<i>Salmonella</i> exploits HLA-B27 and host unfolded protein responses to promote intracellular replication.

Abstract

<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. 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. <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. 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.