Salmonella exploits HLA-B27 and host unfolded protein responses to promote intracellular replication
Antoniou AN., Lenart I., Kriston-Vizi J., Iwawaki T., Turmaine M., McHugh K., Ali S., Blake N., Bowness P., Bajaj-Elliott M., Gould K., Nesbeth D., Powis SJ.
<jats:sec><jats:title>Objective</jats:title><jats:p><jats:italic>Salmonella enterica</jats:italic> 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 <jats:italic>Salmonella</jats:italic> life-cycle within epithelial cells.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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 <jats:italic>Salmonella</jats:italic> 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 <jats:italic>S.</jats:italic><jats:italic>enterica</jats:italic> 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 <jats:italic>de novo</jats:italic> lipid synthesis during UPR, and confocal imaging of ER tracker stained membrane allowed quantification of glibenclamide-associated membrane.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p><jats:italic>S.</jats:italic><jats:italic>enterica</jats:italic> 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. <jats:italic>Salmonella</jats:italic> activated the UPR and required XBP-1 for replication, which was associated with endoreticular membrane expansion and lipid metabolism.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>HLA-B27 misfolding and a UPR cellular environment are associated with enhanced <jats:italic>Salmonella</jats:italic> replication, while <jats:italic>Salmonella</jats:italic> itself can activate XBP-1 and ATF6. These data provide a potential mechanism linking the life-cycle of <jats:italic>Salmonella</jats:italic> 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.</jats:p></jats:sec>