Ebola's 'Achilles heel' treads path towards new treatments

27 May 2015

A new mouse study has found a potential Achilles’ heel for the deadly Ebola virus infection, which could allow development of a new treatment. The international research team found that a gatekeeper protein called Niemann-Pick C1 (NPC1) is needed to transport Ebola virus into cells and cause infection.

Earlier this month the World Health Organisation (WHO) declared Liberia free of the Ebola virus, however, Guinea and Sierra Leone continue to fight the current outbreak, which has killed more people than all other known Ebola outbreaks combined.

Published in the online journal mBio, the researchers found mice lacking NPC1 protein were protected from Ebola infection. The study is the first to establish that NPC1 is necessary for Ebola virus infection in a mouse model.   

Study co-leader Dr John Dye of the US Army Medical Research Institute of Infectious Diseases said: “The science behind the concept of blocking the interaction between NPC1 and the virus is solid. Now, it is just a matter of powering through and identifying drugs that can inhibit NPC1 and moving them forward”. 

Earlier research by the team had found evidence in tissue cultures that Ebola takes advantage of the NPC1 protein to enter the cell’s cytoplasm. The NPC1 protein is located in cell membranes where its role is to transport cholesterol within the cell. People who lack the NPC1 protein develop a fatal disorder called Niemann-Pick disease that causes cells to become loaded with too much cholesterol and die.

The researchers challenged normal ‘wild-type’ mice (with two intact copies of the NPC1 gene and normal levels of NCP1 protein receptors), carrier mice (with just one working copy of NPC1 and half the normal levels of NPC1 receptors) and ‘knockout’ mice (lacking both copies of the gene and therefore having no NPC1 protein at all) with the Ebola virus. The wild type mice succumbed to the infection, the carrier mice were significantly resistant to the infection although not immune, and the ‘knockout’ mice were free of virus replication and completely protected against the disease.

Although a drug that could inhibit NPC1 would also disrupt the normal cholesterol handling pathway, the researchers believe the patients could tolerate the treatment for a short time. Further, as the carrier mice were partly resistant then, “this would suggest that drugs that interfere with Ebola’s interaction with NPC1 –even if some Ebola viruses are able to enter cells- could probably still provide some benefit from lethal infection” said Dr Dye.

Looking to the future, study co-leader Kartik Chadran, of Albert Einstein College of Medicine of Yhesiva University said: “Ideally, future research in humans, based on these findings, will lead to the development of antiviral drugs that can effectively target NPC1 and p revent infection not just by Ebola, but also by other highly virulent filoviruses, which also require NPC1 as a receptor”.

An antiviral drug that effectively targets NPC1 would be the first host-directed therapeutic approach to tackling Ebola virus. All other therapies in the drug pipeline for Ebola concentrate on attacking the virus. 

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