A gene variant that affects cholesterol levels could increase a person’s risk of contracting typhoid fever while a common cholesterol-lowering medication can protect zebrafish against the bacterium Salmonella Typhi, according to a recent study by researchers at Duke University.
Intrigue for the research originally stemmed from the life of Mary Mallon, an Irish immigrant who infected more than 50 people in New York City with typhoid fever, killing three people, but was seemingly immune from the effects of the virus herself.
Dennis C. Ko, assistant professor of molecular genetics and microbiology at the Duke University School of Medicine, and a team of researchers wanted to use their study to answer why some individuals were asymptomatic from the effects of certain pathogens whereas others experienced detrimental outcomes.
The researchers first used hundreds of cells lines from healthy human volunteers and infected them with an equal dose of Salmonella Typhi that was mixed with a green fluorescent marker for visibility. They discovered that a single nucleotide of DNA, called VAC14, was associated with the level of bacterial invasion in cells.
When the researchers blocked the VAC14 gene, they found that the cells were invaded more readily and a higher number of cells were glowing brightly with the fluorescent bacteria. Surprisingly, they also found that more susceptible cells had higher levels of cholesterol, which the Salmonella bacterium uses to bind and invade host cells.
Ko then contacted Sarah Dunstan, a researcher working in Vietnam who had been studying typhoid in the country, to test the DNA of 1,000 subjects, half of whom tested positive for typhoid infection while the other half did not. Dunstan subsequently found that the VAC14 gene variant was associated with a moderately increased risk of typhoid fever.
“Discovering the mechanism was important because plenty of people are on cholesterol-lowering drugs, especially statins for high cholesterol,” Ko said. “We wondered if similar drugs could be given to reduce the risk of Salmonella infection.”
A graduate student on Ko’s team, Monica Alvarez, had experience working with zebrafish in the past so she added a cholesterol-lowering medication called ezetimibe to their water and then injected the fish with Salmonella Typhi. She found that the treated fish were more likely to survive infection than those who did not.
According to Duke, the findings give insight into the mechanisms that govern human susceptibility to infectious disease and possible avenues to protect those who are vulnerable to pathogens that hijack cholesterol to infect cells.
The study was published in detail in a recent issue of the journal Proceedings of the National Academy of Sciences.