Two Perelman School of Medicine microbiologists may have found a way to use statins, the well-known blockbuster cholesterol-lowering drugs, to fight the hantavirus, a mysterious and lethal microorganism that appeared suddenly in the US southwest over 20 years ago. That first outbreak led to the deaths of more than a dozen people, most of them in their prime. The last reported outbreak happened in Yellowstone Park in 2012.
Only about 30 known human cases of hantavirus are reported in the US each year. The respiratory syndrome caused by a hantavirus infection comes from breathing in small viral particles in the excrement of infected rodents. It starts out with flu-like symptoms that quickly deteriorate into a dangerous form of adult respiratory distress syndrome. It is among the most deadly known human viruses: 30 percent to 40 percent of people who are diagnosed die from hantavirus pulmonary fever.
A PLOS Pathogens paper by Penn microbiologists Paul Bates, PhD, and Kenneth Briley, PhD, published this month reports that four proteins key to cholesterol synthesis and uptake are highjacked by the hantavirus to enter human host cells. To identify host-cell genes needed for viral replication, Bates and Briley first used a less dangerous virus that was engineered to exhibit some characteristics of a member of the hantavirus group found in South America called Andes virus (ANDV). Although the molecular details are still being deciphered, it appears that adequate cellular cholesterol levels are needed to transport the virus into the cell.
This is not the first time that cholesterol-related proteins have been implicated in viral entry and infection but Bates says, "the hantaviruses seem to be exquisitely sensitive to the cellular cholesterol levels."
The four proteins identified by the Penn researchers are part of a protein complex that regulates cholesterol production in the cells of mammals. They found that treating cells that originated from human airways with an experimental drug that targets one of the four proteins made the cells less susceptible to infection. The experimental drug also lowers cholesterol levels in cells, so Bates wondered whether statins could be used to fight a hantavirus infection.
The researchers found that pre-treatment of human airway cells with a generic statin called mevastatin, which lowers cholesterol by a mechanism that does not involve the four proteins they identified, made the human airway cells less susceptible to ANDV infection. They tested both the experimental drug, PF-429242, and mevastatin, and both were effective against hantavirus, as measured by how many cells are infected with and without the drugs.
Bates surmises that statins might be given after a known hantavirus infection, or even prophylactically to exposed individuals.
Although the drug inhibition studies initially used the engineered virus, Bates used ANDV itself in high-containment Biosafety Level (BSL)-3 facilities in the Department of Microbiology at Penn to confirm that the results were true for ANDV as well. The next step is to test cholesterol-lowering drugs in an animal model for ANDV infection, working with collaborators to perform the animal studies in a BSL-4 at a national facility.
- Josiah Petersen, Mary Jane Drake, Emily A. Bruce, Amber M. Riblett, Chukwuka A. Didigu, Craig B. Wilen, Nirav Malani, Frances Male, Fang-Hua Lee, Frederic D. Bushman, Sara Cherry, Robert W. Doms, Paul Bates, Kenneth Briley. The Major Cellular Sterol Regulatory Pathway Is Required for Andes Virus Infection. PLoS Pathogens, 2014; 10 (2): e1003911 DOI: 10.1371/journal.ppat.1003911
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