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  • Oral presentation
  • Open Access

From lung to brain: the pathogenesis of cerebral tuberculosis

BMC Proceedings20082 (Suppl 1) :S41

  • Published:


  • Tuberculosis
  • Meningitis
  • Thalidomide
  • Alveolar Macrophage
  • Innate Immune Response

Cerebral tuberculosis kills or disables a higher proportion of sufferers than any other form of tuberculosis, yet little is known about the pathogenesis. The seminal studies of Rich and McCordock, performed more than 70 years ago, demonstrated that the development of tuberculous meningitis requires two steps. First, bacteria travel in the blood from the lungs to the meninges where they form discrete foci of infection (Rich foci). Second, foci rupture and release bacteria into the subarachnoid space so heralding the onset of meningitis [1]. Our understanding of the pathogenesis of cerebral tuberculosis has advanced little since these studies.

The primary focus of tuberculous infection is almost always the lung, but how bacteria travel from lung to blood – a critical step in the development of all extra-pulmonary disease – is unknown. M. tuberculosis primarily infects pulmonary alveolar macrophages, which may transport bacteria from the alveolus to the blood. However, the discovery that M. tuberculosis haematogenous dissemination was dependent upon heparin-binding haemagglutinin adhesin, a bacterial virulence factor that interacts with epithelial cells, suggests other trafficking pathways may be important [2]. Animal models of tuberculosis have reported bacteria can be found in the blood soon after pulmonary infection and before the onset of adaptive immunity. Consequently, it is hypothesized that the development of disseminated tuberculosis reflects a failure of the innate immune response to infection. Human studies have shown an association between the development of tuberculous meningitis and polymorphisms in genes encoding Toll-like receptor-2 and TIRAP (an adaptor protein that mediates signals from Toll-like receptors). Recently, we have shown some strains of M. tuberculosis may be more capable of causing disseminated disease than others [3] and there is increasing evidence that different strains elicit different innate immune responses.

Once M. tuberculosis reaches the brain the nature of the inflammatory response has long been considered important in determining clinical outcome. A rabbit model of tuberculous meningitis suggested tumour necrosis factor alpha (TNF-γ) was a critical determinant of disease severity and progression [4], which led to trials of thalidomide (a TNF-γ antagonist) in humans [5]. Sadly, thalidomide did not benefit children with the disease suggesting a more complex role for TNF-γ in human disease. However, controlled trials of adjunctive corticosteroids in children [6] and adults [7] have shown these drugs improve outcome, although this effect has not been clearly linked to decreased intra-cerebral inflammation and the determinants of a protective rather than a destructive immune response remain unclear.

Authors’ Affiliations

Centre for Molecular Microbiology and Infection, Imperial College, London, SW7 2AZ, UK


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© Thwaites; licensee BioMed Central Ltd. 2008

This article is published under license to BioMed Central Ltd.