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



Antoniou, Antony Nicodemus, Lenart, Izabela, Kriston-Vizi, Janos, Iwawaki, Takao, Turmaine, Mark, McHugh, Kirsty, Ali, Sadfer, Blake, Neil, Bowness, Paul, Bajaj-Elliott, Mona
et al (show 3 more authors) (2018) Salmonella exploits HLA-B27 and host unfolded protein responses to promote intracellular replication. Annals of the Rheumatic Diseases, 78 (1). 74 - 82.

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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.

Item Type: Article
Depositing User: Symplectic Admin
Date Deposited: 31 Oct 2018 11:41
Last Modified: 09 Jan 2021 04:38
DOI: 10.1136/annrheumdis-2018-213532
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3028117