Duke scientists have discovered that a gene variant that affects cholesterol levels could increase your risk of contracting typhoid fever. They also showed that a common cholesterol-lowering drug (ezetimibe or Zetia) could protect zebrafish against Salmonella typhi, the culprit behind the nasty infection. The findings, which appear in this week's Proceedings of the National Academy of Sciences, provide insight to human suspectibilty to infectious disease and how to protect humans.
In this study, Dennis C. Ko, M.D., Ph.D., senior author of the study and assistant professor of molecular genetics and microbiology at Duke University School of Medicine, and his team used hundreds of cell lines from healthy human volunteers and exposed them to the exact same dose of Salmonella typhi, which had been tagged with a green fluorescent marker. They then looked for genetic differences that distinguished cells that had higher rates of bacterial invasion from those that did not.
They found that a single nucleotide of DNA in a gene called VAC14 was associated with the level of bacterial invasion in cells. When they knocked out the gene, the cells were invaded more readily and more of the cells glowed brightly with green bacteria. They also unexpectedly found that those more susceptible cells had higher levels of cholesterol, an essential component of cell membranes that Salmonella binds to invade host cells. Ko then collaborated with Dr. Sarah Dunstan, who had been studying typhoid fever in humans in Vietnam, and found that the VAC14 gene was associated with a moderately elevated risk of typhoid fever.
"Discovering the mechanism was important because plenty of people are on cholesterol-lowering drugs, especially statins for high cholesterol," said Ko. "We wondered if similar drugs could be given to reduce the risk of Salmonella infection."
Monica Alvarez, a graduate student in Ko's lab and lead author on the study, injected Zebrafish with Salmonella typhi and added a cholesterol-lowering drug (ezetimibe or Zetia) to their water. She found that the treated animals were more likely to clear the bacteria out of their system and survive.
The next step for these researchers is to perform similar experiments in mice and possibly try retrospective studies in humans already taking cholesterol-lowering drugs. In addition, they hope to see if this approach can protect against other infectious diseases and other pathogens known to rely on cholesterol at some point during infection.
Image: This digitally colorized scanning electron microscopic image shows Salmonella bacteria (red) invading an immune cell (yellow). Salmonella typhi is the cause of typhoid fever. Researchers at Duke have discovered human genetic variation can impact both invasion of Salmonella into cells and typhoid fever risk in people. Image courtesy of the CDC Public Health Image Library (NIAID).