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J Neuroinflammation. 2015 Jun 26;12:125. doi: 10.1186/s12974-015-0345-1.

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

Author information

1
Division of Immunology, Department of Clinical Laboratory Science, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, 7925, South Africa. franciscongiamb@gmail.com.
2
Division of Immunology, Department of Clinical Laboratory Science, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, 7925, South Africa. nai-jen.hsu@uct.ac.za.
3
Division of Immunology, Department of Clinical Laboratory Science, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, 7925, South Africa. roanne.keeton@gmail.com.
4
Division of Immunology, Department of Clinical Laboratory Science, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, 7925, South Africa. philippa_randall@yahoo.co.uk.
5
Division of Immunology, Department of Clinical Laboratory Science, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, 7925, South Africa. bsebesho@gmail.com.
6
Division of Immunology, Department of Clinical Laboratory Science, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, 7925, South Africa. naallie@uwc.ac.za.
7
Division for Postgraduate Studies, University of the Western Cape, Bellville, South Africa. naallie@uwc.ac.za.
8
Division of Anatomical Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. dhiren.govender@uct.ac.za.
9
National Health Laboratory Service, Johannesburg, South Africa. dhiren.govender@uct.ac.za.
10
Experimental and Molecular Immunology and Neurogenetics, University of Orleans, Orleans, France. quesniaux@cnrs-orleans.fr.
11
CNRS UMR7355, Orleans, France. quesniaux@cnrs-orleans.fr.
12
Experimental and Molecular Immunology and Neurogenetics, University of Orleans, Orleans, France. bryffel@cnrs-orleans.fr.
13
CNRS UMR7355, Orleans, France. bryffel@cnrs-orleans.fr.
14
Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. lauriston.kellaway@uct.ac.za.
15
Division of Immunology, Department of Clinical Laboratory Science, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, 7925, South Africa. muazzam.jacobs@uct.ac.za.
16
National Health Laboratory Service, Johannesburg, South Africa. muazzam.jacobs@uct.ac.za.

Abstract

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.

PMID:
26112704
PMCID:
PMC4488051
DOI:
10.1186/s12974-015-0345-1
[Indexed for MEDLINE]
Free PMC Article

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