title: Saikosaponin A inhibits influenza A virus replication and lung immunopathology.
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.
authors.affiliation: Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
authors.forename: Mubing
authors.initials: M
authors.lastname: Duan
authors.affiliation: Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.|Present address: Xinjiang Institute of Chinese Materia Medica and Ethnic Materia Medica, Urumqi, Xinjiang, China.
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Ling
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
authors.forename: Kun
authors.initials: K
authors.lastname: Xiao
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.|National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
authors.forename: Chunni
authors.initials: C
authors.lastname: Lu
authors.affiliation: Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
authors.forename: Wenbao
authors.initials: W
authors.lastname: Qi
authors.affiliation: Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
authors.forename: Zhenling
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Liao
authors.affiliation: Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
authors.forename: Yahong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
authors.forename: Weisan
authors.initials: W
authors.lastname: Chen
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D009980:Influenza A virus; D007251:Influenza, Human / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D012141:Respiratory Tract Infections / Q000188:drug therapy / Q000473:pathology* / Q000821:virology; D012503:Saponins / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D012503:Saponins; D009828:Oleanolic Acid; C025759:saikosaponin D
keywords: Immune response; Immunity; Immunology and Microbiology Section; PR8; Saikosaponin A; X-31; anti-inflammatory agent; influenza A virus