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

Antony N.  Antoniou; Izabela  Lenart; Janos  Kriston-Vizi; Takao  Iwawaki; Mark  Turmaine; Kirsty  McHugh; Sadfer Ali; Neil  Blake; Paul  Bowness; Mona  Bajaj-Elliott; Keith  Gould; Darren  Nesbeth; Simon John Powis

doi:10.1136/annrheumdis-2018-213532

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

Antony N. Antoniou
, Izabela Lenart
, Janos Kriston-Vizi
, Takao Iwawaki
, Mark Turmaine
, Kirsty McHugh
, Sadfer Ali
, Neil Blake
, Paul Bowness
, Mona Bajaj-Elliott
, Keith Gould
, Darren Nesbeth
, Simon John Powis

Research output: Contribution to journal › Article › peer-review

Abstract

Objective 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.
Methods 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.
Results 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.
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.

Original language	English
Article number	213532
Pages (from-to)	74–82
Number of pages	9
Journal	Annals of the Rheumatic Diseases
Volume	78
Issue number	1
Early online date	24 Oct 2018
DOIs	https://doi.org/10.1136/annrheumdis-2018-213532
Publication status	Published - Jan 2019

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Antoniou, A. N., 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, S. J. (2019). Salmonella exploits HLA-B27 and host unfolded protein responses to promote intracellular replication. Annals of the Rheumatic Diseases, 78(1), 74–82. Article 213532. https://doi.org/10.1136/annrheumdis-2018-213532

@article{f4ff63c7eb894a36834498e8062b8109,

title = "Salmonella exploits HLA-B27 and host unfolded protein responses to promote intracellular replication",

abstract = "Objective 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. Methods 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. Results 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. 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.",

author = "Antoniou, \{Antony N.\} and Izabela Lenart and Janos Kriston-Vizi and Takao Iwawaki and Mark Turmaine and Kirsty McHugh and Sadfer Ali and Neil Blake and Paul Bowness and Mona Bajaj-Elliott and Keith Gould and Darren Nesbeth and Powis, \{Simon John\}",

note = "A.N.A was funded by ARUK Fellowships Non-Clinical Career Development Fellowship Ref No: 18440. I.L. was funded by an ARUK PhD studentship Ref No: 17868. A.N.A and S.J.P were also in part funded by ARUK (grant 21261)",

year = "2019",

month = jan,

doi = "10.1136/annrheumdis-2018-213532",

language = "English",

volume = "78",

pages = "74{\textendash}82",

journal = "Annals of the Rheumatic Diseases",

issn = "0003-4967",

publisher = "Elsevier",

number = "1",

}

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 2019, 'Salmonella exploits HLA-B27 and host unfolded protein responses to promote intracellular replication', Annals of the Rheumatic Diseases, vol. 78, no. 1, 213532, pp. 74–82. https://doi.org/10.1136/annrheumdis-2018-213532

TY - JOUR

T1 - Salmonella exploits HLA-B27 and host unfolded protein responses to promote intracellular replication

AU - Antoniou, Antony N.

AU - Lenart, Izabela

AU - Kriston-Vizi, Janos

AU - Iwawaki, Takao

AU - Turmaine, Mark

AU - McHugh, Kirsty

AU - Ali, Sadfer

AU - Blake, Neil

AU - Bowness, Paul

AU - Bajaj-Elliott, Mona

AU - Gould, Keith

AU - Nesbeth, Darren

AU - Powis, Simon John

N1 - A.N.A was funded by ARUK Fellowships Non-Clinical Career Development Fellowship Ref No: 18440. I.L. was funded by an ARUK PhD studentship Ref No: 17868. A.N.A and S.J.P were also in part funded by ARUK (grant 21261)

PY - 2019/1

Y1 - 2019/1

N2 - Objective 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. Methods 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. Results 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. 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.

AB - Objective 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. Methods 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. Results 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. 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.

U2 - 10.1136/annrheumdis-2018-213532

DO - 10.1136/annrheumdis-2018-213532

M3 - Article

SN - 0003-4967

VL - 78

SP - 74

EP - 82

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

IS - 1

M1 - 213532

ER -

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

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