Saikosaponin A inhibits influenza A virus replication and lung immunopathology

// Jianxin Chen 1,* , Mubing Duan 2,* , Yaqin Zhao 1,4 , Fangfang Ling 1 , Kun Xiao 2 , Qian Li 2 , Bin Li 2,3 , Chunni Lu 2 , Wenbao Qi 1 , Zhenling Zeng 1 , Ming Liao 1 , Yahong Liu 1 and Weisan Chen 2 1 Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China 2 Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia 3 National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, China 4 Present address: Xinjiang Institute of Chinese Materia Medica and Ethnic Materia Medica, Urumqi, Xinjiang, China * These authors have contributed equally to this work as first authors Correspondence to: Jianxin Chen, email: // Weisan Chen, email: // Keywords : Saikosaponin A, anti-inflammatory agent, influenza A virus, PR8, X-31, Immunology and Microbiology Section, Immune response, Immunity Received : July 05, 2015 Accepted : November 22, 2015 Published : December 02, 2015 Abstract Fatal influenza outcomes result from a combination of rapid virus replication and collateral lung tissue damage caused by exaggerated pro-inflammatory host immune cell responses. There are few therapeutic agents that target both biological processes for the attenuation of influenza-induced lung pathology. We show that Saikosaponin A, a bioactive triterpene saponin with previouslyestablished anti-inflammatory effects, demonstrates both in vitro and in vivo anti-viral activity against influenza A virus infections. Saikosaponin A attenuated the replication of three different influenza A virus strains, including a highly pathogenic H5N1 strain, in human alveolar epithelial A549 cells. This anti-viral activity occurred through both downregulation of NF-κB signaling and caspase 3-dependent virus ribonucleoprotein nuclear export as demonstrated by NF-κB subunit p65 and influenza virus nucleoprotein nuclear translocation studies in influenza virus infected A549 cells. Critically, Saikosaponin A also attenuated viral replication, aberrant pro-inflammatory cytokine production and lung histopathology in the widely established H1N1 PR8 model of influenza A virus lethality in C57BL/6 mice. Flow cytometry studies of mouse bronchoalveolar lavage cells revealed that SSa exerted immunomodulatory effects through a selective attenuation of lung neutrophil and monocyte recruitment during the early peak of the innate immune response to PR8 infection. Altogether, our results indicate that Saikosaponin A possesses novel therapeutic potential for the treatment of pathological influenza virus infections.