title: TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Ngiambudulu M
authors.initials: NM
authors.lastname: Francisco
authors.affiliation: 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.
authors.forename: Nai-Jen
authors.initials: NJ
authors.lastname: Hsu
authors.affiliation: 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.
authors.forename: Roanne
authors.initials: R
authors.lastname: Keeton
authors.affiliation: 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.
authors.forename: Philippa
authors.initials: P
authors.lastname: Randall
authors.affiliation: 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.
authors.forename: Boipelo
authors.initials: B
authors.lastname: Sebesho
authors.affiliation: 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.|Division for Postgraduate Studies, University of the Western Cape, Bellville, South Africa. naallie@uwc.ac.za.
authors.forename: Nasiema
authors.initials: N
authors.lastname: Allie
authors.affiliation: Division of Anatomical Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. dhiren.govender@uct.ac.za.|National Health Laboratory Service, Johannesburg, South Africa. dhiren.govender@uct.ac.za.
authors.forename: Dhirendra
authors.initials: D
authors.lastname: Govender
authors.affiliation: Experimental and Molecular Immunology and Neurogenetics, University of Orleans, Orleans, France. quesniaux@cnrs-orleans.fr.|CNRS UMR7355, Orleans, France. quesniaux@cnrs-orleans.fr.
authors.forename: Valerie
authors.initials: V
authors.lastname: Quesniaux
authors.affiliation: Experimental and Molecular Immunology and Neurogenetics, University of Orleans, Orleans, France. bryffel@cnrs-orleans.fr.|CNRS UMR7355, Orleans, France. bryffel@cnrs-orleans.fr.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.affiliation: Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. lauriston.kellaway@uct.ac.za.
authors.forename: Lauriston
authors.initials: L
authors.lastname: Kellaway
authors.affiliation: 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.|National Health Laboratory Service, Johannesburg, South Africa. muazzam.jacobs@uct.ac.za.
authors.forename: Muazzam
authors.initials: M
authors.lastname: Jacobs
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D049109:Cell Proliferation / Q000502:physiology; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000382:microbiology / Q000473:pathology; D004195:Disease Models, Animal; D060467:Disease Resistance / Q000276:immunology; D054884:Host-Pathogen Interactions / Q000276:immunology / Q000502:physiology*; D007113:Immunity, Innate / Q000276:immunology / Q000502:physiology*; D008264:Macrophages / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000382:microbiology / Q000473:pathology; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D009474:Neurons / Q000382:microbiology* / Q000473:pathology*; D020306:Tuberculosis, Central Nervous System / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014779:Virus Replication / Q000502:physiology*
chemical_list: D018925:Chemokines; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha