Characterisation of the Pattern Recognition Receptors required for the development of protective immunity against Salmonella infection

Salmonella enterica causes a wide range of diseases in many animals. Economic losses to the farming industry through Salmonella infection are potentially very high, but also important is the fact that a number of serovars that infect animals can also cause food poisoning and gastroenteritis in humans. In mice, infection with Salmonella enterica serovar Typhimurium (S. Typhimurium) causes clinical signs that are very similar to those seen in invasive infections of humans and chickens. Infection studies in mice will therefore allow us to understand how infection is likely to develop and spread within other species of animals. Vaccination of animals to lower the levels of Salmonella in meat and eggs will reduce the chances of infection spreading to people. The mouse model of infection is also excellent for studying vaccines. A successful vaccine must be generate a strong immune response but must also be safe for application in young and older individuals. Understanding how Salmonella interacts with its host to generate an immune response is critical when trying to design new vaccines. The animal detects the presence of these bacterial molecules through specialised proteins called Pattern Recognition Receptors (PRRs) which then initiate host defence mechanisms to clear the infection. These receptors are also believed to be important in generating a good response to vaccines, but precisely how this happens is currently unclear. The knowledge on whether chickens, for example, use PRRs to control Salmonella infection is too poorly understood to perform these studies in this species, but we can use mice without PRRs to determine whether these proteins are important for the control of, and protection against, Salmonella. Here we will determine which PRRs are important in protecting mice against Salmonella infections. The impact of this work will be to determine which PRRs are important in generating successful protective immune responses against Salmonella and these data will therefore allow us to design better vaccines for chickens, other domestic animals and humans.

Recognition of invading microorganisms by the host is an essential first step in the generation of protective immunity. Various microbial components are known to stimulate a group of receptors collectively known as the Pattern Recognition Receptors (PRR) that include the Toll-like Receptors (TLRs) and Nucleotide-binding domain, Leucine-rich repeat containing Receptors (NLRs). TLRs and NLRs respond to microbial components in different cellular sites and co-ordinated engagement of these receptors leads to intense induction of innate and adaptive immunity. Salmonella enterica is an important bacterial pathogen that causes disease in humans and livestock species. Transmission of some serovars (e.g. Enteritidis and Typhimurium) to humans is in the form of a food-borne zoonosis. To combat human gastroenteritis caused by salmonellae, vaccination of livestock animals to remove the major source of this organism is a more suitable approach than vaccination of people. Current vaccines are not particularly effective so understanding how to induce the most appropriate host immune responses to drive protective anti-Salmonella immunity is critical to optimise vaccination strategies against Salmonella spp. Salmonella can be located in intracellular (in vacuoles) and extracellular compartments but it also uses specialist structures to translocate products directly into the host cell cytoplasm. Hence, molecules derived from Salmonella are available to both the TLR and NLR pathways. PRR biology in domestic animals is in its infancy whereas PRR biology and the tools available to study these receptors in mice are well developed. In this project we will define which PRRs are important in controlling bacterial growth and mounting a protective immune response against infection with S. Typhimurium by infecting mouse strains with engineered deficiencies in the PRR pathways. The impact of this work will be to clearly define which PRRs drive protective anti-Salmonella immunity.