A genome-wide approach to understand the interplay between bacterial virulence genes and host immune responses

Lead Research Organisation: University of Cambridge
Department Name: Veterinary Medicine

Abstract

Salmonella causes serious infections in humans and animals worldwide. Current measures for controlling Salmonella infections are far from ideal. Antibiotics are widely used, but an increasing number of Salmonella isolates are resistant to these drugs. Vaccines can potentially be an effective method to prevent some forms of Salmonella disease. Unfortunately, most of the currently used vaccines are only moderately effective and are based on old technology. There are currently no vaccines against septicaemic salmonellosis that is an emerging form of the disease especially in Africa in young children and immunocompromised individuals. The use of live vaccines can be potentially dangerous, especially in those areas where immunodeficiencies are prevalent. People who may have a latent (as yet undiscovered) immunodeficiency syndrome (e.g. HIV infected individuals or people with subclinical malaria) may be at serious risk if they receive a live vaccine that can potentially revert to virulence when the host immune system is not fully competent.
Here we propose to use a cost effective, global and modern approach to identify bacterial genes that are responsible for the increased virulence of Salmonella in individuals with common forms of immunodeficiencies that can be encountered in the geographical areas where Salmonella is endemic. Deletion of appropriate combinations of such genes, would make live vaccines safe also in those individuals with an impaired immune system.

Technical Summary

The main aim of the research is to understand which genes in Salmonella enterica are required for fitness and virulence in models of immunodeficiencies known to pre-dispose to salmonellosis in humans.
We will use a cost effective, global approach to screen libraries of Tn5 and Mu transposon mutants of S. enterica for their ability to infect gene-targeted immunodeficient mice and grow in their tissues (gp91-/-, IFN-gamma-/- and T-cell deficient mice). These bacterial mutants will be analysed using Transposon Directed Insertion-site Sequencing (TraDIS), which uses Illumina deep-sequencing to assess the genotypes and relative fitnesses of individuals within complex pools of bacterial transposon mutants. The work will give a quantitative measure of the extent to which individual mutants in the pools are negatively or positively selected during infection, with those mutants that are lost during infection being indicators of the genes required to colonise the particular mouse knock-out strain being used as host. The work will allow us to identify candidates for development into live attenuated vaccines that would be safer to use in situations and or/geographical areas where these immunodeficiences might be prevalent and in many cases latent or undiagnosed.
 
Description Foreign guest speaker at the Congress of the Brazilian Society of Immunology, Sao Paulo, Brazil, 29 October - 2 November 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Foreign guest speaker at the Congress of the Brazilian Society of Immunology, Sao Paulo, Brazil, 29 October - 2 November 2016. Title of the presentation: Imaging, omics, and immunology to understand the pathogenesis, prevention and treatment of invasive bacterial infections. The talk increased awareness on the need for multidisciplinary in designing rational treatments and prevention strategies for bacterial infections
Year(s) Of Engagement Activity 2016
 
Description Keynote speaker at the 2nd World Congress on Antibiotics and Antibiotic Resistance, Manchester, UK, 13-15 October 2016. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Keynote speaker at the 2nd World Congress on Antibiotics and Antibiotic Resistance, Manchester, UK, 13-15 October 2016. Title of the presentation: Relationships between pathogen behavior, immunity and efficacy of antimicrobial drugs within a mammalian host. The talk generated interest in the relationships between in vivo behaviour of bacteria and out use of vaccines and antimicrobials. The talk increased awareness that we must take care of the characteristics of the infection before designing treatment and prevention strategies
Year(s) Of Engagement Activity 2016
 
Description Talk at Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Keynote speaker at the 3rd Euro-Global conference on Infectious Disease, Frankfurt, Germany, 5-7 September 2016. Title of the presentation: Immunity, vaccination, antimicrobial treatment and in vivo pathogen behaviour: from the laboratory to clinical setting in endemic regions. Increased awareness on linking fundamental vaccinology with the needs in clinical settings
Year(s) Of Engagement Activity 2016