Salmonella exploits HLA-B27 and host unfolded protein responses to promote intracellular replication.
Salmonella exploits HLA-B27 and host unfolded protein responses to promote intracellular replication.
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DOI：
10.1136/annrheumdis-2018-213532
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发表时间：
2019-01
影响因子：
27.4
通讯作者：
Powis SJ
中科院分区：
文献类型：
--
作者：
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
肠道沙门氏菌感染可导致反应性关节炎（ReA），其可表现出与人白细胞抗原（HLA）-B*27：05的相关性，HLA-B*27：05是一种易于错误折叠和启动未折叠蛋白应答（UPR）的分子。本研究探讨了HLA-B*27：05表达和UPR如何影响沙门氏菌在上皮细胞内的生命周期。产生表达HLA-B*27：05和对照HLA-B*35：01重链（HC）的两个拷贝的同基因上皮细胞系，以确定对沙门氏菌感染生命周期的影响。还产生了表达HLA-B*27：05.HC的细胞系，该细胞系与轻链β-2-微球蛋白和特异性肽（称为单链三聚体，SCT）物理连接，以确定HLA-B27折叠状态对S.肠道生命周期XBP-1 venus和AMP依赖性转录因子（ATF 6）-FLAG报告基因用于监测感染细胞中的UPR活化。Triacin C用于抑制UPR期间的从头脂质合成，ER示踪剂染色膜的共聚焦成像允许定量格列本脲相关膜。S.肠杆菌表现出在HLA-B*27：05.HC存在下具有改变的细胞定位的增强的复制，但在HLA-B*27：05.SCT或HLA-B*35：01存在下没有。HLA-B*27：05.HC改变了UPR诱导的阈值。沙门氏菌激活UPR并需要XBP-1进行复制，这与内质网膜扩张和脂质代谢有关。HLA-B27错误折叠和UPR细胞环境与沙门氏菌复制增强有关，而沙门氏菌本身可以激活XBP-1和ATF 6。这些数据提供了一个潜在的机制，沙门氏菌的生命周期与HLA-B27的理化性质和细胞事件，可能有助于ReA的发病机制。我们的观察表明，UPR途径可能是未来治疗干预的目标。
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. 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. 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. 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.
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DOI：
10.1111/tra.12002
发表时间：
2012-12
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
--
作者：
Dumoux M;Clare DK;Saibil HR;Hayward RD
通讯作者：
Hayward RD
影响因子：
27.4
作者：
Hannu, T;Mattila, L;Leirisalo-Repo, M
通讯作者：
Leirisalo-Repo, M
影响因子：
13.3
作者：
Huang, Ju;Birmingham, Cheryl L.;Brumell, John H.
通讯作者：
Brumell, John H.
影响因子：
3.1
作者：
Brumell, JH;Tang, P;Finlay, BB
通讯作者：
Finlay, BB
影响因子：
82.9
作者：
Iwawaki, T;Akai, R;Miura, M
通讯作者：
Miura, M