Dissecting the <i>Mycobacterium bovis</i> BCG Response to Macrophage Infection to Help Prioritize Targets for Anti-Tuberculosis Drug and Vaccine Discovery
New strategies are required to reduce the worldwide burden of tuberculosis. Intracellular survival and replication of <i>Mycobacterium tuberculosis</i> after macrophage phagocytosis is a fundamental step in the complex host–pathogen interactions that lead to granuloma formation and disea...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-01-01
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| Series: | Vaccines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-393X/10/1/113 |
| _version_ | 1797489901491453952 |
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| author | Jamie Medley Aaron Goff Paulo J. G. Bettencourt Madelaine Dare Liam Cole Daire Cantillon Simon J. Waddell |
| author_facet | Jamie Medley Aaron Goff Paulo J. G. Bettencourt Madelaine Dare Liam Cole Daire Cantillon Simon J. Waddell |
| author_sort | Jamie Medley |
| collection | DOAJ |
| description | New strategies are required to reduce the worldwide burden of tuberculosis. Intracellular survival and replication of <i>Mycobacterium tuberculosis</i> after macrophage phagocytosis is a fundamental step in the complex host–pathogen interactions that lead to granuloma formation and disease. Greater understanding of how the bacterium survives and thrives in these environments will inform novel drug and vaccine discovery programs. Here, we use in-depth RNA sequencing of <i>Mycobacterium bovis</i> BCG from human THP-1 macrophages to describe the mycobacterial adaptations to the intracellular environment. We identify 329 significantly differentially regulated genes, highlighting cholesterol catabolism, the methylcitrate cycle and iron homeostasis as important for mycobacteria inside macrophages. Examination of multi-functional gene families revealed that 35 PE/PPE genes and five cytochrome P450 genes were upregulated 24 h after infection, highlighting pathways of potential significance. Comparison of the intracellular transcriptome to gene essentiality and immunogenicity studies identified 15 potential targets that are both required for intracellular survival and induced on infection, and eight upregulated genes that have been demonstrated to be immunogenic in TB patients. Further insight into these new and established targets will support drug and vaccine development efforts. |
| first_indexed | 2024-03-10T00:23:15Z |
| format | Article |
| id | doaj.art-e30311ee306a4585972e2cd4ebe46002 |
| institution | Directory Open Access Journal |
| issn | 2076-393X |
| language | English |
| last_indexed | 2024-03-10T00:23:15Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Vaccines |
| spelling | doaj.art-e30311ee306a4585972e2cd4ebe460022023-11-23T15:39:38ZengMDPI AGVaccines2076-393X2022-01-0110111310.3390/vaccines10010113Dissecting the <i>Mycobacterium bovis</i> BCG Response to Macrophage Infection to Help Prioritize Targets for Anti-Tuberculosis Drug and Vaccine DiscoveryJamie Medley0Aaron Goff1Paulo J. G. Bettencourt2Madelaine Dare3Liam Cole4Daire Cantillon5Simon J. Waddell6Global Health and Infection, Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9PX, UKGlobal Health and Infection, Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9PX, UKFaculty of Medicine, Catholic University of Portugal, 1649-023 Lisbon, PortugalGlobal Health and Infection, Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9PX, UKGlobal Health and Infection, Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9PX, UKGlobal Health and Infection, Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9PX, UKGlobal Health and Infection, Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9PX, UKNew strategies are required to reduce the worldwide burden of tuberculosis. Intracellular survival and replication of <i>Mycobacterium tuberculosis</i> after macrophage phagocytosis is a fundamental step in the complex host–pathogen interactions that lead to granuloma formation and disease. Greater understanding of how the bacterium survives and thrives in these environments will inform novel drug and vaccine discovery programs. Here, we use in-depth RNA sequencing of <i>Mycobacterium bovis</i> BCG from human THP-1 macrophages to describe the mycobacterial adaptations to the intracellular environment. We identify 329 significantly differentially regulated genes, highlighting cholesterol catabolism, the methylcitrate cycle and iron homeostasis as important for mycobacteria inside macrophages. Examination of multi-functional gene families revealed that 35 PE/PPE genes and five cytochrome P450 genes were upregulated 24 h after infection, highlighting pathways of potential significance. Comparison of the intracellular transcriptome to gene essentiality and immunogenicity studies identified 15 potential targets that are both required for intracellular survival and induced on infection, and eight upregulated genes that have been demonstrated to be immunogenic in TB patients. Further insight into these new and established targets will support drug and vaccine development efforts.https://www.mdpi.com/2076-393X/10/1/113tuberculosis<i>Mycobacterium</i>macrophagehost-pathogen interactionstranscriptomicsBCG |
| spellingShingle | Jamie Medley Aaron Goff Paulo J. G. Bettencourt Madelaine Dare Liam Cole Daire Cantillon Simon J. Waddell Dissecting the <i>Mycobacterium bovis</i> BCG Response to Macrophage Infection to Help Prioritize Targets for Anti-Tuberculosis Drug and Vaccine Discovery Vaccines tuberculosis <i>Mycobacterium</i> macrophage host-pathogen interactions transcriptomics BCG |
| title | Dissecting the <i>Mycobacterium bovis</i> BCG Response to Macrophage Infection to Help Prioritize Targets for Anti-Tuberculosis Drug and Vaccine Discovery |
| title_full | Dissecting the <i>Mycobacterium bovis</i> BCG Response to Macrophage Infection to Help Prioritize Targets for Anti-Tuberculosis Drug and Vaccine Discovery |
| title_fullStr | Dissecting the <i>Mycobacterium bovis</i> BCG Response to Macrophage Infection to Help Prioritize Targets for Anti-Tuberculosis Drug and Vaccine Discovery |
| title_full_unstemmed | Dissecting the <i>Mycobacterium bovis</i> BCG Response to Macrophage Infection to Help Prioritize Targets for Anti-Tuberculosis Drug and Vaccine Discovery |
| title_short | Dissecting the <i>Mycobacterium bovis</i> BCG Response to Macrophage Infection to Help Prioritize Targets for Anti-Tuberculosis Drug and Vaccine Discovery |
| title_sort | dissecting the i mycobacterium bovis i bcg response to macrophage infection to help prioritize targets for anti tuberculosis drug and vaccine discovery |
| topic | tuberculosis <i>Mycobacterium</i> macrophage host-pathogen interactions transcriptomics BCG |
| url | https://www.mdpi.com/2076-393X/10/1/113 |
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