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Toosendanin suppresses African swine fever virus replication through upregulating IRF1 in porcine alveolar macrophage cultures

ABSTRACT: African swine fever virus (ASFV) is a highly infectious and lethal swine pathogen that causes severe socio-economic consequences in affected countries. Unfortunately, effective vaccine for combating ASF is unavailable so far, and the prevention and control strategies for ASFV are still very limited. Toosendanin (TSN), a triterpenoid saponin extracted from the medicinal herb Melia toosendan Sieb. Et Zucc, has been demonstrated to possess analgesic, anti-inflammatory, anti-botulism and anti-microbial activities, and was used clinically as an anthelmintic, while the antiviral effect of TSN on ASFV has not been reported. In this study, we revealed that TSN exhibited a potent inhibitory effect on ASFV GD955-38 strain in porcine alveolar macrophages (PAMs) (EC50=0.085 μM, SI = 365) in a dose-dependent manner. TSN showed robust antiviral activity in different doses of ASFV infection and reduced the transcription and translation levels of ASFV p30 protein, viral genomic DNA quantity as well as viral titer at 24 and 48 hours post-infection. In addition, TSN did not affect virion attachment and release but intervened in its internalization in PAMs. Further investigations disclosed that TSN played its antiviral role by upregulating the host IFN-stimulated gene (ISG) IRF1 rather than by directly inactivating the virus particles. Overall, our results suggest that TSN is an effective antiviral agent against ASFV replication in vitro and may have the potential for clinical use.

ORGANISM(S): Sus scrofa

PROVIDER: GSE206118 | GEO | 2022/08/08

REPOSITORIES: GEO

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Project description:African swine fever virus (ASFV) is an infectious disease with a mortality rate of nearly 100% in pigs; however, no safe commercial vaccines or antiviral drugs are currently available, which seriously threatens the global pig industry. Therefore, effective biologicals against ASFV are urgently needed. Here, we screened 138 Bacillus subtilis strains, four of which evidently inhibited ASFV replication in vitro. Pigs fed with biologics of different types from the four B. subtilis strains showed reduced pathological changes and viral loads in tissues, with a survival rate of up to 100%. The antiviral activity of B. subtilis was attributed to small-molecule metabolites, rather than to secretory proteins. A total of 169 small molecules were obtained from the metabolites of B. subtilis using LC-MS/MS, arctiin and genistein, which showed the highest inhibition efficiency, suppressing ASFV proliferation at the mid-stage of infection. These molecules acted as competitive inhibitors by complexing the ATP-binding domain of viral topoisomerase II, as demonstrated using molecular docking, biolayer interferometry binding and a competitive decatenation assay, thereby disrupting the catalytic activity of the enzyme and inhibiting ASFV replication. Furthermore, pigs administered arctiin and genistein orally showed decreased mortality and tissue damage. Collectively, these results suggest that the four B. subtilis strains screened may be preventative biologicals against ASFV infection. Our findings pave the way for ASFV prevention and control strategies in the pig industry to curb the economic losses caused by the disease. IMPORTANCE: African swine fever virus (ASFV) is a highly fatal swine disease that severely affects the pig industry. Although ASFV has been prevalent for more than 100 years, effective vaccines or antiviral strategies are still lacking. In this study, we identified four Bacillus subtilis strains that inhibited ASFV proliferation in vitro. Pigs fed with liquid biologicals or powders derived from four B. subtilis strains mixed with pellet feed showed reduced morbidity and mortality when challenged with ASFV. Further analysis showed that the antiviral activity of B. subtilis was based on its metabolites arctiin and genistein interfering with the function of viral topoisomerase II. Our findings offer a promising new strategy for the prevention and control of ASFV that may significantly alleviate the economic losses in the pig industry.

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Toosendanin suppresses African swine fever virus replication through upregulating IRF1 in porcine alveolar macrophage cultures

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