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

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

The influence of noise exposure on the parameters of a convolution model of the compound action potential

The influence of noise exposure on the parameters of a convolution model of the compound action potential (CAP) was examined. CAPs were recorded in normal-hearing gerbils and in gerbils exposed to a 117 dB SPL 8 kHz band of noise for various durations. The CAPs were fitted with an analytic CAP to obtain the parameters representing the number of nerve fibers (N), the probability density function [P(t)] from a population of nerve fibers, and the single-unit waveform [U(t)]. The results showed that the analytic CAP fitted the physiologic CAPs well with correlations of approximately 0.90. A subsequent analysis using hierarchical linear modeling quantified the change in the parameters as a function of both signal level and hearing threshold. The results showed that noise exposure caused some of the parameter-level functions to simply shift along the signal level axis in proportion to the amount of hearing loss, whereas others shifted along the signal level axis and steepened. Significant changes occurred in the U(t) parameters, but they were not related to hearing threshold. These results suggest that noise exposure alters the physiology underlying the CAP, some of which can be explained by a simple lack of gain, whereas others may not