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Integrated transcriptomic analysis of human tuberculosis granulomas and a biomimetic model identifies therapeutic targets

Integrated transcriptomic analysis of human tuberculosis granulomas and a biomimetic model identifies therapeutic targets
Integrated transcriptomic analysis of human tuberculosis granulomas and a biomimetic model identifies therapeutic targets

Tuberculosis (TB) is a persistent global pandemic, and standard treatment for it has not changed for 30 years. Mycobacterium tuberculosis (Mtb) has undergone prolonged coevolution with humans, and patients can control Mtb even after extensive infection, demonstrating the fine balance between protective and pathological host responses within infected granulomas. We hypothesized that whole transcriptome analysis of human TB granulomas isolated by laser capture microdissection could identify therapeutic targets, and that comparison with a noninfectious granulomatous disease, sarcoidosis, would identify disease-specific pathological mechanisms. Bioinformatic analysis of RNAseq data identified numerous shared pathways between TB and sarcoidosis lymph nodes, and also specific clusters demonstrating TB results from a dysregulated inflammatory immune response. To translate these insights, we compared 3 primary human cell culture models at the whole transcriptome level and demonstrated that the 3D collagen granuloma model most closely reflected human TB disease. We investigated shared signaling pathways with human disease and identified 12 intracellular enzymes as potential therapeutic targets. Sphingosine kinase 1 inhibition controlled Mtb growth, concurrently reducing intracellular pH in infected monocytes and suppressing inflammatory mediator secretion. Immunohistochemical staining confirmed that sphingosine kinase 1 is expressed in human lung TB granulomas, and therefore represents a host therapeutic target to improve TB outcomes.

0021-9738
Reichmann, Michaela T
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Tezera, Liku Bekele
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Vallejo Pulido, Andres
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Vukmirovic, Milica
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Xiao, Rui
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Reynolds, James
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Jogai, Sanjay
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Wilson, Susan
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Marshall, Benjamin
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Jones, Mark
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Leslie, Alasdair
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D’Armiento, Jeanine
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Kaminski, Naftali
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Polak, Marta
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Elkington, Paul
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
Reichmann, Michaela T
c003a2e1-1a8d-4da6-8ec0-90d020798a66
Tezera, Liku Bekele
c5598dbf-23a8-4934-96a4-7c783bf9e776
Vallejo Pulido, Andres
27bc0b94-0c40-4fd1-9533-7e267d588c0a
Vukmirovic, Milica
3ec7cabb-df9e-4fc9-923c-70620ee9080d
Xiao, Rui
1144bff4-71f3-4f18-9f43-8f3018aeb7ec
Reynolds, James
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Jogai, Sanjay
18c2f36b-4572-46d5-b17d-a6d2cdaa916c
Wilson, Susan
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Marshall, Benjamin
9abf382c-977f-459c-9b91-5ed8cbf2284f
Jones, Mark
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Leslie, Alasdair
84d4f578-f3c0-46cc-9c83-a8d9bb40c38c
D’Armiento, Jeanine
be114eb0-bca9-49f2-80b8-931637e32dcb
Kaminski, Naftali
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Polak, Marta
e0ac5e1a-7074-4776-ba23-490bd4da612d
Elkington, Paul
60828c7c-3d32-47c9-9fcc-6c4c54c35a15

Reichmann, Michaela T, Tezera, Liku Bekele, Vallejo Pulido, Andres, Vukmirovic, Milica, Xiao, Rui, Reynolds, James, Jogai, Sanjay, Wilson, Susan, Marshall, Benjamin, Jones, Mark, Leslie, Alasdair, D’Armiento, Jeanine, Kaminski, Naftali, Polak, Marta and Elkington, Paul (2021) Integrated transcriptomic analysis of human tuberculosis granulomas and a biomimetic model identifies therapeutic targets. Journal of Clinical Investigation, 131 (15), [e148136]. (doi:10.1172/JCI148136).

Record type: Article

Abstract

Tuberculosis (TB) is a persistent global pandemic, and standard treatment for it has not changed for 30 years. Mycobacterium tuberculosis (Mtb) has undergone prolonged coevolution with humans, and patients can control Mtb even after extensive infection, demonstrating the fine balance between protective and pathological host responses within infected granulomas. We hypothesized that whole transcriptome analysis of human TB granulomas isolated by laser capture microdissection could identify therapeutic targets, and that comparison with a noninfectious granulomatous disease, sarcoidosis, would identify disease-specific pathological mechanisms. Bioinformatic analysis of RNAseq data identified numerous shared pathways between TB and sarcoidosis lymph nodes, and also specific clusters demonstrating TB results from a dysregulated inflammatory immune response. To translate these insights, we compared 3 primary human cell culture models at the whole transcriptome level and demonstrated that the 3D collagen granuloma model most closely reflected human TB disease. We investigated shared signaling pathways with human disease and identified 12 intracellular enzymes as potential therapeutic targets. Sphingosine kinase 1 inhibition controlled Mtb growth, concurrently reducing intracellular pH in infected monocytes and suppressing inflammatory mediator secretion. Immunohistochemical staining confirmed that sphingosine kinase 1 is expressed in human lung TB granulomas, and therefore represents a host therapeutic target to improve TB outcomes.

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Accepted/In Press date: 11 June 2021
e-pub ahead of print date: 15 June 2021
Published date: 2 August 2021

Identifiers

Local EPrints ID: 449915
URI: http://eprints.soton.ac.uk/id/eprint/449915
ISSN: 0021-9738
PURE UUID: 87dc6bfd-4ead-4a99-8778-86ab4256aaa9
ORCID for Michaela T Reichmann: ORCID iD orcid.org/0000-0002-3015-9827
ORCID for Liku Bekele Tezera: ORCID iD orcid.org/0000-0002-7898-6709
ORCID for Andres Vallejo Pulido: ORCID iD orcid.org/0000-0002-4688-0598
ORCID for Susan Wilson: ORCID iD orcid.org/0000-0003-1305-8271
ORCID for Mark Jones: ORCID iD orcid.org/0000-0001-6308-6014
ORCID for Paul Elkington: ORCID iD orcid.org/0000-0003-0390-0613

Catalogue record

Date deposited: 25 Jun 2021 16:30
Last modified: 26 Nov 2021 03:16

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Contributors

Author: Michaela T Reichmann ORCID iD
Author: Andres Vallejo Pulido ORCID iD
Author: Milica Vukmirovic
Author: Rui Xiao
Author: James Reynolds
Author: Sanjay Jogai
Author: Susan Wilson ORCID iD
Author: Mark Jones ORCID iD
Author: Alasdair Leslie
Author: Jeanine D’Armiento
Author: Naftali Kaminski
Author: Marta Polak
Author: Paul Elkington ORCID iD

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