Salmonella exploits HLA-B27 and host unfolded protein responses to promote intracellular replication. Issue 1 (24th October 2018)

• Record Type: Journal Article
• Authors: Antoniou, Antony Nicodemus; Lenart, Izabela; Kriston-Vizi, Janos; Iwawaki, Takao; Turmaine, Mark; McHugh, Kirsty; Ali, Sadfer; Blake, Neil; Bowness, Paul; Bajaj-Elliott, Mona; Gould, Keith; Nesbeth, Darren; Powis, Simon J
• Is Part Of: Annals of the rheumatic diseases. Volume 78:Issue 1(2019)
• Page Start: 74
• Page End: 82
• Publication Date: 2018-10-24
• Subjects: ankylosing spondylitis -- infections -- reactive arthritis -- spondyloarthritis -- lipids; Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2018-213532
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : 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.