More work needs to be done before this discovery can be translated into a therapeutic solution, but researchers have gained insights into why some people become infected with a pathogen and others don't.
As far-fetched as it seems, everyday drugs to lower cholesterol may protect you against scores of infection diseases, including typhoid fever, malaria, and chlamydia.
That’s what researchers at Duke University are reporting in in Proceedings of the National Academy of Sciences, where a molecular biologist, intrigued by the story of the Irish immigrant “Typhoid Mary,” took another look at one of the most famous cases in the history of infectious disease.
Mary Mallon was a cook who was apparently immune to the bacteria she carried in her gallbladder, but infected more than 50 people in New York City between 1900 and 1915. Still, many people who came in contact with her never contracted typhoid. Molecular biologist Dennis C. Ko, MD, PhD, wondered what made the difference.
Ko and his team used hundreds of cell lines from healthy human volunteers, and exposed them to same-size doses of Salmonella Typhi, which was tagged with green fluorescent marker. They watched for genetic variations between those cells that had high rates of bacterial invasion and those that didn’t, and found their answer: a single nucleotide of DNA, in a gene VAC14, was associated with how rapidly the bacteria spread.
Researchers were able to confirm this by knocking out the gene, and the bacteria invaded even more easily, as seen by the fluorescent marker. They found that that the cells more vulnerable to invasion had elevated levels of cholesterol, and that the bacteria latched on to it to attach to the host cells.
Did this discovery translate beyond the experiment?
Ko asked a Vietnamese researcher studying typhoid fever to test DNA for a group of 1000 Vietnamese subjects, half of whom had typhoid fever and half who did not. She found that the VAC14 gene variant was associated with a moderate risk of typhoid fever. A member of the team also added a cholesterol drug to the water with zebrafish, and then injected with the fish with Salmonella Typhi. The fish given the cholesterol drug, ezetimibe, were more likely to survive.
More experiments are planned. “By figuring out the mechanism, you an uncover possible therapeutic strategies that you wouldn’t think about when just looking at a gene,” Ko said in a statement.
There’s much more work to be done before this approach can be tried in a clinic, but Ko is enthused that these techniques could shed light on why some people are more suspectible to infection than others, and how existing therapies could offer protection.
“This is just the first step,” he said.
Alvarez MI, Glover LC, Luo P, et al. Human genetic variation in VAC14 regulates salmonella invasion and typhoid fever through modulation of cholesterol [published August 21, 2017]. PNAS, 2017. DOI: 10.1073/pnas.1706070114