Tuesday, May 01, 2018

mBio: Statins Suppress Ebola Infectivity In Vitro


Should we ever endure another 1918-style pandemic the medical advances made over the past 100 years - antivirals, ventilators, ICU care, and eventually a vaccine - will surely be in short supply (or late to arrive) and will only be available to a small segment of the world's population.
While wealthier nations will undoubtedly fare better than poorer ones - at least early on -  they too would eventually run out of stockpiled antivirals, hospital beds, and medical staff to care for victims. 
Vaccine development, production, and deployment takes times.  For many in the world, a pandemic would likely be over before a vaccine was available.

What is desperately needed is a reasonably safe, effective, and inexpensive medication that could lower morbidity and mortality from influenza (or other viral infections), that can be quickly produced, distributed, and self administered - even in developing countries.

For many years Dr. David Fedson – former Professor of Medicine at the University of Virginia School of Medicine and formerly Director of Medical Affairs, Aventis Pasteur MSD - has championed the idea that we should be looking at cheap, easy to produce, generic statins for this role, which he believes may help modulate the immune response.

Over the years we've looked at his proposal, and some (admittedly) conflicting studies, on the effectiveness of statins against influenza and pneumonia.
Pandemic Influenza: A Potential Role for Statins in Treatment and Prophylaxis - David S. Fedson

New Approaches to Confronting an Imminent Influenza Pandemic - Dr. Fedson and Peter Dunnill, DSc,FREng

Statins & Pneumonia: Revisited
Study: Statins, Influenza, & Mortality

Beyond pandemic influenza, we've also seen the pleiotropic effects of statins explored for other types of life threatening infections, including:
mBio Letter: Statins Suggested As Possible Treatment For MERS
Study: Statins & Cerebral Malaria
Today mBio carries a new study which looks at the effect of statins on the Ebola virus (in vitro), and finds that while it doesn't prevent viral entry into cells, it did reduce the infectivity of the virus.
While not a cure, this could (as an adjunct therapy) help reduce morbidity and mortality, and perhaps lower the transmission of the virus.
First a link, and some excerpts, from this open-access study by researchers at the CDC and UPMC, then I'll return with a bit more.

Statins Suppress Ebola Virus Infectivity by Interfering with Glycoprotein Processing

Punya Shrivastava-Ranjan a, Mike Flint a, Éric Bergeron a, Anita K. McElroya ,b, Payel Chatterjeea, César G. Albariño a, Stuart T. Nichol a, Christina F. Spiropoulou a
a Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
b Division of Pediatric Infectious Disease, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA

W. Ian Lipkin, Editor

- Author Affiliations
Mailman School of Public Health, Columbia University
Address correspondence to Christina F. Spiropoulou, ccs8@cdc.gov.


Ebola virus (EBOV) infection is a major public health concern due to high fatality rates and limited effective treatments. Statins, widely used cholesterol-lowering drugs, have pleiotropic mechanisms of action and were suggested as potential adjunct therapy for Ebola virus disease (EVD) during the 2013–2016 outbreak in West Africa.
Here, we evaluated the antiviral effects of statin (lovastatin) on EBOV infection in vitro. Statin treatment decreased infectious EBOV production in primary human monocyte-derived macrophages and in the hepatic cell line Huh7. Statin treatment did not interfere with viral entry, but the viral particles released from treated cells showed reduced infectivity due to inhibition of viral glycoprotein processing, as evidenced by decreased ratios of the mature glycoprotein form to precursor form.
Statin-induced inhibition of infectious virus production and glycoprotein processing was reversed by exogenous mevalonate, the rate-limiting product of the cholesterol biosynthesis pathway, but not by low-density lipoprotein. Finally, statin-treated cells produced EBOV particles devoid of the surface glycoproteins required for virus infectivity.
Our findings demonstrate that statin treatment inhibits EBOV infection and suggest that the efficacy of statin treatment should be evaluated in appropriate animal models of EVD.

IMPORTANCE Treatments targeting Ebola virus disease (EVD) are experimental, expensive, and scarce. Statins are inexpensive generic drugs that have been used for many years for the treatment of hypercholesterolemia and have a favorable safety profile. Here, we show the antiviral effects of statins on infectious Ebola virus (EBOV) production. Our study reveals a novel molecular mechanism in which statin regulates EBOV particle infectivity by preventing glycoprotein processing and incorporation into virus particles. Additionally, statins have anti-inflammatory and immunomodulatory effects. Since inflammation and dysregulation of the immune system are characteristic features of EVD, statins could be explored as part of EVD therapeutics.

In summary, we provide evidence that statin treatment decreases production of infectious EBOV virions in a human liver cell line (Huh7) and primary human macrophages, both of which are primary target cells for EBOV infection. Statin reduced production of infectious EBOV particles in Huh7 cells by interfering with GP processing and reducing the amount of GP1 incorporated into virus particles. 
The results of this study clearly show that statin inhibits EBOV infection. Our results, combined with statins’ known role in suppressing inflammation (74) and preserving endothelial integrity (75), pathways that are impaired in EVD, argue for a potential benefit of using statins as adjunctive therapy in patients with EVD. Ideally, the use of an antiviral that exhibits additional effects in combination with a statin has the potential both to block virus replication and to decrease the deleterious effects of inflammation on the host.
Clearly, the next step for evaluating statins for use in EVD would require testing in a nonhuman primate model of disease to ensure both safety and potential efficacy.  

        (Continue . . . )

It should be noted that the idea of treating Ebola with statins was promoted back in 2014 by Dr. Fedson (see A Practical Treatment for Patients With Ebola Virus Disease) in the Journal of Infectious Diseases during the height of the West Africa outbreak.

Apparently a small, privately funded attempt was made to incorporate statins at an Ebola treatment center in Sierra Leone, which Dr. Fedson describes in a Letter to the Editor of the JECCM in 2017.
. . .  Nonetheless, thanks to a donation from a private physician, approximately 100 Ebola patients in Sierra Leone were treated with a combination of a statin (atorvastatin) and an angiotensin receptor blocker (ARB) (irbesartan). Some of these patients also received a three-day course of clomiphene, a selective estrogen receptor modifier known to have antiviral effects against Ebola virus.
Only three inadequately treated patients are known to have died (2,26,27). Local physicians who treated these patients refused to publicly release information on their experience, but their letters and memoranda provided convincing evidence of patient benefit.
Anecdotal, based on a small cohort of patients, and used in combination with other medications - but it is another data point to consider.  For now, researchers at the CDC and UPMC see enough merit in the use of statins for Ebola to recommend moving on to nonhuman primate testing.

While the role of statins in an influenza pandemic remains debatable, we've yet another recent (2018) study to look at from researchers at St. Jude Children's Research Hospital. 

They conducted a mouse study that found that obese (but not normal weight) mice receiving prophylactic statin therapy were less susceptible to influenza infection, and had a 40% greater survivability, than obese mice receiving a placebo, writing:
Statin intervention was found to reduce influenza viral burden in the lungs 6 days post-infection though no alteration in viral titers at either earlier time points or in the wild-type animals in response to either mock or statin treatment was observed (Figure 2C). These data indicate that statin intervention may confer protective benefit in the context if influenza mediated pneumonia.
Unexpectedly, however, they also found that obese mice receiving statins were significantly more susceptible to S. pneumoniae infection, and saw a significant increase in mortality, writing:
These data indicate that statin treatment has minimal effect in wild-type animals, but can potentially confer both a protective, in the case of influenza, and a detrimental, in the case of S. pneumoniae, effect on survival following infection.
The full study in Frontiers in Cellular and Infection Microbiology can be accessed at the link below:.
Protective Capacity of Statins during Pneumonia Is Dependent on Etiological Agent and Obesity 
Erik A. Karlsson, Stacey Schultz-Cherry and Jason W. Rosch*
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, United States

Acute respiratory infections are a leading cause of death worldwide. Clinical data is conflicted regarding whether statins improve outcomes for pneumonia. Potential confounding factors including specific etiology of pneumonia as well as obesity could potentially mask protective benefit.  Obesity is a risk factor for high cholesterol, the main target for statin therapy. 
We demonstrate that statin intervention conferred no protective benefit in the context of wild-type mice regardless of infectious agent. Statin intervention conferred either a protective benefit, during influenza infection, or detrimental effect, in the case of pneumococcal infection, in obese animals. These data suggest etiology of pneumonia in the context of obesity could be dramatically altered by the protective effects of statin therapy during bacterial and viral pneumonia.
        (Continue . . . )

This study suggests that statins could be a double-edged sword, at least in obese mice with pneumonia. Whether these results are representative of prophylactic statin therapy in humans is another matter entirely, and I have to imagine we'd have seen a safety signal by now if it were a big factor.

Instead, we continue to see studies suggesting the opposite; that statins may actually improve outcomes from CAP (Community Acquired Pneumonia) - which are admittedly a mix of viral and bacterial strains (see Role of Statins in Treatment and Prevention of Community-acquired Pneumonia:A Meta-analysis. - Abstract).
The problem with statins is that these are are cheap, generic drugs.  They provide little financial incentive for their manufacturers to mount expensive human trials in order to prove their effectiveness against malaria, pneumonia, sepsis, Ebola, or influenza.
So, while the evidence continues to suggest benefits to using statins for `off label’ purposes, definitive proof of their effectiveness may be a long time in coming.

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