Effect of Statin Treatments on Highly Pathogenic Avian Influenza H5N1, Seasonal and H1N1pdm09 Virus Infections in BALB/c Mice

Abstract

Statins are used to control elevated cholesterol or hypercholesterolemia, but have previously been reported to have antiviral properties. Aims To show efficacy of statins in various influenza virus mouse models. Materials & methods BALB/c mice were treated intraperitoneally or orally with several types of statins (simvastatin, lovastatin, mevastatin, pitavastatin, atorvastatin or rosuvastatin) at various concentrations before or after infection with either influenza A/Duck/ MN/1525/81 H5N1 virus, influenza A/Vietnam/1203/2004 H5N1 virus, influenza A/ Victoria/3/75 H3N2 virus, influenza A/NWS/33 H1N1 virus or influenza A/CA/04/09 H1N1pdm09 virus. Results The statins administered intraperitoneally or orally at any dose did not significantly enhance the total survivors relative to untreated controls. In addition, infected mice receiving any concentration of statin were not protected against weight loss due to the infection. None of the statins significantly increased the mean day of death relative to mice in the placebo treatment group. Furthermore, the statins had relatively few ameliorative effects on lung pathology or lung weights at day 3 and 6 after virus exposure, although mice treated with simvastatin did have improved lung function as measured by arterial saturated oxygen levels in one experiment. Conclusion Statins showed relatively little efficacy in any mouse model used by any parameter tested.

Roles of the Mevalonate Pathway and Cholesterol Trafficking in Pulmonary Host Defense

“…Finally, statins have been examined in murine models of influenza A pneumonia. Collectively, it has been shown that several statins have no significant effect on viral clearance, lung injury, weight loss, or mortality [169], although one group found reduced survival in simvastatin-treated mice [170]. …”

Multi-Omics Studies towards Novel Modulators of Influenza A Virus-Host Interaction

“…In particular, anti-influenza activity was reported for benzbromarone, ambraxol and tannic acid [168][169][170]. Kinase inhibitors, such as dinaciclib, flavopiridol, SNS-032, and MK2206, and TNF inhibitors, such as etanercept, adalimumab and infliximab, as well as a lipid-lowering simvastatin and antibacterial vancomycin, rifampicin, and erythromycin, were also reported to possess anti-IAV activity [13,104,107,108,116,128,129,147,166,170]. Interestingly, some of the identified inhibitors could be used for treatment of pain and inflammation associated with severe infections [96] (Patent US 20130123345 A1).…”

The controversy over H5N1 transmissibility research

“…81 In a much larger study, several different statins were tested against several different influenza viruses in BALB/c mice. 82 No meaningful evidence of protection was shown, but again the infecting dose of virus was highly lethal. Moreover, treatment was given for only a few days, and it is well known that early cessation of statin treatment during an inflammatory illness in both mice and humans leads to a rebound hypercytokinemia and increased mortality.…”

“…81,82 For example, studies by several virologists have yet to show that statins are effective in mouse models of influenza, yet many human studies suggest that they are (see above). There is no ready explanation for these discordant results, but it is worth noting that although the molecular mechanisms for the inflammatory responses of humans and mice are in many ways similar, they are quantitatively very different.…”