It has been suggested that apoptosis of infected macrophages is one way in which the host deals with intracellular pathogens and that M. tuberculosis can inhibit this process. To assess the relevance of this process for

human disease, we compared the expression of multiple genes involved in the activation of the extrinsic (“death receptor initiated”) pathway of apoptosis BVD-523 mw in 29 tuberculosis patients, 70 tuberculosis contacts and 27 community controls from Ethiopia. We found that there is a strong upregulation of genes for factors that promote apoptosis in PBMC from individuals with active disease, including TNF-α and its receptors, Fas and FasL and pro-Caspase 8. The anti-apoptotic factor FLIP, however, was also upregulated. A possible explanation for this dichotomy was given by fractionation of PBMC using CD14, which suggests that macrophage/monocytes may regulate several key molecules differently from non-monocytic cells (especially TNF-α and its receptors, a finding confirmed by protein ELISA) potentially reducing the sensitivity to apoptotic death of monocyte/macrophages – the primary host cell for M. tuberculosis. This may represent an important survival strategy for the pathogen. Despite vaccination and drug treatment campaigns, tuberculosis (TB) causes an estimated 8–9 million new cases and mortality of 2–3 million deaths annually 1. The TB epidemic is largely

confined to developing countries, and is particularly serious in Sub-Saharan Africa 2, where it is fanned by the HIV epidemic. Despite the RXDX-106 in vivo high mortality, most infected people do not immediately develop active disease, but become latently infected – though they may later reactivate their disease, if they become immunocompromised 3. It is thought that perhaps as much

as a third of the world’s population is latently infected, 4 complicating control Thalidomide efforts by providing a reservoir from which new cases continually arise. Understanding immunity to Mycobacterium tuberculosis, so that more effective vaccines can be developed, is thus an international priority. The response to infection with M. tuberculosis is characterized by a strong inflammatory cell-mediated immune response, with elevated expression of both TNF-α 5–7 and IFN-γ 8–10. These two cytokines are essential for controlling mycobacterial infections 11–13 but in most cases, M. tuberculosis survives to establish a latent infection – which can rapidly reactivate if TNF-α production is blocked 14. The precise mechanisms involved in this process are still only poorly known. We and others have previously shown that a bias towards IL-4 expression is associated with elevated risk of disease 15 while a bias towards the IL-4 antagonist IL-4δ2, or towards IFN-γ, is associated with reduced pathology, a better prognosis after infection, recovery after treatment and with the ability to maintain the infection in a latent state 16–19. Thus, the immune response to M.