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

Ngiambudulu M Francisco,Nasiema Allie,Lauriston Kellaway,Dhirendra Govender,Philippa Randall,Bernhard Ryffel,Muazzam Jacobs,Roanne Keeton,Valerie Quesniaux,Boipelo Sebesho,Nai-Jen Hsu

doi:10.1186/s12974-015-0345-1

Abstract

BackgroundTuberculosis (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.MethodsWe 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).ResultsIntracerebral 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.ConclusionOur 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.

Highlights

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
tumour necrosis factor (TNF) regulates M. tuberculosis dissemination into the brain but infection of neurons is TNF independent TNF plays an important role in host immunity against M. tuberculosis dissemination and latent infection [30,31,32]
Inhibition of TNF leads to M. tuberculosis dissemination which causes extrapulmonary TB including severe Central nervous system (CNS)-TB [35, 36]

Summary

Introduction

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. Tuberculosis of the central nervous system (CNS-TB) is associated with significant mortality and high distressing levels of neurological morbidity, the majority of survivors suffering permanent neurologic complications [1,2,3]. It disproportionately affects children, especially in the developing world and immunocompromised individuals despite the availability of anti-tuberculosis treatment [3,4,5]. The latter hypothesis seems controversial, as myeloid cellular traffic is severely restricted into the CNS prior to invasion by M. tuberculosis [11], lymphoid cells in physiological state can bypass the BBB by entering the subarachnoid space via the meningeal veins or the choroid plexus [12, 13]

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