(Press-News.org) Washington, D.C. -- May 26, 2015 -- A new study has demonstrated that a protein called Niemann-Pick C1 (NPC1) is critical for the Ebola virus to infect a host. The study, published in the May/June issue of mBio, the online open-access journal of the American Society for Microbiology, suggests that drugs that block NPC1 could be used to treat this deadly disease.
"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," said John Dye, Jr., PhD, co-principal investigator of the study and Viral Immunology Branch Chief, US Army Medical Research Institute of Infectious Diseases (USAMRIID), Frederick, Maryland.
Currently, there are no FDA approved treatments for Ebola, and all of the therapies in the drug pipeline focus on attacking the virus. Targeting NPC1 is the first host-based therapeutic approach.
"Our work also illustrates the value of studying rare diseases like Niemann-Pick type C, which occurs in individuals who lack the NPC1 protein. That research has provided a body of knowledge that scientists could immediately apply to Ebola once it became known that Ebola exploits NPC1 for infection," said Steven Walkley, DVM, PhD, director of the Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, New York City. Kartik Chandran, PhD, associate professor of microbiology & immunology at Einstein, was also co-principal investigator of the study. Drs. Chandran and Dye were members of the team that originally identified NPC1 as the Ebola receptor.
Previous in vitro studies have demonstrated that Ebola enters host cells by binding directly to NPC1, and that blocking the ability of the virus to engage NPC1 prevents Ebola infection
To test whether this was also true in vivo, investigators exposed three types of mice to Ebola: wild-type mice (normal mice), mice that were genetically engineered to be completely deficient in NPC1 (NPC1-/-), and mice engineered to have both a normal and a mutant NPC1 allele (NPC+/-).
While wild-type mice had high viral loads and died from Ebola infection by day nine, mice that were 100% deficient in NPC1 were completely free of the virus. "NPC1 is absolutely essential for in vivo pathogenesis, and if you can disrupt this, there are no signs of Ebola virus replication or pathogenesis," said Andrew Herbert, PhD, senior research scientist in the Viral Immunology Branch at USAMRIID.
NPC1+/- mice initially developed high levels of Ebola viremia, but these levels quickly decreased as the host immune response effectively cleared the virus. "The underlying story of an Ebola infection is that your immune system and the virus are in a race. If you can do anything to control the amount of virus that is in the system, keep it below a certain threshold, your immune system in many cases will win that race," said Dr. Dye.
The researchers also tested the efficacy of three NPC1 inhibitors in mice exposed to Ebola. Only two of the drugs provided minimal protection, but the researchers are not discouraged because it is unclear exactly how these inhibitors work. "We were not able to achieve great protection, but if we can disrupt NPC1 function more directly or more efficiently, targeting NPC1 should be a viable option for developing therapeutics against Ebola and other filoviruses," said Dr. Herbert.
Five filoviruses, including Ebola and Marburg viruses, are currently associated with severe disease in humans, "Every filovirus that we have evaluated so far requires NPC1, so if this works, we will have potentially found a silver bullet against all filoviruses," said Dr. Dye.
INFORMATION:
The American Society for Microbiology is the largest single life science society, composed of over 39,000 scientists and health professionals. ASM's mission is to advance the microbiological sciences as a vehicle for understanding life processes and to apply and communicate this knowledge for the improvement of health and environmental and economic well-being worldwide.
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