Title: Investigating the interactions of Salmonellae with the human intestinal epithelium and macrophages
Funder: The Academy of Medical Sciences

Abstract: This project aims to gather data on the interactions of S. Paratyphi A with the intestinal epithelium and immune cells, in the form of human induced pluripotent stem cell (hiPSC)-derived intestinal organoids and macrophages. This will be achieved via comparison of invasion of different clinical strains of S. Paratyphi A in the organoid and macrophage models and use of bulk RNA-Seq to elucidate transcriptomic commonalities and differences between strains and their behaviour in the epithelium and in macrophages. This data will be compared with data already obtained for S. Typhi and S. Typhimurium strains, with the objective of identifying whether commonalities between these key clades of Salmonella can be noted. The project also aims to establish whether interactions differ during conditions likely to be experienced during clinical infections, for example with differing inoculum causing infection, or in those patients treated with antibiotics. This work is important as there are large gaps in our knowledge of the pathogenesis of S. Paratyphi infections, due to a prior lack of an appropriate human disease model or animal proxy. The need to establish more about how this bacteria behaves becomes more pressing, as S. Paratyphi A is responsible for an increasing burden of disease across parts of Asia, and the frequency of antimicrobial resistant strains is increasing. At present, there is not a vaccine available against Paratyphi A, therefore work done during this study hopes to form the basis of efforts to identify targets for multivalent vaccines against different clades of Salmonella.

Lay abstract: Salmonella are bacteria, usually found in the gut, which cause over 100 million infections in humans per year worldwide. Different types of Salmonella cause illnesses ranging from gastroenteritis to typhoid fever, where the bacteria reaches a person’s bloodstream and can cause severe illness and death. Typhoid fever usually occurs in parts of the world where access to clean water and sanitation facilities are limited. Humans have lots of ways of trying to prevent Salmonella from invading our body through the lining of the gut, as well as the body's immune response from white blood cells once the bacteria have crossed into the bloodstream. Scientists often use infected animals to help us learn about how humans might respond to infections. Unfortunately, this is not possible for Salmonella that cause typhoid fever as animals don’t become unwell in the same way as humans with the condition. However, we can use intestinal ‘organoids’ which are tiny models of the lining of the human intestine, containing all of the types of cell that are seen in the human intestine. We can also produce replicas of white blood cells called macrophages. We will infect these organoids and macrophages with Salmonella, allowing us to directly study how the different cells in the human intestine respond to Salmonella, and to look at the immune response in white blood cells. This will allow us to try and identify factors which would be important in creating a vaccine for the different types of Salmonella that can cause typhoid disease.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION