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.
Highlights
Influenza A virus (IAV) infection remains a global health burden due to both seasonal IAV disease susceptibilities in young, chronically afflicted and elderly populations and the potential re-emergence of highly fatal pandemic IAV strains which do not respond to current treatments
Minimal cytotoxicity was observed for Saikosaponin A (SSa) concentrations ≤ 7.6 μΜ 48 h posttreatment on A549 cells in vitro (Supplementary Figure 1A) and 7.6 μΜ SSa selected as the maximal drug concentration used for subsequent IAV infection studies
As heightened virus proliferation and proinflammatory innate immune responses are concurrently linked to the severity of IAV-induced lung pathogenesis [13, 35, 39], the discovery of new therapeutic agents that can indirectly inhibit IAV replication whilst attenuating tissue-damaging pro-inflammatory host responses remains a critical priority
Summary
Influenza A virus (IAV) infection remains a global health burden due to both seasonal IAV disease susceptibilities in young, chronically afflicted and elderly populations and the potential re-emergence of highly fatal pandemic IAV strains which do not respond to current treatments. Vaccination strategies are well-established for influenza prevention and control, seasonal IAV vaccines exhibit decreased www.impactjournals.com/oncotarget efficacies in elderly individuals [4] and a prophylactic response against pandemic IAV strains can be delayed by lengthy vaccine production cycles. Antiviral agents are the current standard for primary care in highly susceptible individuals, treatment efficacy decreases with delayed administration times [5] and sporadic resistance is possible [6, 7]. Novel anti-IAV pharmaceutical agents must navigate a critical balance between the engagement of sufficient innate immune cell signaling to control IAV propagation and the attenuation of excessive proinflammatory and tissue damaging effectors
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
