Enteric fever (also known as typhoid fever) is a life-threatening infection caused by the bacteria Salmonella Typhi and Paratyphi, usually through ingestion of contaminated food or water. The acute illness is characterized by prolonged fever, headache, nausea, loss of appetite, and constipation or sometimes diarrhoea. This disease is responsible for around 20 million new infections and 150,000 deaths each year, mainly in South and South-East Asia and Africa. Despite its impact, a vaccine able to protect against all types of Salmonella is still lacking.
In a study published this week in Nature Immunology researchers in the Cerundolo group, led by Giorgio Napolitani, at the MRC Human Immunology Unit (MRC Weatherall Institute of Molecular Medicine), in collaboration with the Oxford Vaccine Group, and the Singapore Immunology Network used a combination of techniques to make important advances in understanding how the immune system responds to these pathogens. One of the major hurdles in the development of vaccines against enteric fever is that Salmonella Typhi and Salmonella Paratyphi infect only humans, so the disease cannot be studied in laboratory animals. To overcome this issue, researchers at the Oxford Vaccine Group deliberately infected volunteers with the bacteria, so that they could study how the immune system copes with the infection.
The team at the MRC Human Immunology Unit particularly focused on a type of immune cell thought to play a major protective role against Salmonella, called CD4 positive T cells. The authors were able to isolate and characterize individual immune cells from the blood of infected volunteers, and looked for those that were able to recognise different types of Salmonella. Using this ground-breaking approach, the Oxford team could reconstruct the immune response to Salmonella in a dish. They discovered that some T cells can recognise many different types of Salmonella, while others were very selective and could recognise the very small differences that distinguish the two different types of Salmonella bacteria which cause enteric fever. “We were surprised to find that, despite these bacteria containing more than 4,000 proteins, during infection most of the T cells recognize only a handful of Salmonella proteins, and variation of a single amino-acid in these proteins can make a difference in whether some T cells can recognize or not these bacteria.”, said Dr Napolitani.
This careful study paves the way for the design of better, and wider ranging, vaccines against Salmonella bacteria. “Our work has led to the identification of the distinct Salmonella proteins that different T cells are able to detect. This knowledge will help design better vaccines against these pathogens in the future” said Prof Cerundolo.
This work was funded by an Experimental Medicine Challenge Grant from the Medical Research Council.