Abstract
Tuberculosis (TB) is a chronic infectious disease in which prolonged, non-resolutive inflammation of the lung may lead to metabolic and neuroendocrine dysfunction. Previous studies have reported that individuals coursing pulmonary TB experience cognitive or behavioural changes; however, the pathogenic substrate of such manifestations have remained unknown. Here, using a mouse model of progressive pulmonary TB, we report that, even in the absence of brain infection, TB is associated with marked increased synthesis of both inflammatory and anti-inflammatory cytokines in discrete brain areas such as the hypothalamus, the hippocampal formation and cerebellum accompanied by substantial changes in the synthesis of neurotransmitters. Moreover, histopathological findings of neurodegeneration and neuronal death were found as infection progressed with activation of p38, JNK and reduction in the BDNF levels. Finally, we perform behavioural analysis in infected mice throughout the infection, and our data show that the cytokine and neurochemical changes were associated with a marked onset of cognitive impairment as well as depressive- and anxiety-like behaviour. Altogether, our results suggest that besides pulmonary damage, TB is accompanied by an extensive neuroinflammatory and neurodegenerative state which explains some of the behavioural abnormalities found in TB patients.
Highlights
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (M. tb) [1] and is considered a global priority due to the high number of new diagnoses and its 1.2 million deaths annually [2]
As we wanted to know if pulmonary infection without brain infection generates neuroinflammation, it was mandatory to confirm the lack of cultivable mycobacteria in the brain
Brains collected from mice infected by the intratracheal route with M. tb H37Rv did not show bacillary growth in any day of infection, which confirms the previous report [21], while in the lungs there was a progressive increase in bacillary loads (quantification of colony-forming units (CFUs)) after 21 days of infection
Summary
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (M. tb) [1] and is considered a global priority due to the high number of new diagnoses and its 1.2 million deaths annually [2]. Pro-inflammatory cytokines such as interferon-gamma (IFNγ) and tumour necrosis factor-alpha (TNFα) might affect the progress of depressive disorder by regulating neuronal excitability, synaptic transmission, synaptic plasticity, excitotoxicity and neuronal survival [11]. These mechanisms generate brain inflammation which impacts established depression and pathophysiological anxiety processes, such as monoaminergic neurotransmission alteration, activation of Kynurenine Metabolism pathways, decrease in the synthesis of serotonin (5-HT) [12,13], hippocampal neuronal damage [14] and dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis [15]
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