Lowering cholesterol may help protect against typhoid

Lowering cholesterol may help protect against typhoid

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.