期刊
ANNALS OF THE RHEUMATIC DISEASES
卷 78, 期 1, 页码 74-82出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/annrheumdis-2018-213532
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类别
资金
- ARUK Fellowships Non-Clinical Career DevelopmentFellowship [18440]
- ARUK PhD studentship [17868]
- ARUK [21261]
Objective Salmonella enterica infections can lead to Reactive Arthritis (ReA), which can exhibit an association with human leucocyte antigen (HLA)-B(star)27:05, a molecule prone to misfolding and initiation of the unfolded protein response (UPR). This study examined how HLA-B(star)27:05 expression and the UPR affect the Salmonella life-cycle within epithelial cells. Methods I sogenic epithelial cell lines expressing two copies of either HLA-B(star)27:05 and a control HLA-B(star)35:01 heavy chain (HC) were generated to determine the effect on the Salmonella infection life-cycle. A cell line expressing HLA-B(star)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(star)27:05. HC but not in the presence of HLA-B(star)27:05. SCT or HLA-B(star)35:01. HLA-B(star)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.
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