Dennis Ko, assistant professor at the department of molecular genetics and microbiology, Duke University, US, and an author of the study published last month (August) in PNAS, said his team was researching on why some people were more susceptible to typhoid than others when they stumbled on the cholesterol link.
“It was pretty unexpected,” Ko says. “We found a human genetic difference (single nucleotide polymorphism or SNP) associated with the susceptibility of cells to being invaded by Salmonella typhi, the typhoid bacterium. By screening cell lines from hundreds of people in the lab, we found that the SNP regulates the levels of a gene called VAC14.”
“If you have the version of SNP that results in lower invasion in our cell-based model, the odds of getting typhoid fever were also reduced.”
Dennis Ko, Duke University
According to Ko, the VAC14 gene affects S. typhi entry into host cells and this was in line with earlier studies which showed that S.typhi directly binds to cholesterol in the plasma membrane of host cells.
To confirm the laboratory finding, Ko contacted Sarah Dustan, a typhoid researcher at the Oxford University Clinical Research Unit in Vietnam. When she carried out genome tests on 496 typhoid-infected people and 500 healthy people, the results showed consistency with Ko’s findings.
“I was very happy to see that if you have the version of SNP that results in lower invasion in our cell-based model, the odds of getting typhoid fever were also reduced,” Ko tells SciDev.Net.
“Since genetic difference was also associated with risk of typhoid fever, we tested to see whether cholesterol levels in these cells were being altered. We then decided to test whether using a cholesterol-lowering drug could affect S.typhi infection in a zebrafish model,” Ko explains.
Zebrafish has many of the same immune cell types and signalling pathways as humans do. When Ko’s team injected cholesterol-lowering drugs into zebrafish, it was found eliminating the bacteria.
Typhoid fever is a life-threatening disease with the risk of death as high as 20 per cent if left untreated. But its symptoms is similar to many other infectious diseases including fever, weakness, abdominal pain, constipation and headache. It is spread by eating or drinking food or water contaminated with the faeces of an infected person. In 2015, there were 12.5 million new cases worldwide with most cases occurring in India. Ko is optimistic about developing cholesterol-lowering drugs to protect people against typhoid fever. “The presence of a human genetic difference which confers resistance makes me optimistic that targeting the same mechanism through a drug could potentially be beneficial. But, again, much work remains to be done,” he says.
Sangkot Marzuki, head of the Jakarta-based Eijkman Research Institute, says many questions remain unanswered. “In practical terms, how will we use cholesterol-lowering drugs as a preventive agent? Will we use it when there is a typhoid outbreak only? Will we give it to the whole population? Is there any side-effect to this drug? I think we need to answer those questions.”
Marzuki, however, thinks that research on the role of cholesterol is important for Asia where people are exposed to several infectious diseases.
This piece was produced by SciDev.Net’s Asia & Pacific desk.