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


Antoniou, Antony Nicodemus, Lenart, Lzabela, Kriston-Vizi, Janos, Lwawaki, Takao, Turmaine, Mark, McHugh, Kirsty, Ali, Sadfer, Blake, Neil, Bowness, Paul, Bajaj-Elliott, Mona et al (show 3 more authors) (2019) Salmonella exploits HLA-B27 and host unfolded protein responses to promote intracellular replication. ANNALS OF THE RHEUMATIC DISEASES, 78 (1). pp. 74-82.

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Abstract

<h4>Objective</h4><i>Salmonella enterica</i> 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 <i>Salmonella</i> life-cycle within epithelial cells.<h4>Methods</h4>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 <i>Salmonella</i> 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 <i>S.</i> <i>enterica</i> 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 <i>de novo</i> lipid synthesis during UPR, and confocal imaging of ER tracker stained membrane allowed quantification of glibenclamide-associated membrane.<h4>Results</h4><i>S.</i> <i>enterica</i> 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. <i>Salmonella</i> activated the UPR and required XBP-1 for replication, which was associated with endoreticular membrane expansion and lipid metabolism.<h4>Conclusions</h4>HLA-B27 misfolding and a UPR cellular environment are associated with enhanced <i>Salmonella</i> replication, while <i>Salmonella</i> itself can activate XBP-1 and ATF6. These data provide a potential mechanism linking the life-cycle of <i>Salmonella</i> 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
Uncontrolled Keywords: Cell Line, Epithelial Cells, Humans, Salmonella enterica, Salmonella Infections, Arthritis, Reactive, HLA-B27 Antigen, HLA-B35 Antigen, Cell Cycle, Activating Transcription Factor 6, Unfolded Protein Response, X-Box Binding Protein 1, Prohibitins
Depositing User: Symplectic Admin
Date Deposited: 10 Sep 2018 06:40
Last Modified: 19 Jan 2023 01:25
DOI: 10.1136/annrheumdis-2018-213532
Open Access URL: https://ard.bmj.com/content/78/1/74
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3025919
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