TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis

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dc.contributor.authorFrancisco, Ngiambuduluen_ZA
dc.contributor.authorHsu, Nai-Jenen_ZA
dc.contributor.authorKeeton, Roanneen_ZA
dc.contributor.authorRandall, Philippaen_ZA
dc.contributor.authorSebesho, Boipeloen_ZA
dc.contributor.authorAllie, Nasiemaen_ZA
dc.contributor.authorGovender, Dhirendraen_ZA
dc.contributor.authorQuesniaux, Valerieen_ZA
dc.contributor.authorRyffel, Bernharden_ZA
dc.contributor.authorKellaway, Lauristonen_ZA
dc.contributor.authorJacobs, Muazzamen_ZA
dc.date.accessioned2015-12-07T08:50:56Z
dc.date.available2015-12-07T08:50:56Z
dc.date.issued2015en_ZA
dc.description.abstractBACKGROUND: Tuberculosis (TB) affects one third of the global population, and TB of the central nervous system (CNS-TB) is the most severe form of tuberculosis which often associates with high mortality. The pro-inflammatory cytokine tumour necrosis factor (TNF) plays a critical role in the initial and long-term host immune protection against Mycobacterium tuberculosis (M. tuberculosis) which involves the activation of innate immune cells and structure maintenance of granulomas. However, the contribution of TNF, in particular neuron-derived TNF, in the control of cerebral M. tuberculosis infection and its protective immune responses in the CNS were not clear. METHODS: We generated neuron-specific TNF-deficient (NsTNF / ) mice and compared outcomes of disease against TNF f/f control and global TNF / mice. Mycobacterial burden in brains, lungs and spleens were compared, and cerebral pathology and cellular contributions analysed by microscopy and flow cytometry after M. tuberculosis infection. Activation of innate immune cells was measured by flow cytometry and cell function assessed by cytokine and chemokine quantification using enzyme-linked immunosorbent assay (ELISA). RESULTS: Intracerebral M. tuberculosis infection of TNF / mice rendered animals highly susceptible, accompanied by uncontrolled bacilli replication and eventual mortality. In contrast, NsTNF / mice were resistant to infection and presented with a phenotype similar to that in TNF f/f control mice. Impaired immunity in TNF / mice was associated with altered cytokine and chemokine synthesis in the brain and characterised by a reduced number of activated innate immune cells. Brain pathology reflected enhanced inflammation dominated by neutrophil influx. CONCLUSION: Our data show that neuron-derived TNF has a limited role in immune responses, but overall TNF production is necessary for protective immunity against CNS-TB.en_ZA
dc.identifier.apacitationFrancisco, N., Hsu, N., Keeton, R., Randall, P., Sebesho, B., Allie, N., ... Jacobs, M. (2015). TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis. <i>Journal of Neuroinflammation</i>, http://hdl.handle.net/11427/15640en_ZA
dc.identifier.chicagocitationFrancisco, Ngiambudulu, Nai-Jen Hsu, Roanne Keeton, Philippa Randall, Boipelo Sebesho, Nasiema Allie, Dhirendra Govender, et al "TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis." <i>Journal of Neuroinflammation</i> (2015) http://hdl.handle.net/11427/15640en_ZA
dc.identifier.citationFrancisco, N. M., Hsu, N. J., Keeton, R., Randall, P., Sebesho, B., Allie, N., ... & Jacobs, M. (2015). TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis. Journal of neuroinflammation, 12(1), 125.en_ZA
dc.identifier.ris TY - Journal Article AU - Francisco, Ngiambudulu AU - Hsu, Nai-Jen AU - Keeton, Roanne AU - Randall, Philippa AU - Sebesho, Boipelo AU - Allie, Nasiema AU - Govender, Dhirendra AU - Quesniaux, Valerie AU - Ryffel, Bernhard AU - Kellaway, Lauriston AU - Jacobs, Muazzam AB - BACKGROUND: Tuberculosis (TB) affects one third of the global population, and TB of the central nervous system (CNS-TB) is the most severe form of tuberculosis which often associates with high mortality. The pro-inflammatory cytokine tumour necrosis factor (TNF) plays a critical role in the initial and long-term host immune protection against Mycobacterium tuberculosis (M. tuberculosis) which involves the activation of innate immune cells and structure maintenance of granulomas. However, the contribution of TNF, in particular neuron-derived TNF, in the control of cerebral M. tuberculosis infection and its protective immune responses in the CNS were not clear. METHODS: We generated neuron-specific TNF-deficient (NsTNF / ) mice and compared outcomes of disease against TNF f/f control and global TNF / mice. Mycobacterial burden in brains, lungs and spleens were compared, and cerebral pathology and cellular contributions analysed by microscopy and flow cytometry after M. tuberculosis infection. Activation of innate immune cells was measured by flow cytometry and cell function assessed by cytokine and chemokine quantification using enzyme-linked immunosorbent assay (ELISA). RESULTS: Intracerebral M. tuberculosis infection of TNF / mice rendered animals highly susceptible, accompanied by uncontrolled bacilli replication and eventual mortality. In contrast, NsTNF / mice were resistant to infection and presented with a phenotype similar to that in TNF f/f control mice. Impaired immunity in TNF / mice was associated with altered cytokine and chemokine synthesis in the brain and characterised by a reduced number of activated innate immune cells. Brain pathology reflected enhanced inflammation dominated by neutrophil influx. CONCLUSION: Our data show that neuron-derived TNF has a limited role in immune responses, but overall TNF production is necessary for protective immunity against CNS-TB. DA - 2015 DB - OpenUCT DO - 10.1186/s12974-015-0345-1 DP - University of Cape Town J1 - Journal of Neuroinflammation LK - https://open.uct.ac.za PB - University of Cape Town PY - 2015 T1 - TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis TI - TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis UR - http://hdl.handle.net/11427/15640 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/15640
dc.identifier.urihttp://dx.doi.org/10.1186/s12974-015-0345-1
dc.identifier.vancouvercitationFrancisco N, Hsu N, Keeton R, Randall P, Sebesho B, Allie N, et al. TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis. Journal of Neuroinflammation. 2015; http://hdl.handle.net/11427/15640.en_ZA
dc.language.isoengen_ZA
dc.publisherBioMed Central Ltden_ZA
dc.publisher.departmentDivision of Anatomical Pathologyen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an Open Access article distributed under the terms of the Creative Commons Attribution Licenseen_ZA
dc.rights.holder2015 Francisco et al.en_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/4.0en_ZA
dc.sourceJournal of Neuroinflammationen_ZA
dc.source.urihttp://www.jneuroinflammation.com/en_ZA
dc.subject.otherMycobacterium tuberculosisen_ZA
dc.subject.otherInfectionen_ZA
dc.subject.otherTumour necrosis factoren_ZA
dc.subject.otherNeuronen_ZA
dc.titleTNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosisen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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