Poster Presentation 23rd Annual Lorne Proteomics Symposium 2018

Unravelling the connection between Salmonella and Ankylosing Spondylitis (#94)

Terry C.C Lim Kam Sian 1 , Ralf B Schittenhelm 1 , Anthony W Purcell 1 , Nancy Wang 2
  1. Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
  2. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia

The association of HLA-B27 with Ankylosing Spondylitis (AS) is one of the strongest associations between a HLA molecule and an autoimmune disease. This association can, in part, be explained by the atypical characteristics of HLA-B27 to form homodimers, which act through non-classical pathways and trigger aberrant immune responses. Various cellular stresses have been proposed to induce homodimer formation, and here we show that infection by Salmonella typhimurium can also induce homodimer formation. Considering that AS patients often report developing disease post infection with gastrointestinal bacteria and as a sequela of infection induced reactive arthritis, HLA-B27 homodimers could play role in disease pathogenesis. The aim of this study is to understand the cellular requirements for homodimer formation and to provide insights on how these homodimer species trigger the immune system.

Methods: Differences in the proteome between Salmonella typhimurium infected and uninfected cells were analysed by data dependent acquisition mass spectrometry. Significantly regulated proteins were identified and further analysed.

Results: Our analysis identified 122 upregulated and 533 downregulated proteins post wild-type Salmonella typhimurium infection. These include proteins involved in the MHC presentation pathway, oxidative phosphorylation, glutathione metabolism, cell cycle and apoptosis. Proteins in the toll-like receptor signalling pathway, TRIF and part of NF-kb signalling pathway, which are generally involved in bacterial detection and signalling, were also observed to be modulated. The pathways important for homodimer formation have subsequently been interrogated using pharmacological inhibition and using mutant Salmonella typhimurium strains.

Conclusion: This study provides insights on how homodimers are formed and their potential mode of action in disease. Consequently, opening the doorway for designing targeted therapies for Ankylosing Spondylitis.