Genes lend natural resistance to typhoid fever, scientists find

The research team, jointly led by A*STAR's Genome Institute of Singapore (GIS) and the Oxford University Clinical Research Unit (OUCRU) in Vietnam had their findings published in the advanced online issue of Nature Genetics.

Typhoid fever is a disease caused by the bacterium Salmonella typhi and is usually contracted through the consumption of contaminated food or water. Most infected individuals recover without any lasting detriment to their health. However, a number of infected individuals are unable to clear the infection, and develop typhoid fever.

An estimated 21 million cases of typhoid fever and 200,000 deaths occur annually worldwide[1]. Without therapy, the illness can last up to four weeks, ending in death in up to 25 percent of cases. Increasing resistance to available antimicrobial agents may result in dramatic increases in case-fatality rates. Epidemics and high endemic disease rates have occurred in the Central Asian Republics, the Indian subcontinent, and across Asia and the Pacific Islands.

The scientists compared the genomic profiles of typhoid patients with healthy individuals from Vietnam and Nepal. They found that a genetic variant mapping near the human leukocyte antigen (HLA) locus showed very strong association with resistance to typhoid fever. This locus is responsible for the general activation of the immune response upon contact with invading bacteria.

Co-lead author and principal investigator at the Human Genetics unit in GIS, Dr Khor Chiea Chuen, co-lead author and principal investigator at the Human Genetics unit in GIS, said, "We were very surprised to observe such strong association between an HLA marker and individual susceptibility to typhoid. Current typhoid vaccines are not completely effective. The resistance allele acts like a 'natural vaccine', and this discovery by our team could help direct and focus future studies to make a truly efficacious typhoid vaccine."

It was found that individuals carrying one copy of the DNA sequence associated with resistance showed up to four-fold protection against typhoid fever, while those carrying two copies of the same DNA sequence almost never contracted typhoid. This observation suggests that the outcome of the body's effort to successfully clear an infection by Salmonella typhi depends on how bacterial components interact with the body's HLA to produce a robust immune response.

Dr Sarah Dunstan, co-lead author and Senior Research Fellow at the Nossal Institute of Global Health, University of Melbourne, added, "Typhoid fever remains a considerable health burden in many lower income countries in Asia. Our study is the first large-scale, search for human genes that affect a person's risk of typhoid. We found that carrying a particular form of the HLA-DRB1 gene provides natural resistance against typhoid. The HLA molecules are in general very important because they are able to recognise invading bacteria and turn on the body's immune system. If we can understand this natural mechanism of disease resistance, then we can use this knowledge to help inform improved vaccine and therapeutic design." Dr Dunstan was Senior Scientist at the OUCRU in Vietnam at the time of the study.

Dr Guy Thwaites, Director of OUCRU in Vietnam, said, "This important study shows the value of multi-centre, collaborative clinical infectious diseases research in Asia. Many of the participants were recruited to clinical trials investigating the best treatment regimens for typhoid fever in Vietnam and Nepal. These patients also provided their consent for later genetic testing, therefore the trials were not only able to provide answers to key clinical questions, but also -- as this paper demonstrates beautifully -- answers to fundamental questions about shared disease susceptibility mechanisms in different populations."