Rabbit haemorrhagic disease (RHD) is an acute fatal disease caused by the Lagovirus rabbit haemorrhagic disease virus (RHDV), which was first reported in 1984 in China. Strains of two different genotypes (GI.1a and GI.1c) have been detected in China to date. In 2010, a new RHDV variant with a unique genetic and antigenic profile was identified in France, designated RHDV2, which rapidly spread throughout continental Europe and nearby islands. Here, we report the first outbreak of RHD induced by RHDV2 (GI.2) in rabbit farms in the Sichuan province of China. We conducted haemagglutination tests and phylogenetic analysis of the new RHDV isolate SC2020/04, which was identified as a non‐haemagglutinating strain belonging to the RHDV2 (GI.2) genogroup. Considering the serious risk of RHDV2 to the Chinese rabbit industry, the circulation of RHDV2 in the population should be carefully monitored in China.

Recent studies have reported that rabbit hemorrhagic disease virus (RHDV) infection reduced Nrf2-related antioxidant function. However, the regulatory mechanisms underlying this process remain unclear. The current study showed that the NF-κB p50 subunit partners with Keap1 to form the Keap1-NF-κB complex, which plays a key role in the inhibition of Nrf2 transcriptional activity. More importantly, upregulated Nrf2 activity delayed the death of RHDV-infected rabbits, strongly indicating the importance of oxidative damage during RHDV infection. These findings may provide novel insights into the pathogenesis of RHDV.

Rabbit hemorrhagic disease (RHD) is a highly contagious disease caused by rabbit hemorrhagic disease virus (RHDV). Previous research has shown that RHDV induces apoptosis in numerous cell types, although the molecular mechanisms underlying the apoptosis induced by RHDV are not well understood. One possible factor is non-structural protein 6 (NSP6), a 3C-like protease that plays an important role in processing viral polyprotein precursors into mature non-structural proteins. To fully establish a role for NSP6, the present study examined the effects of ectopic expression of the protein in rabbit (RK13) and human (HeLa and HepG2) cells. We found that NSP6 suppressed cell viability and promoted apoptosis in all three cell types in a dose-dependent manner. We also identified increased caspase-3, -8, and -9 activities in RK13 cell, and an increased Bax to Bcl2 mRNA ratio. Mechanistically, the ability of NSP6 to induce apoptosis was impaired by mutation of the catalytic His27 residue. Our study has shown that RHDV NSP6 can induce apoptosis in host cells and is likely an important contributor to RHDV-induced apoptosis and pathogenesis.

Purpose: Targeted treatment of solid or liquid tumors with antibody-drug conjugates (ADCs) can lead to pronounced clinical benefit. The aim of the study is to investigate the most promising combination regimens of auristatin-based conjugates in preclinical models of cancer. Experimental Design: An auristatin-based anti-5T4 antibody conjugate (5T4-ADC) and auristatin payloads were combined with the dual PI3K/mTOR catalytic site inhibitor PF-05212384 (PF-384) or taxanes in a panel of tumor cell lines. Drug interactions in vitro were evaluated using cell viability assays, apoptosis induction, immunofluorescence, mitotic index, and immunoblotting. Breast cancer cells treated with auristatin analog or 5T4-ADC were profiled by total- and phospho-proteomics. Anti-tumor efficacy of selected combinations was evaluated in 5T4-positive human breast or lung tumor xenografts in vivo. Results: In vitro, auristatin-based agents displayed strong synergistic or additive activity when combined with PF-384 or taxanes respectively. Further, treatment of 5T4-ADC plus PF-384 resulted in stronger induction of apoptosis and cell-line-specific attenuation of pAKT and pGSK. Interestingly, proteomic analysis revealed unique effects of auristatins on multiple components of mRNA translation. Addition of PF-384 further amplified effects of 5T4-ADC on translational components, providing a potential mechanism of synergy between these drugs. In human tumor xenografts, dual targeting with 5T4-ADC/PF-384 or 5T4-ADC/paclitaxel produced substantially greater antitumor effects with longer average survival as compared to monotherapy treatments. Conclusions: Our results provide a biologic rationale for combining 5T4-ADC with either PI3K/mTOR pathway inhibitors or taxanes and suggest that mechanisms underlying the synergy may be attributed to cellular effects of the auristatin payload.