Salmonella exploits HLA-B27 and host unfolded protein responses to promote intracellular replication.
Ann Rheum Dis
; 78(1): 74-82, 2019 01.
Article
em En
| MEDLINE
| ID: mdl-30355574
ABSTRACT
OBJECTIVE:
Salmonella enterica infections can lead to Reactive Arthritis (ReA), which can exhibit an association with human leucocyte antigen (HLA)-B*2705, a molecule prone to misfolding and initiation of the unfolded protein response (UPR). This study examined how HLA-B*2705 expression and the UPR affect the Salmonella life-cycle within epithelial cells.METHODS:
Isogenic epithelial cell lines expressing two copies of either HLA-B*2705 and a control HLA-B*3501 heavy chain (HC) were generated to determine the effect on the Salmonella infection life-cycle. A cell line expressing HLA-B*2705.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*2705.HC but not in the presence of HLA-B*2705.SCT or HLA-B*3501. HLA-B*2705.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.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Infecções por Salmonella
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Antígeno HLA-B27
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Salmonella enterica
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Células Epiteliais
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Resposta a Proteínas não Dobradas
Limite:
Humans
Idioma:
En
Revista:
Ann Rheum Dis
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Reino Unido