitope, 1134 SVQSFDGKL 1142 , located in the Gc protein of AKAV. We further demonstrated its high degree of conservation across diverse AKAV genotypes. Methods  We produced and verified a novel virus-like particle (VLP) by incorporating the neutralizing epitope 1134 SVQSFDGKL 1142 into a recombinant hepatitis B virus core antigen (HBcAg) scaffold. Then the immunogenicity of this VLP was evaluated by detecting the antibody titer targeting the AKAV Gc antigen and the neutralizing activity against AKAV in sera from the VLP-immunized mice. Furthermore, a preliminary indirect ELISA method was established based on this VLP for AKAV detection. Results The successful construction of VLP expressing the AKAV epitope was confirmed by using SDS-PAGE, followed by Western blot (WB) and transmission electron microscopy (TEM). Indirect ELISA results indicated that antisera from immunized mice contained antibodies specific to the AKAV Gc protein. Furthermore, neutralization assays demonstrated that the antisera could effectively neutralize AKAV in vitro and inhibit its replication in BHK-21 cells. The developed VLP-based indirect ELISA method successfully identified AKAV antibody-positive serum, with a detection sensitivity of up to a 1:1600 serum dilution. Conclusions In conclusion, we successfully constructed a VLP presenting the highly conserved neutralizing epitope of AKAV. This VLP is proved to be immunogenic and can serve as an effective coating antigen to establish an indirect ELISA method for AKAV detection. Collectively, our findings provide proof-of-concept for this epitope-presenting VLP as a promising candidate in the pursuit of a safe and effective epitope-based vaccine against AKAV and also highlight its utility as a diagnostic antigen for serological detection.

Diagnosing the cause of bovine congenital malformations (BCMs) is challenging for bovine veterinary practitioners and laboratory diagnosticians as many known as well as a large number of not-yet reported syndromes exist. Foetal infection with certain viruses, including bovine virus diarrhea virus (BVDV), Schmallenberg virus (SBV), blue tongue virus (BTV), Akabane virus (AKAV), or Aino virus (AV), is associated with a range of congenital malformations. It is tempting for veterinary practitioners to diagnose such infections based only on the morphology of the defective offspring. However, diagnosing a virus as a cause of BCMs usually requires laboratory examination and even in such cases, interpretation of findings may be challenging due to lack of experience regarding genetic defects causing similar lesions, even in cases where virus or congenital antibodies are present. Intrauterine infection of the foetus during the susceptible periods of development, i.e. around gestation days 60–180, by BVDV, SBV, BTV, AKAV and AV may cause malformations in the central nervous system, especially in the brain. Brain lesions typically consist of hydranencephaly, porencephaly, hydrocephalus and cerebellar hypoplasia, which in case of SBV, AKAV and AV infections may be associated by malformation of the axial and appendicular skeleton, e.g. arthrogryposis multiplex congenita. Doming of the calvarium is present in some, but not all, cases. None of these lesions are pathognomonic so diagnosing a viral cause based on gross lesions is uncertain. Several genetic defects share morphology with virus induced congenital malformations, so expert advice should be sought when BCMs are encountered.

Orthobunyaviruses (order Bunyavirales, family Peribunyaviridae) in the Simbu serogroup have been responsible for widespread epidemics of congenital disease in ruminants. Australia has a national program to monitor arboviruses of veterinary importance. While monitoring for Akabane virus, a novel orthobunyavirus was detected. To inform the priority that should be given to this detection, a scoping review was undertaken to (1) characterise the associated disease presentations and establish which of the Simbu group viruses are of veterinary importance; (2) examine the diagnostic assays that have undergone development and validation for this group of viruses; and (3) describe the methods used to monitor the distribution of these viruses. Two search strategies identified 224 peer-reviewed publications for 33 viruses in the serogroup. Viruses in this group may cause severe animal health impacts, but only those phylogenetically arranged in clade B are associated with animal disease. Six viruses (Akabane, Schmallenberg, Aino, Shuni, Peaton, and Shamonda) were associated with congenital malformations, neurological signs, and reproductive disease. Diagnostic test interpretation is complicated by cross-reactivity, the timing of foetal immunocompetence, and sample type. Serological testing in surveys remains a mainstay of the methods used to monitor the distribution of SGVs. Given significant differences in survey designs, only broad mean seroprevalence estimates could be provided. Further research is required to determine the disease risk posed by novel orthobunyaviruses and how they could challenge current diagnostic and surveillance capabilities.