Although hantaviruses cause significant human diseases worldwide, no specific antiviral treatments are available, in part because gaps in the understanding of how the viruses enter human cells have hampered the search for therapeutics. In Europe and Asia, hantavirus strains have caused hemorrhagic fever with kidney failure, while in the Americas the viruses have caused hantavirus cardiopulmonary syndrome, a severe, sometimes fatal respiratory disease.
“They’re not influenza viruses, but they’re significant pathogens,” says Kartik Chandran, PhD, an associate professor of microbiology and immunology, and Harold and Muriel Block Faculty Scholar in Virology, at the Albert Einstein College of Medicine in the Bronx, N.Y. Like Ebola virus, which for years people thought was an exotic rare virus, hantaviruses have the potential to cause significant outbreaks and should be studied, he says.
While searching for the genes that hantaviruses use to gain entry to human cells and cause infection, Chandran and colleagues found that these viruses are highly dependent on cholesterol in cell membranes, and lowering cholesterol was enough to slow down or prevent the virus from replicating. Their research appears this week in mBio.
“Our work demonstrates that hantaviruses are extremely sensitive to the amount of cholesterol in the membranes of the cells they are trying to infect,” Dr. Chandran says. “Cholesterol seems to control the ability of hantaviruses to fuse with cell membranes and get into the cytoplasm, which is where all the goodies are to make more virus.”
In laboratory experiments with isolated human cells, researchers found that multiple genes involved in cholesterol sensing, regulation and production, including key components to a chemical pathway called sterol response element binding protein, or SREBP, are critical to hantaviruses gaining entry. Disrupting S1P, a chemical component of the pathway, dramatically reduced the ability of hantaviruses to infect cells, although other types of viruses like rhabdoviruses (such as rabies) and alphaviruses (such as encephalitis) could still yield infection.
“It is conceivable that cholesterol-lowering drugs could lead to treatments for hantavirus infection,” says study co-senior author John M. Dye, Jr., PhD, viral immunology branch chief at the U.S. Army Medical Research Institute of Infectious Diseases at Ft. Detrick, Md. “However, such drugs would need to reduce cholesterol levels in key hantavirus target tissues in a human, whereas typical cholesterol-lowering drugs like statins target primarily the liver. It remains to be seen if this can be done safely.”
Researchers stitched the gene encoding the hantavirus entry machinery into an innocuous virus, and studied its ability to attack isolated, mutated human cells. Their experiments identified seven genes that regulate cellular cholesterol metabolism that were involved in hantavirus infection: four that play key roles in the SREBP pathway (SREBP2, S1P, S2P, and SCAP) and three that encode cholesterol biosynthetic enzymes (LSS, SQLE, and ACAT2). They also found that S1P is required for hantavirus cell entry and infection; and found that inhibiting S1P could hamper hantavirus infection, among other results.
While other human viruses also depend on cholesterol to gain entry, the requirement for these particular genes reflects that hantaviruses are sensitive to cellular cholesterol “to an unusual degree,” Dr. Chandran says. Additional studies are required to better understand precisely why hantaviruses are so dependent on cholesterol, and if that characteristic is shared by other viruses in the Bunyavirus family, he says.
The work is part of a series of studies by Drs. Chandran and Dye looking at how viruses enter cells to cause infection and disease. Another study showing that Ebola virus requires the Niemann-Pick C1 (NPC1) protein to infect and kill mice was published in mBio on May 26.
-- Karen Blum