Cellular Garbage Collectors Beat West Nile, Study ShowsElizabeth Lopatto
Augmenting the body’s innate ability to rid itself of “garbage” that regularly builds up in human cells may help defend against the West Nile and chikungunya virus, and slow the spread of HIV, scientists said.
Mice infected with chikungunya, a mosquito-borne illness in humans, were given a peptide that’s known to rev up the cleaning system for cells, said Beth Levine, a professor at the University of Texas Southwestern Medical Center in Dallas who led the study. About 37 percent survived, compared to none in the control group, according to the study today in the journal Nature. In mice with West Nile disease, 20 percent survived.
While scientists were aware that the cleansing process called autophagy occurred in cells, this is the first agent known to increase it, a potential key to fighting aggressive pathogens in the future, Levine said in a telephone interview.
“Autophagy is a survival mechanism, to get rid of garbage,” said Kay MacLeod, an associate professor at the University of Chicago, in a telephone interview. She wasn’t involved in the study. “This peptide is waking the cleaning person up, and getting them back on the job.”
In cell cultures, introduction of the peptide called Tat-Beclin 1 slowed replication of HIV and the foodborne illness listeria and cleared the characteristic protein of Huntington’s disease from cells, Levine reported.
Levine is looking for a pharmaceutical company to take Tat-Beclin 1, into clinical development. Until then, her group is continuing with the trials needed to register the compound with the U.S. Food and Drug Administration as an investigational new drug that may be tested in humans, she said.
The group hasn’t seen signs of toxicity, although they aren’t finished with all the tests required, Levine said.
“We’re really excited about the possibility of moving forward to address this, to find out if this will work,” Levine said in a telephone interview. She is in early phase discussions with drug companies about later research, though she declined to say which.
There is no treatment beyond symptomatic relief for West Nile or chikungunya, infections that are largely carried to humans by mosquitos. Symptoms for both can include fever, headache and nausea that can last for weeks and months.
West Nile is common the U.S., with 48 states reporting 3,969 human cases and more than 160 deaths last year, according to the U.S. Centers for Disease Control and Prevention. The largest outbreaks happened in Greece, Israel, Romania, Russia and the U.S., according to the World Health Organization. The worst cases can cause neurological damage.
Chikungunya, which isn’t yet in the U.S., has been cited in outbreaks in Africa, Asia and Europe. It can also cause severe joint pain and long term fatigue, and is particularly dangerous to the very young and the elderly.
Levine’s group discovered the protein that led to this peptide 15 years ago, and has been studying it since.
Cell structures called lysosomes regularly clear debris, invaders, and defective proteins to keep cells from choking. The lysosomes rip apart the material, spitting useful parts back into the cell, where they can be reused in the autophagy process.
Over the last several years, researchers have found links between autophagy and heart disease, diabetes, some brain illnesses, cancer, and infections, said Daniel Klionsky, a professor of life scientists at the University of Michigan, who studies the process.
The implications of Levine’s study may end up being “huge because the connections of autophagy and disease are tremendous,” said Klionsky, who wasn’t involved in the research, by telephone.
Cultures to Mice
Levine’s group tested its peptide first in cell cultures, where Tat-Beclin 1 cleared small aggregations of the characteristic protein of Huntington’s disease. It decreased the survival of the chikungunya virus, West Nile, HIV and listeria in cell culture as well.
Then the group tested mice. By the 20th day of infection with the chikungunya virus, all the control mice were dead, compared to 37 percent of those dosed with Tat-Beclin 1.
In the West Nile mice, all control mice died by day 10. By day 20, about 20 percent of the treated mice were still alive.
The research was funded by National Institutes of Health grants.