1887

Journal of General Virology header logo

Volume 96, Issue 1

Combinations of oseltamivir and fibrates prolong the mean survival time of mice infected with the lethal H7N9 influenza virus Free

Abstract

The outbreak of human infections caused by the novel avian-origin H7N9 influenza viruses in China since March 2013 underscores the urgent need to find an effective treatment strategy against H7N9 infection in humans. In this study, we assessed the effectiveness of combinations of oseltamivir and two immunomodulators (simvastatin and fenofibrate) against H7N9 infection in a mouse model. Mice treated with oseltamivir plus fenofibrate exhibited the longest mean survival time, the largest reduction of viral titre in lung tissue, the highest levels of CD4 and CD8 T-lymphocytes, and the greatest decrease in pulmonary inflammation. Thus, the combination of oseltamivir plus fenofibrate improved the outcomes of mice infected with H7N9 virus by simultaneously reducing viral replication and normalizing the aberrant immune response. This drug combination should be considered in randomized controlled trials of treatments for H7N9 patients.

  • Received:
  • Accepted:
  • Published Online:
© 2015 The Authors
Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.069799-0
2015-01-01
2024-04-19
Loading full text...

Full text loading...

/deliver/fulltext/jgv/96/1/46.html?itemId=/content/journal/jgv/10.1099/vir.0.069799-0&mimeType=html&fmt=ahah

References

  1. An S. C., Xu L. L., Li F. D., Bao L. L., Qin C., Gao Z. C. 2011; Triple combinations of neuraminidase inhibitors, statins and fibrates benefit the survival of patients with lethal avian influenza pandemic. Med Hypotheses 77:1054–1057 [View Article][PubMed]
     [Google Scholar]
  2. Arnold R., König W. 2006; Peroxisome proliferator-activated receptor-gamma agonists inhibit the replication of respiratory syncytial virus (RSV) in human lung epithelial cells. Virology 350:335–346 [View Article][PubMed]
     [Google Scholar]
  3. Baranovich T., Burnham A. J., Marathe B. M., Armstrong J., Guan Y., Shu Y., Peiris J. M., Webby R. J., Webster R. G., Govorkova E. A. 2014; The neuraminidase inhibitor oseltamivir is effective against A/Anhui/1/2013 (H7N9) influenza virus in a mouse model of acute respiratory distress syndrome. J Infect Dis 209:1343–1353 [View Article][PubMed]
     [Google Scholar]
  4. Barnard D. L. 2009; Animal models for the study of influenza pathogenesis and therapy. Antiviral Res 82:A110–A122 [View Article][PubMed]
     [Google Scholar]
  5. Becker J., Delayre-Orthez C., Frossard N., Pons F. 2006; Regulation of inflammation by PPARs: a future approach to treat lung inflammatory diseases?. Fundam Clin Pharmacol 20:429–447 [View Article][PubMed]
     [Google Scholar]
  6. Belser J. A., Szretter K. J., Katz J. M., Tumpey T. M. 2013; Simvastatin and oseltamivir combination therapy does not improve the effectiveness of oseltamivir alone following highly pathogenic avian H5N1 influenza virus infection in mice. Virology 439:42–46 [View Article][PubMed]
     [Google Scholar]
  7. Blanc M., Hsieh W. Y., Robertson K. A., Watterson S., Shui G., Lacaze P., Khondoker M., Dickinson P., Sing G.other authors 2011; Host defense against viral infection involves interferon mediated down-regulation of sterol biosynthesis. PLoS Biol 9:e1000598 [View Article][PubMed]
     [Google Scholar]
  8. Chinetti G., Fruchart J. C., Staels B. 2000; Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm Res 49:497–505 [View Article][PubMed]
     [Google Scholar]
  9. Cuzzocrea S. 2006; Peroxisome proliferator-activated receptors and acute lung injury. Curr Opin Pharmacol 6:263–270 [View Article][PubMed]
     [Google Scholar]
  10. Delayre-Orthez C., Becker J., Guenon I., Lagente V., Auwerx J., Frossard N., Pons F. 2005; PPARalpha downregulates airway inflammation induced by lipopolysaccharide in the mouse. Respir Res 6:91 [View Article][PubMed]
     [Google Scholar]
  11. Fedson D. S. 2006; Pandemic influenza: a potential role for statins in treatment and prophylaxis. Clin Infect Dis 43:199–205 [View Article][PubMed]
     [Google Scholar]
  12. Gao R., Cao B., Hu Y., Feng Z., Wang D., Hu W., Chen J., Jie Z., Qiu H.other authors 2013; Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med 368:1888–1897 [View Article][PubMed]
     [Google Scholar]
  13. Gardner O. S., Dewar B. J., Graves L. M. 2005; Activation of mitogen-activated protein kinases by peroxisome proliferator-activated receptor ligands: an example of nongenomic signaling. Mol Pharmacol 68:933–941 [View Article][PubMed]
     [Google Scholar]
  14. Grundy S. M., Vega G. L., Yuan Z., Battisti W. P., Brady W. E., Palmisano J. 2005; Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial). Am J Cardiol 95:462–468 [View Article][PubMed]
     [Google Scholar]
  15. Hu Y., Lu S., Song Z., Wang W., Hao P., Li J., Zhang X., Yen H. L., Shi B.other authors 2013; Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance. Lancet 381:2273–2279 [View Article][PubMed]
     [Google Scholar]
  16. Li Q., Zhou L., Zhou M., Chen Z., Li F., Wu H., Xiang N., Chen E., Tang F.other authors 2014; Epidemiology of human infections with avian influenza A(H7N9) virus in China. N Engl J Med 370:520–532 [View Article][PubMed]
     [Google Scholar]
  17. Ludwig S., Pleschka S., Planz O., Wolff T. 2006; Ringing the alarm bells: signalling and apoptosis in influenza virus infected cells. Cell Microbiol 8:375–386 [View Article][PubMed]
     [Google Scholar]
  18. Mok C. K., Lee H. H., Chan M. C., Sia S. F., Lestra M., Nicholls J. M., Zhu H., Guan Y., Peiris J. M. 2013; Pathogenicity of the novel A/H7N9 influenza virus in mice. MBio 4:e00362-13 [View Article][PubMed]
     [Google Scholar]
  19. Osterholm M. T., Ballering K. S., Kelley N. S. 2013; Major challenges in providing an effective and timely pandemic vaccine for influenza A(H7N9). JAMA 309:2557–2558 [View Article][PubMed]
     [Google Scholar]
  20. Paola R. D., Cuzzocrea S. 2007; Peroxisome proliferator-activated receptors and acute lung injury. PPAR Res 2007:63745 [View Article][PubMed]
     [Google Scholar]
  21. Paumelle R., Blanquart C., Briand O., Barbier O., Duhem C., Woerly G., Percevault F., Fruchart J. C., Dombrowicz D.other authors 2006; Acute antiinflammatory properties of statins involve peroxisome proliferator-activated receptor-alpha via inhibition of the protein kinase C signaling pathway. Circ Res 98:361–369 [View Article][PubMed]
     [Google Scholar]
  22. Radigan K. A., Urich D., Misharin A. V., Chiarella S. E., Soberanes S., Gonzalez A., Perlman H., Wunderink R. G., Budinger G. R., Mutlu G. M. 2012; The effect of rosuvastatin in a murine model of influenza A infection. PLoS ONE 7:e35788 [View Article][PubMed]
     [Google Scholar]
  23. Samson M., Pizzorno A., Abed Y., Boivin G. 2013; Influenza virus resistance to neuraminidase inhibitors. Antiviral Res 98:174–185 [View Article][PubMed]
     [Google Scholar]
  24. The ACCORD Study Group 2010; Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 362:1563–1574 [View Article][PubMed]
     [Google Scholar]
  25. Xu L., Bao L., Deng W., Zhu H., Chen T., Lv Q., Li F., Yuan J., Xiang Z.other authors 2013; The mouse and ferret models for studying the novel avian-origin human influenza A (H7N9) virus. Virol J 10:253 [View Article][PubMed]
     [Google Scholar]
  26. Zheng B. J., Chan K. W., Lin Y. P., Zhao G. Y., Chan C., Zhang H. J., Chen H. L., Wong S. S., Lau S. K.other authors 2008; Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus. Proc Natl Acad Sci U S A 105:8091–8096 [View Article][PubMed]
     [Google Scholar]
  27. Zhou J., Wang D., Gao R., Zhao B., Song J., Qi X., Zhang Y., Shi Y., Yang L.other authors 2013; Biological features of novel avian influenza A (H7N9) virus. Nature 499:500–503 [View Article][PubMed]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.069799-0
Loading
Combinations of oseltamivir and fibrates prolong the mean survival time of mice infected with the lethal H7N9 influenza virus
J. Gen. Virol. 96, 46 (2015); https://doi.org/10.1099/vir.0.069799-0
/content/journal/jgv/10.1099/vir.0.069799-0
/content/journal/jgv/10.1099/vir.0.069799-0
Loading

Data & Media loading...

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error