Worldwide, Salmonella enterica serovar Typhi (S. Typhi) causes around 20 million typhoid infections every year, and 1–5% of infected individuals chronically carry the pathogen, notable among which is the storied case of Typhoid Mary. Yet the genetic determinants of typhoid risk remain unclear.
Researchers performed a genome-wide association study to uncover host factors that influence the ability of S. Typhi to invade human cells—a property associated with bacterial virulence. A single-nucleotide variant dubbed rs8060947 in the lipid metabolism-related VAC14 gene, that reduced expression of the encoded protein (a phosphoinositide-regulating protein) increased the ability of S. Typhi to invade human cells; the finding was corroborated through RNA interference and CRISPR-Cas9–mediated knockout of VAC14.
By reducing the cholesterol content in the membrane surrounding host cells, VAC14, the authors found, blocks the bacterium from docking with cells. As predicted, a cholesterol-depleting compound mimicked the action of VAC14, reducing bacterial invasion in a dose-dependent fashion.
Similarly, zebrafish treated with ezetimibe, an FDA-approved cholesterol-lowering drug, exhibited increased bacterial clearance and improved survival upon exposure to S. Typhi, compared with mock-treated fish.
Genotyping of rs8060947 in 496 people with typhoid and 500 healthy people from a Vietnamese cohort revealed that individuals with the allele that increased S. Typhi invasion exhibited increased susceptibility to typhoid fever.
The findings raise the intriguing possibility that cholesterol-lowering drugs, combined with vaccines, might help protect against typhoid, according to the authors.
Lowering cholesterol may help protect against typhoid
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