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

被引：45

作者：

Antoniou, Antony Nicodemus ^{[1
,2
,3
]}

Lenart, Lzabela ^{[4
]}

Kriston-Vizi, Janos ^{[5
]}

Lwawaki, Takao ^{[6
]}

Turmaine, Mark ^{[7
]}

McHugh, Kirsty ^{[8
]}

Ali, Sadfer ^{[1
]}

Blake, Neil ^{[9
]}

Bowness, Paul ^{[8
]}

Bajaj-Elliott, Mona ^{[10
]}

Gould, Keith ^{[11
]}

Nesbeth, Darren ^{[1
]}

Powis, Simon J. ^{[12
]}

机构：

[1] UCL, Adv Ctr Biochem Engn, London, England

[2] UCL, Ctr Rheumatol, Div Infect & Immun, London, England

[3] Northumbria Univ, Fac Hlth & Life Sci, Dept Appl Sci, Newcastle Upon Tyne NE1 8ST, Tyne & Wear, England

[4] SciPharma, Warsaw, Poland

[5] UCL, Med Res Council, Lab Mol Cell Biol, London, England

[6] Kanazawa Med Univ, Med Res Inst, Dept Life Sci, Div Cell Med, Uchinada, Ishikawa, Japan

[7] UCL, Div Biosci, London, England

[8] Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Oxford, England

[9] Univ Liverpool, Inst Infect & Global Hlth, Liverpool, Merseyside, England

[10] UCL, Inst Child Hlth, Great Ormond St, London, England

[11] Imperial Coll London, Wright Fleming Inst, London, England

[12] Univ St Andrews, Sch Med & Biol Sci, Res Complex, London, England

来源：

ANNALS OF THE RHEUMATIC DISEASES | 2019年 / 78卷 / 01期

关键词：

ENTERICA SEROVAR TYPHIMURIUM; ENDOPLASMIC-RETICULUM; REACTIVE ARTHRITIS; CONTAINING VACUOLE; TRANSGENIC RATS; ER STRESS; BIOSYNTHESIS; TRAFFICKING; ACTIVATION; EXPRESSION;

D O I：

10.1136/annrheumdis-2018-213532

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objective Salmonella enterica infections can lead to Reactive Arthritis (ReA), which can exhibit an association with human leucocyte antigen (HLA)-B(star)27:05, a molecule prone to misfolding and initiation of the unfolded protein response (UPR). This study examined how HLA-B(star)27:05 expression and the UPR affect the Salmonella life-cycle within epithelial cells. Methods I sogenic epithelial cell lines expressing two copies of either HLA-B(star)27:05 and a control HLA-B(star)35:01 heavy chain (HC) were generated to determine the effect on the Salmonella infection life-cycle. A cell line expressing HLA-B(star)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(star)27:05. HC but not in the presence of HLA-B(star)27:05. SCT or HLA-B(star)35:01. HLA-B(star)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.

引用

页码：74 / 82

页数：9

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