As Ebola Spreads: Scientists Developing New Drugs to Treat Lethal Viruses

The development of a new generation of drugs which attenuate the lethal effects of a whole range of viral and bacterial infections may benefit people suffering from less-researched diseases such as Ebola.

Reuters

The Ebola epidemic in West Africa has taken the lives of over 4,500 people so far and is the most severe outbreak of the disease since its discovery in 1976. The strain currently afflicting Guinea, Sierra Leone and Liberia has a mortality rate of approximately 70 percent; other strains not seen in the current epidemic can prove lethal in up to 90 percent of cases.

There are currently only experimental vaccines for Ebola, and these are in short supply. But the lack of proven treatments after more than four decades cannot be attributed merely to scientific impediments in R&D. Corporate profit plays a central role here: pharmaceutical companies have little interest in covering the heavy costs of researching diseases that afflict small, sporadically affected and generally poor communities.

Efforts to develop an Ebola vaccine taking place despite these conditions, mostly with government funding, have focused on halting the disease at the first stage of infection, when the virus first enters the body. That is the typical approach to anti-viral vaccines.

How Ebola kills

Like all viruses, Ebola can infect only certain species, and typically replicates in certain cells within the organism. It attacks cells comprising the inner lining of blood vessels, the liver and other organs – and also effectively evades the immune system's defense mechanism, thwarting the body's ability to fight the virus' spread in the body.

Inside each infected cell, the virus takes over its host cell's protein-making machinery for the sake of its own replication. Instead of producing the proteins the body needs, the cell finds itself enslaved to make more viruses.

But the high fatality rate of Ebola does not stem from the early stage of infection, during the incubation phase of the virus. Patients dying from Ebola generally suffer from overreaction by their own immune system to the viral attack, says Raymond Kaempfer, a professor of biochemistry and molecular biology at The Hebrew University-Hadassah Medical School. “The symptoms of vomiting, diarrhea and subcutaneous bleeding fit this explanation," he adds.

As the infected cells produce Ebola virus particles, these cells burst and spill their contents, leading to the release of cytokines as part of the natural immune response. Cytokines are molecules that signal the immune system to severely attack foreign bodies. Consequently, the attack targets the body's own tissues, and can spiral to the point of a fatal overreaction by the immune system.

Since among other targets, Ebola replicates in the walls of blood vessels, the immune system attacks the cells there too. This lethal, all-out attack by the immune system against a patient's own body is dubbed by researchers a “cytokine storm”. It typically results in massive hemorrhaging, a drop in blood pressure and the patient's eventual death.

Victim of your strong immune system

Immune system storms are far from unique to Ebola. They occur in influenza, other lethal viruses as well as acute bacterial infections. Researchers believe that the 1918 flu epidemic, which killed approximately 50 million people, had high mortality rates among young adults because cytokine storms cause the deaths of those with the strongest immune systems.

“Influenza and Ebola belong to the broader family of viruses that have in common that they kill by over-stimulating the immune response,” says Kaempfer. This being the case, researchers may be able to develop a treatment that targets the immune system's excessive response to a given infection, regardless of which intruding virus or bacterium is involved.

Clearly there is a potential downside to trying to override one's immune system. “Treatments that suppress the immune system are of course dangerous to use when one deals with an acute infection, since they'll reduce protective immunity where it is needed most," says Kaempfer. Thus, the excessive immune response must only be attenuated while leaving the normal response intact.

Moderating the immune system

Kaempfer and his colleagues have recently reported a promising discovery in this direction. They have developed a molecule that subdues – but doesn't completely shut down – the immune system's response to different pathogens, so the body doesn't wind up killing itself rather than the intruders.

“The molecule, a short peptide, protected both animals and human patients from a lethal infection," Kaempfer says. The treatment has worked well against both flesh eating bacteria and bacterial toxins, and can potentially work against viruses that cause a cytokine storm.

Such a general-purpose treatment might avoid in part a central challenge facing researchers working on anti-viral vaccines: viruses constantly mutate. The flu virus, for instance, mutates quite a lot, and rapidly: it doesn't take long for flu strains to adapt to a new vaccine, to the point that the vaccine loses its efficacy. Because of this genetic instability, says Kaempfer, it is crucial to develop a supplementary treatment that doesn't directly target a specific virus, but addresses the immune system's excessive response to the viral infection. In the case of influenza, such a treatment might help against all strains of influenza, regardless of changes they undergo as a result of mutation.

There is of course no indication whether the molecule Kaempfer and his colleagues are developing will be effective against any specific virus, such as Ebola, but he says it points to a promising path of research.

“Kaempfer's work is important and will likely lead to various therapeutic modalities in the future," says Dr. Leslie Lobel from the department of Microbiology and Immunology at Ben Gurion University. “The concept of modulating the cytokine response to diseases such as Ebola and other viruses is not new, and a growing number of researchers are now working in this direction. But this not the final say," he adds.

While such a treatment may attenuate the disease in the body and consequently save many lives, it will not completely cure the virus.

"When it comes to diseases such as Ebola, the cytokine storm causes a lot of damage and modulating it makes a difference, but it takes us only part of the way toward a comprehensive therapeutic," says Lobel. "What we are going to see in the future is a cocktail of therapeutics that will include conventional anti-viral molecules targeting specific viruses along with a drug of the sort that Kaempfer is developing, which can be applied to many different pathogens and lower fatality rates by attenuating the immune system's overreaction.”