Simvastatin treatment showed no prophylactic effect in influenza virus‐infected mice

Glück, Brigitte; Schmidtke, Michaela; Walther, Mario; Meerbach, Astrid; Wutzler, Peter

doi:10.1002/jmv.23682

Cited by 16 publications

(12 citation statements)

References 13 publications

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“…1), treatment of BL6 mice with statins prior to and during acute MHV68 infection did not attenuate MHV68 replication but, instead, produced a mild delay in the clearance of infectious virus. These results are in agreement with similar findings in the influenza virus system, where the clearly delineated antiviral effects of statins in vitro failed to manifest in influenza virus-infected wild-type mice (20,21). In contrast, treatment of IFNAR1 Ϫ/Ϫ mice with statins dramatically reduced acute MHV68 replication in the lungs, supporting the model where MHV68 usurps type I IFN signaling to overcome the antiviral effects of statins.…”

Section: Discussionsupporting

confidence: 90%

“…For some viruses (i.e., respiratory syncytial virus and hepatitis C virus), statins decrease viral replication both in vitro and in vivo (5,18,19). In contrast, in spite of the antiviral effects of statins on influenza virus replication in tissue culture, treatment of influenza virus-infected mice with statins either has no effect on viral replication, clearance, and lung pa-thology or actually decreases survival rates (20)(21)(22). Interestingly, statin treatment of older hospitalized patients suffering from seasonal influenza correlates with improved overall survival; however, the factors directing improved survival are not known (23).…”

mentioning

confidence: 99%

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Type I Interferon Counteracts Antiviral Effects of Statins in the Context of Gammaherpesvirus Infection

Lange

Darrah

Vonderhaar

et al. 2016

J Virol

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The cholesterol synthesis pathway is a ubiquitous cellular biosynthetic pathway that is attenuated therapeutically by statins. Importantly, type I interferon (IFN), a major antiviral mediator, also depresses the cholesterol synthesis pathway. Here we demonstrate that attenuation of cholesterol synthesis decreases gammaherpesvirus replication in primary macrophages in vitro and reactivation from peritoneal exudate cells in vivo. Specifically, the reduced availability of the intermediates required for protein prenylation was responsible for decreased gammaherpesvirus replication in statin-treated primary macrophages. We also demonstrate that statin treatment of a chronically infected host attenuates gammaherpesvirus latency in a route-of-infection-specific manner. Unexpectedly, we found that the antiviral effects of statins are counteracted by type I IFN. Our studies suggest that type I IFN signaling counteracts the antiviral nature of the subdued cholesterol synthesis pathway and offer a novel insight into the utility of statins as antiviral agents. IMPORTANCEStatins are cholesterol synthesis inhibitors that are therapeutically administered to 12.5% of the U.S. population. Statins attenuate the replication of diverse viruses in culture; however, this attenuation is not always obvious in an intact animal model. Further, it is not clear whether statins alter parameters of highly prevalent chronic herpesvirus infections. We show that statin treatment attenuated gammaherpesvirus replication in primary immune cells and during chronic infection of an intact host. Further, we demonstrate that type I interferon signaling counteracts the antiviral effects of statins. Considering the fact that type I interferon decreases the activity of the cholesterol synthesis pathway, it is intriguing to speculate that gammaherpesviruses have evolved to usurp the type I interferon pathway to compensate for the decreased cholesterol synthesis activity. I ntracellular cholesterol is acquired via two major mechanisms: internalization of exogenous cholesterol via the low-density lipoprotein receptor (LDLR) and endogenous cholesterol synthesis. The latter mechanism (Fig. 1A) operates in all cell types and is positively regulated by sterol regulatory element-binding protein 2 (Srebp2). Srebp2, a transcription factor synthesized as an inactive membrane-associated precursor, is cleaved by Golgi apparatus-specific proteases under conditions of low cholesterol to release an active product (1). This active cleaved product induces expression of most enzymes involved in cholesterol synthesis, including the rate-limiting enzyme hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR) (2). Active Srebp2 also increases the expression of LDLR to promote the acquisition of exogenous cholesterol. Due to the critical role of cholesterol for cell viability, genetic disruption of Srebp2 leads to early embryonic lethality (3).Elevated plasma cholesterol levels are a potent risk factor for atherosclerosis, and the targeting of the cholesterol synth...

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Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 99%

Type I Interferon Counteracts Antiviral Effects of Statins in the Context of Gammaherpesvirus Infection

Lange

Darrah

Vonderhaar

et al. 2016

J Virol

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“…It has been shown to reduce lung inflammation in mouse models of airway injury (31–34) and bacterial infections (35–37). However, simvastatin was not shown to have a significant effect on influenza A virus pathogenesis in mice (38–40). Besides rosiglitazone and simvastatin, mainly immunomodulatory drugs were predicted to have inhibitory effects on pathological host responses to A/Anhui/1/2013 infection.…”

Section: Resultsmentioning

confidence: 99%

Influenza Virus A/Anhui/1/2013 (H7N9) Replicates Efficiently in the Upper and Lower Respiratory Tracts of Cynomolgus Macaques

Wit

Rasmussen

Feldmann

et al. 2014

mBio

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In March 2013, three fatal human cases of infection with influenza A virus (H7N9) were reported in China. Since then, human cases have been accumulating. Given the public health importance of this virus, we performed a pathogenicity study of the H7N9 virus in the cynomolgus macaque model, focusing on clinical aspects of disease, radiographic, histological, and gene expression profile changes in the upper and lower respiratory tracts, and changes in systemic cytokine and chemokine profiles during infection. Cynomolgus macaques developed transient, mild to severe disease with radiographic evidence of pulmonary infiltration. Virus replicated in the upper as well as lower respiratory tract, with sustained replication in the upper respiratory tract until the end of the experiment at 6 days after inoculation. Virus shedding occurred mainly via the throat. Histopathological changes in the lungs were similar to those observed in humans, albeit less severe, with diffuse alveolar damage, infiltration of polymorphonuclear cells, formation of hyaline membranes, pneumocyte hyperplasia, and fibroproliferative changes. Analysis of gene expression profiles in lung lesions identified pathways involved in tissue damage during H7N9 infection as well as leads for development of therapeutics targeting host responses rather than virus replication. Overall, H7N9 infection was not as severe in cynomolgus macaques as in humans, supporting the possible role of underlying medical complications in disease severity as discussed for human H7N9 infection (H. N. Gao et al., N. Engl. J. Med. 368:2277–2285, 2013, doi:10.1056/NEJMoa1305584).

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“…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]. …”

Section: A Role For Statins In Host Defense?mentioning

confidence: 99%

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

Gabor¹,

Fessler

2017

CMP

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It has become increasingly recognized that cholesterol and lipoproteins play significant roles in both lung physiology and the innate immune response. It is now known that the innate immune response and the cholesterol biosynthesis/trafficking network regulate one another, with important implications for pathogen invasion and host defense. The activation of pathogen recognition receptors and downstream cellular host defense functions are critically sensitive to cellular cholesterol. Conversely, microorganisms can co-opt the sterol/lipoprotein network in order to facilitate their own replication. Given that over 50% of adults in the U.S. have cholesterol abnormalities and pneumonia remains a leading cause of death, the potential impact of cholesterol on pulmonary host defense is of tremendous public health significance. This review addresses the emerging link between the innate immune response and sterol homeostasis, with a focus upon implications for respiratory infection. Clinical translations, including in the area of potential therapeutic development for infectious lung disease, are also discussed.

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Simvastatin treatment showed no prophylactic effect in influenza virus‐infected mice

Cited by 16 publications

References 13 publications

Type I Interferon Counteracts Antiviral Effects of Statins in the Context of Gammaherpesvirus Infection

Type I Interferon Counteracts Antiviral Effects of Statins in the Context of Gammaherpesvirus Infection

Influenza Virus A/Anhui/1/2013 (H7N9) Replicates Efficiently in the Upper and Lower Respiratory Tracts of Cynomolgus Macaques

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

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