Recent advances in understanding the human host immune response in tuberculous meningitis
Tuberculous meningitis (TBM), the most severe form of tuberculosis, causes death in approximately 25% cases despite antibiotic therapy, and half of survivors are left with neurological disability. Mortality and morbidity are contributed to by a dysregulated immune response, and adjunctive host-direc...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1326651/full |
| _version_ | 1797361334997745664 |
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| author | James R. Barnacle James R. Barnacle James R. Barnacle Angharad G. Davis Angharad G. Davis Robert J. Wilkinson Robert J. Wilkinson Robert J. Wilkinson |
| author_facet | James R. Barnacle James R. Barnacle James R. Barnacle Angharad G. Davis Angharad G. Davis Robert J. Wilkinson Robert J. Wilkinson Robert J. Wilkinson |
| author_sort | James R. Barnacle |
| collection | DOAJ |
| description | Tuberculous meningitis (TBM), the most severe form of tuberculosis, causes death in approximately 25% cases despite antibiotic therapy, and half of survivors are left with neurological disability. Mortality and morbidity are contributed to by a dysregulated immune response, and adjunctive host-directed therapies are required to modulate this response and improve outcomes. Developing such therapies relies on improved understanding of the host immune response to TBM. The historical challenges in TBM research of limited in vivo and in vitro models have been partially overcome by recent developments in proteomics, transcriptomics, and metabolomics, and the use of these technologies in nested substudies of large clinical trials. We review the current understanding of the human immune response in TBM. We begin with M. tuberculosis entry into the central nervous system (CNS), microglial infection and blood-brain and other CNS barrier dysfunction. We then outline the innate response, including the early cytokine response, role of canonical and non-canonical inflammasomes, eicosanoids and specialised pro-resolving mediators. Next, we review the adaptive response including T cells, microRNAs and B cells, followed by the role of the glutamate-GABA neurotransmitter cycle and the tryptophan pathway. We discuss host genetic immune factors, differences between adults and children, paradoxical reaction, and the impact of HIV-1 co-infection including immune reconstitution inflammatory syndrome. Promising immunomodulatory therapies, research gaps, ongoing challenges and future paths are discussed. |
| first_indexed | 2024-03-08T15:53:08Z |
| format | Article |
| id | doaj.art-dfa5c04e53fc4d41b642d444bfe22383 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-08T15:53:08Z |
| publishDate | 2024-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-dfa5c04e53fc4d41b642d444bfe223832024-01-09T04:21:58ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-01-011410.3389/fimmu.2023.13266511326651Recent advances in understanding the human host immune response in tuberculous meningitisJames R. Barnacle0James R. Barnacle1James R. Barnacle2Angharad G. Davis3Angharad G. Davis4Robert J. Wilkinson5Robert J. Wilkinson6Robert J. Wilkinson7The Francis Crick Institute, London, United KingdomDepartment of Infectious Disease, Imperial College, London, United KingdomCentre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, South AfricaThe Francis Crick Institute, London, United KingdomCentre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, South AfricaThe Francis Crick Institute, London, United KingdomDepartment of Infectious Disease, Imperial College, London, United KingdomCentre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, South AfricaTuberculous meningitis (TBM), the most severe form of tuberculosis, causes death in approximately 25% cases despite antibiotic therapy, and half of survivors are left with neurological disability. Mortality and morbidity are contributed to by a dysregulated immune response, and adjunctive host-directed therapies are required to modulate this response and improve outcomes. Developing such therapies relies on improved understanding of the host immune response to TBM. The historical challenges in TBM research of limited in vivo and in vitro models have been partially overcome by recent developments in proteomics, transcriptomics, and metabolomics, and the use of these technologies in nested substudies of large clinical trials. We review the current understanding of the human immune response in TBM. We begin with M. tuberculosis entry into the central nervous system (CNS), microglial infection and blood-brain and other CNS barrier dysfunction. We then outline the innate response, including the early cytokine response, role of canonical and non-canonical inflammasomes, eicosanoids and specialised pro-resolving mediators. Next, we review the adaptive response including T cells, microRNAs and B cells, followed by the role of the glutamate-GABA neurotransmitter cycle and the tryptophan pathway. We discuss host genetic immune factors, differences between adults and children, paradoxical reaction, and the impact of HIV-1 co-infection including immune reconstitution inflammatory syndrome. Promising immunomodulatory therapies, research gaps, ongoing challenges and future paths are discussed.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1326651/fulltuberculous meningitis (TBM)tuberculosisMycobacterium tuberculosisextrapulmonary tuberculosis (EPTB)immune responsehost-directed therapy |
| spellingShingle | James R. Barnacle James R. Barnacle James R. Barnacle Angharad G. Davis Angharad G. Davis Robert J. Wilkinson Robert J. Wilkinson Robert J. Wilkinson Recent advances in understanding the human host immune response in tuberculous meningitis Frontiers in Immunology tuberculous meningitis (TBM) tuberculosis Mycobacterium tuberculosis extrapulmonary tuberculosis (EPTB) immune response host-directed therapy |
| title | Recent advances in understanding the human host immune response in tuberculous meningitis |
| title_full | Recent advances in understanding the human host immune response in tuberculous meningitis |
| title_fullStr | Recent advances in understanding the human host immune response in tuberculous meningitis |
| title_full_unstemmed | Recent advances in understanding the human host immune response in tuberculous meningitis |
| title_short | Recent advances in understanding the human host immune response in tuberculous meningitis |
| title_sort | recent advances in understanding the human host immune response in tuberculous meningitis |
| topic | tuberculous meningitis (TBM) tuberculosis Mycobacterium tuberculosis extrapulmonary tuberculosis (EPTB) immune response host-directed therapy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1326651/full |
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