Orthobunyaviruses, including La Crosse virus (LACV), Oropouche virus (OROV), Schmallenberg virus (SBV), and Akabane virus (AKAV), pose substantial threats to global public health and livestock industries. This review focuses on the interplay between these viruses and the host immune systems, highlighting key mechanisms of viral entry and immune evasion. The viruses exploit vulnerabilities in host innate immunity, particularly through nonstructural protein NSs, which disrupts type I interferon signaling and transcriptional machinery. Additionally, this review delineates how host restriction factors counteract viral proliferation through compartmentalized defense mechanisms including BST-2 and MxA. The review also discusses antiviral strategies, including vaccines and inhibitors. Hence, this review synthesizes current knowledge on host recognition, immune evasion, and therapies for Orthobunyaviruses infections (focusing on LACV, OROV, AKAV, SBV) to guide targeted antiviral and broad-spectrum countermeasure development against emerging Orthobunyaviruses threats.

Rotavirus A (RVA) is a prevalent cause of enteric diarrhea in infants, bovine, pigs, and sheep globally. Currently, the G6P[1]‐type rotaviruses are prevalent in sheep or goat in Bangladesh, Turkey, and Uganda. However, this genotype has not been reported in Chinese sheep or goat. Therefore, 12 anal swabs were collected from diarrheal sheep in Gansu Province, China, in 2023 and tested for rotavirus using reverse transcription‐polymerase chain reaction (RT‐PCR). Pathological sections and immunohistochemistry were used to observe pathological changes and rotavirus antigens in the duodenum, respectively. The sheep rotavirus was isolated in MA‐104 cells and characterized through indirect immunofluorescence and transmission electron microscopy. The genes of the strain were obtained using the next‐generation sequencing technology and analyzed phylogenetically. One sheep was positive for rotavirus by RT‐PCR, and immunohistochemistry revealed numerous rotavirus antigens in the apical portion of the duodenal villi. Transmission electron microscopy revealed that the strain was characterized by virus particles that were “wheel‐shaped” and measured 70–80 nm in size. The gene constellations of this strain is G6‐P[1]‐I2‐R2‐C2‐M2‐A11‐N2‐T6‐E2‐H3. BLASTn and phylogenetic tree analyses suggest that this strain is likely a recombinant of human rotavirus, goat rotavirus, and bovine rotavirus. The comparison of amino acid similarities revealed three differences in the key antigenic epitopes of the VP7 and VP4 proteins between the GO34 strain and this study strain despite the identical gene constellations of the two strains. To date, this is the first report of this constellation of RVA being found in sheep.

Orf (ORF) is an acute disease caused by the Orf virus (ORFV), and poses a certain threat to animal and human health. Live attenuated vaccines play an important role in the prevention and control of ORF. The effectiveness of the live attenuated Orf virus vaccine is influenced by several factors, including the genomic match between the vaccine strain and circulating epidemic strains. Genomic differences between an ORFV epidemic strain (ORFV-2W) and a vaccine strain (ORFV-1V) were identified in this study via analysis of multiple sequence alignments, phylogenetic trees, and single nucleotide polymorphisms. Phylogenetic analysis revealed that ORFV-2W and ORFV-1V were closely related, with a whole genome homology of 99.8%. Furthermore, a deletion in the non-coding region at the end of the whole genome of ORFV-1V was detected. Such non-essential genes in the terminal regions are usually unnecessary for virus replication but may play important roles in pathogenicity, host and tissue tropism. Single nucleotide polymorphism analysis identified three missense mutations in ORF067, ORF072, and the terminal non-coding region of ORFV-1V. Moreover, a frameshift mutation in ORF102 of ORFV-1V was detected. Mutations in individual genes and deletion of terminal non-coding regions may be related to the attenuation of the vaccine strain. These results provide useful context for improving ORFV vaccines.

Akabane virus (AKAV), an emerging arthropod-borne Orthobunyavirus, is a significant pathogen of ruminants which causes severe congenital abnormalities and recurrent outbreaks in China and other Asian countries. However, no effective therapeutic options are available. In this study, structure-based virtual screening was performed using an FDA-approved compound library to identify potential compounds targeting the AKAV Gc protein. Ten candidate compounds were identified based on their high-affinity binding to the Gc protein. Among these ten candidates, Protoporphyrin IX (PPIX) demonstrated the most potent inhibitory effect on AKAV replication in vitro. Subsequent dose-response assays confirmed the antiviral efficacy of PPIX. Additionally, PPIX demonstrated antiviral activity at the pre-entry stage of infection. Notably, co-incubation of PPIX with AKAV virions resulted in rapid inactivation of the virus. Further experiments revealed that PPIX inactivates AKAV through direct binding to the Gc glycoprotein, leading to the disruption of its spike structure. In vivo experiments showed that pre-incubation of PPIX with AKAV can effectively inhibit the infectivity and pathogenicity of AKAV in sucking mice. Our findings demonstrate that PPIX exerts potent virucidal activity against AKAV both in vitro and in vivo, underscoring its potential potential use in preventing AKAV infection.

Akabane virus (AKAV) causes abortion, stillbirth, and congenital malformations in ruminants, yet the transcriptional response of Madin–Darby bovine kidney (MDBK) cells and the roles of infection-responsive host genes in AKAV replication remain incompletely characterized. We profiled AKAV-infected and time-matched mock-infected MDBK cells by RNA sequencing at 12 and 24 h post-infection (hpi). Differentially expressed genes (DEGs) were examined using Gene Ontology functional classification and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, six DEGs were evaluated by RT-qPCR, and OAS2 and ZBP1 were assessed by overexpression in BHK-21 cells. We identified 119 DEGs at 12 hpi (82 upregulated and 37 downregulated) and 149 at 24 hpi (85 upregulated and 64 downregulated). The DEG sets were associated with antiviral defense, interferon responses, pattern recognition receptor signaling, DNA replication, cell cycle regulation, chromosome organization, and metabolism. RT-qPCR measurements were consistent with the RNA-seq trends. OAS2 and ZBP1 transcripts were significantly upregulated at 12 hpi, while ZBP1 transcript levels remained significantly elevated at 24 hpi. Overexpression of either gene was associated with reductions in AKAV Gc protein abundance, viral RNA levels, and infectious titers. These results define transcriptional changes in AKAV-infected MDBK cells and nominate OAS2 and ZBP1 as candidate host factors for further investigation, while their endogenous roles in bovine cells remain to be established.