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

Antony Nicodemus Antoniou, Izabela Lenart, Janos Kriston-vizi, Takao Iwawaki, Mark Turmaine, Kirsty Mchugh, Sadfer Ali, Neil Blake, Paul Bowness, Mona Bajaj-elliott, Keith Gould, Darren Nesbeth, Simon J Powis

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)
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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.
Original languageEnglish
Pages (from-to)74-82
Number of pages9
JournalAnnals of the Rheumatic Diseases
Volume78
Issue number1
Early online date24 Oct 2018
DOIs
Publication statusPublished - Jan 2019

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