Salmonella exploits HLA-B27 and host unfolded protein responses to promote intracellular replication

Journal article

OBJECTIVE:Salmonella enterica infections can lead to Reactive Arthritis (ReA), which can exhibit an association with human leucocyte antigen (HLA)-B*27:05, a molecule prone to misfolding and initiation of the unfolded protein response (UPR). This study examined how HLA-B*27:05 expression and the UPR affect the Salmonella life-cycle within epithelial cells. METHODS:Isogenic epithelial cell lines expressing two copies of either HLA-B*27:05 and a control HLA-B*35:01 heavy chain (HC) were generated to determine the effect on the Salmonella infection life-cycle. A cell line expressing HLA-B*27:05.HC physically linked to the light chain beta-2-microglobulin and a specific peptide (referred to as a single chain trimer, SCT) was also generated to determine the effects of HLA-B27 folding status on S. enterica life-cycle. XBP-1 venus and AMP dependent Transcription Factor (ATF6)-FLAG reporters were used to monitor UPR activation in infected cells. Triacin C was used to inhibit de novo lipid synthesis during UPR, and confocal imaging of ER tracker stained membrane allowed quantification of glibenclamide-associated membrane. RESULTS:S. enterica demonstrated enhanced replication with an altered cellular localisation in the presence of HLA-B*27:05.HC but not in the presence of HLA-B*27:05.SCT or HLA-B*35:01. HLA-B*27:05.HC altered the threshold for UPR induction. Salmonella activated the UPR and required XBP-1 for replication, which was associated with endoreticular membrane expansion and lipid metabolism. CONCLUSIONS:HLA-B27 misfolding and a UPR cellular environment are associated with enhanced Salmonella replication, while Salmonella itself can activate XBP-1 and ATF6. These data provide a potential mechanism linking the life-cycle of Salmonella with the physicochemical properties of HLA-B27 and cellular events that may contribute to ReA pathogenesis. Our observations suggest that the UPR pathway maybe targeted for future therapeutic intervention.

Authors: Antoniou, A; Lenart, I; Kriston-Vizi, J; Iwawaki, T; Turmaine, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: BMJ Publishing Group
• Journal: Annals of the Rheumatic Diseases
• Volume: 78
• Issue: 1
• Pages: 74-82
• Publication date: 2018-10-24
• Acceptance date: 2018-07-27
• DOI: 10.1136/annrheumdis-2018-213532
• EISSN: 1468-2060
• ISSN: 0003-4967
• Pmid: 30355574
• Language: English
• Keywords: ankylosing spondylitis; infections; reactive arthritis; lipids; spondyloarthritis