MICA: Study of disease mechanisms in enteric fever to characterise innate & adaptive immunity in mucosa & blood in controlled human infection model

Typhoid fever (also known as enteric fever), an infection characterised by diarrhoea and rash, is most often caused by a type of bacteria called Salmonella enterica. After gaining entry to the body via contaminated food or drink, the Salmonellae travel first to the gut, and then the bloodstream, from where they can infect the lymph nodes, gallbladder, liver, spleen, and other parts of the body. Treatment of enteric fever is by rehydration either intravenously or by drinking uncontaminated water mixed with electrolytes. Antibiotics are used to kill the bacteria, but as there are increasing rates of antibiotic resistant S. enterica throughout the world, this means of treatment is becoming less effective. Two Salmonella variants, known as serovars Typhi and Paratyphi, cause around 27 million cases of enteric fever and more than 200,000 deaths per year worldwide, mostly in the developing countries. Even though improved sanitation through economic development should eventually eliminate enteric fever, reduction of the disease burden in the medium term is achievable through effective immunisation, especially in the face of increasing antibiotic resistance. Although effective vaccines are likely to be available for mass vaccination against typhoid in the near future, these vaccines will be effective only against those strains of S. Typhi and S. Paratyphi that bear the Vi polysaccaharide capsule proteins. Strains that do not have these capsule proteins, or that have no capsule (acapsulate) will be unaffected by vaccination and could fill the ecological space vacated by the capsulate strains. Indeed, enteric fever caused by S. Paratyphi A which does not carry the Vi protein and for which there is currently no vaccine, has risen during the past decade and accounts for more than half of all cases in some areas. Thus it is important that effective vaccines are available to protect against infection by both capsulated and non-encapsulated Salmonella enterica. To develop such vaccines, we need a full understanding of the human immune response to the acapsulate Salmonella including the interactions between the inbuilt immune system and disease-specific immunity, contributions of immunity in the gut and the bloodstream, immune response to protein and to polysaccharide determinants, and the role of antibodies. How much cross-protection there is between capsulate and non-capsulate typhoidal Salmonellae after natural infection or vaccination is not known, but this is critically important to vaccine development. With this project we aim to fill in the knowledge gaps highlighted above, by fully characterising the infection process and immune response in enteric fever.