Mice who did not have the NPC1 protein were found by the researchers to be completely resistant to Ebola infection.
Niemann-Pick C1 (NPC1) is found in the membranes of tiny enzyme-filled compartments known as lysosomes that digest and recycle cellular components and are located within cells.
“Our study reveals NPC1 to be an Achilles’ heel for Ebola virus infection,” says co-study leader Kartik Chandran, an associate professor of microbiology and immunology at Albert Einstein College of Medicine of Yeshiva University, NY.
“Mice lacking both copies of the NPC1 gene, and therefore devoid of the NPC1 protein, were completely resistant to infection.”
Ebola virus infection is highly lethal, proving fatal for up to 90% of those it affects. According to the Centers for Disease Control and Prevention (CDC), the 2014 Ebola epidemic – the largest in history – has led to a total of 11,140 deaths as of May 22nd, 2015.
When the Ebola virus attaches to the outer membrane of a host cell, part of the host cell’s cell membrane wraps around the virus to form a membrane-bound compartment called an endosome. This endosome carries the virus into the cell where it eventually becomes a lysosome.
For the virus to avoid being destroyed within the lysosome it exploits components of the cell, allowing it to access the cell’s cytoplasm where the virus is then able to replicate. Many of the components exploited by the virus are unknown, but the new study suggests that NPC1 could be one.
The NPC1 protein is located within cell membranes where its role is to assist transportation of cholesterol within the cell. Individuals who do not have enough NPC1 develop a fatal disorder known as Niemann-Pick disease that causes cells to become full with too much cholesterol and die.
Drugs that interfere with NPC1 ‘could provide some benefit from lethal infection’
Previously, Dr. Chandran and his colleagues discovered that NPC1 was involved in the Ebola virus gaining access to cell cytoplasm, following analysis of tissue culture in mice.
Following this work, the researchers aimed to confirm whether NPC1 was essential for the Ebola virus infection to occur. To do this, they studied Ebola infection in mice with two intact copies of the NPC1 gene (“wild type” mice) and mice without both copies of the gene (“knockout” mice).
“While the wild-type mice succumbed to the infection, the knockout mice were entirely free of virus replication and completely protected against the disease,” reports co-study leader Dr. Steven Walkley.
Another group of mice referred to as “carrier” mice had just one working copy of the NPC1 gene and, therefore, half the regular number of NPC1 receptors. These mice were significantly resistant to Ebola infection, although they were not completely immune.
“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,” says co-study leader Dr. John M. Dye, Branch Chief of Viral Immunology at the US Army Medical Research Institute of Infectious Diseases.
In humans, a treatment that blocked NPC1 would also disrupt the cholesterol transport pathway. Despite this, the authors believe that patients receiving such a treatment would be able to tolerate it, particularly as it would only be required for a short period of time.
“Ideally, future research in humans, based on these findings, will lead to the development of antiviral drugs that can effectively target NPC1 and prevent infection not just by Ebola, but also by other highly virulent filoviruses, which also require NPC1 as a receptor,” Dr. Chandran concludes.
Previously, Medical News Today reported on calls from health experts for the creation of a global research and development fund to reach solutions to global health crises such as the Ebola outbreak and the growing problem of antimicrobial resistance.
Written byJames McIntosh