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TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis
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نویسنده
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francisco n.m. ,hsu n.-j. ,keeton r. ,randall p. ,sebesho b. ,allie n. ,govender d. ,quesniaux v. ,ryffel b. ,kellaway l. ,jacobs m.
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منبع
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journal of neuroinflammation - 2015 - دوره : 12 - شماره : 1
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چکیده
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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 tnff/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 tnff/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. © 2015 francisco et al.
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کلیدواژه
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Infection; Mycobacterium tuberculosis; Neuron; Tumour necrosis factor
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آدرس
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institute of infectious disease and molecular medicine,faculty of health sciences,university of cape town,division of immunology,department of clinical laboratory science,observatory,cape town,7925, South Africa, institute of infectious disease and molecular medicine,faculty of health sciences,university of cape town,division of immunology,department of clinical laboratory science,observatory,cape town,7925, South Africa, institute of infectious disease and molecular medicine,faculty of health sciences,university of cape town,division of immunology,department of clinical laboratory science,observatory,cape town,7925, South Africa, institute of infectious disease and molecular medicine,faculty of health sciences,university of cape town,division of immunology,department of clinical laboratory science,observatory,cape town,7925, South Africa, institute of infectious disease and molecular medicine,faculty of health sciences,university of cape town,division of immunology,department of clinical laboratory science,observatory,cape town,7925, South Africa, institute of infectious disease and molecular medicine,faculty of health sciences,university of cape town,division of immunology,department of clinical laboratory science,observatory,cape town,7925,south africa,university of the western cape,division for postgraduate studies,bellville, South Africa, university of cape town,division of anatomical pathology,faculty of health sciences,cape town,south africa,national health laboratory service,johannesburg, South Africa, university of orleans,experimental and molecular immunology and neurogenetics,orleans,france,cnrs umr7355,orleans, France, university of orleans,experimental and molecular immunology and neurogenetics,orleans,france,cnrs umr7355,orleans, France, university of cape town,department of human biology,faculty of health sciences,cape town, South Africa, institute of infectious disease and molecular medicine,faculty of health sciences,university of cape town,division of immunology,department of clinical laboratory science,observatory,cape town,7925,south africa,national health laboratory service,johannesburg, South Africa
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Authors
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