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A new treatment option for Ebola virus

On January 14, 2016, the World Health Organization (WHO) declared the end of Ebola virus transmission in Liberia, a country that was worst hit by the 2014 outbreak with more than 4800 deaths reported as of March 2016. Previously, Guinea and Sierra Leone, two other West African countries severely impacted by Ebola, were also declared free of Ebola transmission on December 29, 2015 and November 7, 2015, respectively. These declarations mark the end of one of the worst Ebola outbreak, in which, according to the WHO nearly 29,000 people became ill, and 11,314 lost their lives during a short period of two years.

Those who survived the infection suffer from a myriad of health conditions with symptoms ranging from joint pain, vision problems, headaches, memory loss, trouble sleeping and hearing. Ebola experts believe that the virus can survive in certain body fluids, such as semen and ocular fluid even after recovery, although it is not known for how long the virus persists and is transmissible to others. The WHO has also warned that various small outbreaks may occur in previously infected populations in future, especially in Liberia, Sierra Leone, and Guinea. The global health community must be ready with an active surveillance and emergency response system to prevent another outbreak of this magnitude.

Image Courtesy: European Commission DG ECHO (www.flickr.com/photos/69583224@N05/14592031507), Licensed under the Creative Commons Attribution-NoDerivs 2.0 Generic | Flickr
Image Courtesy: European Commission DG ECHO (www.flickr.com/photos/69583224@N05/14592031507), Licensed under the Creative Commons Attribution-NoDerivs 2.0 Generic | Flickr

What we know about Ebola

Ebola virus disease (EVD) also called as Ebola hemorrhagic disease is characterized by severe bleeding, organ failure and oftentimes death. It is caused by infection with members of Ebola virus family. Of the five known species of Ebola virus (Zaire, Bundibugyo, Sudan, Reston and Taï Fores), four are known to affect humans. Generally, the term Ebola virus is used to refer Zaire Ebola virus, which was responsible for the 2014 outbreak.

It is a zoonotic virus and it is believed that the virus occurs naturally in fruit bats and is transmitted from animals to humans through bodily fluids. The average case fatality rate of EVD is 50% and can be as high as 90%. EVD was first seen in 1976 in Central Africa when a mysterious illness developed among people living in a small village, Yambuku, and other surrounding areas in the Democratic Republic of Congo. In just two months, there were 280 deaths. Later investigations revealed Zaire Ebola virus to be the causative agent. Another outbreak caused by Sudan Ebola virus occurred simultaneously in South Sudan.

Since the first outbreak, there have been more than 20 outbreaks of Ebola in Africa. Most of the previous outbreaks were small; the health authorities were able to control them within a few weeks, and the outbreak occurred mostly in the central African region. The 2014 Ebola epidemic was the largest on record, mostly impacting Sierra Leone, Liberia, and Guinea. Epidemiologists tracked the origins of the outbreak to a small isolated village in Southern Guinea, near borders of Sierra Leone and Liberia.

Currently, there is no approved anti-viral medicine for treating Ebola and its symptoms, and complications are treated as they appear. However, scientists around the world are busy finding a cure that is cost-effective. A recent research article published in PLOS Pathogens suggests that interferon gamma (IFN-γ), which is an FDA-approved drug to treat chronic granulomatous disease and osteoporosis, could be used to treat the Ebola infection. Interferons, or IFNs, are a group of proteins that are made and released by a cell in response to a viral or bacterial attack.

There are three different types of IFNs based on the structure of cell surface receptor through which they work. Due to their antiviral effects, IFNs, particularly type I (IFN-α/β) are used in the treatment of many viral infections including Hepatitis B and C virus (HBV and HCV). In a previous study, type I interferon, IFN-α2b was investigated for its use in the treatment of Ebola, however the results were not entirely successful, as it was noted that treatment with IFN-α2b only caused a delay in death in Ebola-exposed monkeys. Apart from type I IFN, a type II IFN, IFN-γ has also been studied to treat viral infections including HIV, HBV, and HCV. However IFN-γ has not yet been considered for controlling the Ebola infection. In the PLOS Pathogens study, Dr. Maury and colleagues examined if IFN-γ could be used to control Ebola infection.

Figure 1. Reduction of Ebola infection in mouse macrophages on treatment with IFN-γ (Image from Bethany Rhein et al., PLOS Pathogens, 2015)
Figure 1. Reduction of Ebola infection in mouse macrophages on treatment with IFN-γ (Image from Bethany Rhein et al., PLOS Pathogens, 2015)

IFN-γ blocks Ebola infection of macrophages

To assess the effect of IFN-γ on the virus growth, the lead author of this paper, Dr. Bethany Rhein and colleagues treated mouse macrophages, a type of immune cells that play a vital role in viral propagation and spread of infection, with a mouse IFNγ and then 24 hours later infected those mice with a recombinant Ebola virus. The research team had previously identified these immune cells to be highly permissive to persistent Ebola infection. These experiments showed that murine IFN-γ reduced Ebola infection in a dose-dependent manner, meaning higher doses provided more protection; a higher dose even providing greater than 95% protection.

The authors observed a similar effect of IFN-γ on Ebola virus when they used human macrophages instead of the mouse. These results suggested that IFN-γ has the potential to reduce Ebola infection.

IFNγ blocks viral replication

Having shown that the IFN-γ has the capacity to reduce Ebola infection, the authors next investigated which components of the viral life cycle are impacted by IFN-γ. This process entails looking for effects of IFN-γ on production for viral RNA at different times post-infection. Their results showed that viral RNA synthesis was significantly reduced at later time points, indicating that the IFN-γ affects later events of viral life cycle. The authors then further narrowed these life cycle events, by comparing IFN-γ with an inhibitor, cycloheximide, known to inhibit viral RNA production. Both cycloheximide and IFN-γ suppressed viral RNA production equally. These findings indicate that IFN-γ treatment interferes with RNA synthesis and blocks viral replication.

IFN-γ protects mice from lethal Ebola infection

All the experiments until now showed encouraging results that IFN-γ blocks Ebola infection of the macrophages. The next big question was whether IFN-γ will have the same effect on live animals.

To test their theory, the authors infected mice with Ebola virus and injected IFN-γ into these mice at different time points relative to Ebola infection. These time points were: at the time of Ebola infection, six hours before infection, 24 hours before and 24 hours after Ebola infection. The study showed all of the mice treated with IFN-γ had higher rates of survival than the untreated mice. Furthermore, all mice treated with IFN-γ 24 hours after Ebola infection survived. Similarly, these mice also showed lowest virus levels in their blood. These results indicate that IFN-γ administration after infection may have a protective effect against Ebola.

The findings of this paper are promising, leading authors to believe that “IFN-γ may serve as an effective prophylactic and/or therapeutic drug against EBOV infection”. As previously stated, IFN-γ is already approved by FDA to treat certain chronic medical conditions and is safe to use in humans. The scientists are hopeful that it can be used as a novel antiviral therapy to curb transmission during future epidemics. The authors also suggest that administering IFN-γ to people recently exposed to the virus, or at high risk of exposure, could be an effective prophylactic measure.

Another way to use IFN-γ would be to use it as a post-infection measure, as the study shows that all the mice who were given IFN-γ 24 hours after infection survived, thus indicating that IFN-γ can be used as a post-infection drug. However, the incubation period of Ebola, the time interval from infection to development of symptoms, is two to 21 days. Because there is a long latency period, many people will not know if they are infected with the virus for a long time. Future tests must determine if IFN-γ will still be an effective post-infection measure many days after exposure and infection.

It is always scary when new infectious diseases appear. The fear the follows an infectious disease outbreak, such as the Ebola outbreak in West Africa and more recently the global Zika outbreak, often motivates scientists to scale-up discovery research, including the search for a preventative vaccine or a cure. Although the WHO has declared West Africa Ebola-free, there were reports of some isolated cases after the announcement. It is critical that the scientific community is equipped with effective treatment options to make sure that any future cases do not lead to major epidemics. The findings in PLOS Pathogens give us a ray of hope that IFN-γ could be developed into an effective measure against Ebola.


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