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Cholesterol-Regulating Gene Variant Found to Affect Bacterial Infection Susceptibility

NEW YORK (GenomeWeb) – Scientists at Duke University have found that a gene variant that affects cholesterol levels can potentially increase a patient's risk of contracting typhoid fever. At the same time, they discovered that a common cholesterol-lowering drug called Zetia could protect zebrafish (and possibly humans) against Salmonella typhi, the culprit behind typhoid.

The scientists' findings, published today in Proceedings of the National Academy of Sciences, provides understanding into the mechanisms that dictate human vulnerability to infectious disease. The research also highlights potential avenues to protect patients who are most vulnerable to diseases that hijack cholesterol to infect host cells.

"We need to try this approach in different model organisms, such as mice, and likely pathogens, before we consider taking this into the clinic," senior author Dennis Ko said in a statement. "Our study provides a blueprint for combining different techniques for understanding why some people are more susceptible to disease than others, and what can be done about it."

Ko and his team used hundreds of cell lines from healthy human volunteers and exposed them to the same dose of S. typhi, which was tagged with a green fluorescent marker. Ko searched for genetic differences that differentiated cells that had higher rates of bacterial invasion from those that had minimal amounts of bacteria.

Using a genome-wide association study approach called "Hi-HOST" (high-throughput human in vitro susceptibility testing), they identified a SNP that affects expression of a single nucleotide in a gene called VAC14, a phosphoinositide-regulating protein. The SNP decreases the expression of VAC14, which leads to a higher level of cholesterol in cell membranes which enhances docking of Salmonella to the host cell. 

When Ko decreased VAC14 expression using gene editing techniques, Salmonella docked and invaded more cells, glowing brightly with the green fluorescent marker. Researchers also unexpectedly found that the more susceptible cells contained higher levels of cholesterol, a crucial component of cell membranes that S. typhi binds to invade host cells.  

To see if the genetic difference was relevant to the human population, Ko reached out to Sarah Dunstan, a researcher who had been studying typhoid fever in Vietnam. When Dunstan tested DNA from 1,000 test subjects, half of whom had typhoid fever and half of whom did not, she discovered that the VAC14 gene variant was linked to a moderately elevated risk of typhoid fever.

The researchers' next step was to figure out a potential way to correct the genetic susceptibility.

"Discovering the mechanism was important because plenty of people are on cholesterol-lowering drugs, especially statins for high cholesterol" added Ko. "We wondered if similar drugs could be given to reduce the risk of Salmonella infection."  

Lead author Monica Alvarez added a cholesterol-lowering drug (ezetimibe) in a tank filled with zebrafish. Injecting the fish with S. typhi, Alvarez noticed that the treated animals were more likely to purge the bacteria out of their system and survive.

Ko and his team believe that coupling multiple genetic association studies with mechanistic dissection may open doors to new prophylactic approaches.

"Our cell-based human genetic approach is a way for us to connect cell biology to disease," he said. "By figuring out the mechanism, you can uncover possible therapeutic strategies that you wouldn't think about when just looking at the gene."