A natural product, (S)-10-Hydroxycamptothecin inhibits pseudorabies virus proliferation through DNA damage dependent antiviral innate immunity

Pseudorabies virus (PRV), a member of the subfamily alphaherpesvirinae, is one of the most important pathogenes that cause acute death in infected pigs and leads to substantial economic losses in the global swine industry. Recently, China's emerging PRV mutant strains resulted in the traditionally commercial vaccines not providing complete protection. Some studies reported that PRV could infect humans and cause endophthalmitis and encephalitis under certain circumstances. It is necessary to develop alternative manners to control the virus infection. Here, by screening a library of natural products, (S)-10-Hydroxycamptothecin (10-HCPT) was revealed to inhibit PRV replication with a selective index of 270.04. And 10-HCPT inhibited PRV replication by blocking the viral genome replication but not inhibiting the viral attachment, internalization, and release. RNA interference assay showed that 10-HCPT inhibited PRV replication by targeting DNA topoisomerase 1 (TOP1). Meanwhile, 10-HCPT treatment induced DNA damage response and stimulated antiviral innate immunity. Animal challenge experiments showed that 10-HCPT effectively alleviated clinical signs and hispathology, and increased INF-β responses in lung and brain tissues of mice induced by PRV infection. The results demonstrate that 10-HCPT is a promising therapeutic agent to control PRV infection.