Mycobacterium tuberculosis resides within a host macrophage for most of its infection cycle. The bacterium exerts an extreme influence over the metabolism of both the host cell and the surrounding tissue. The altered metabolic state of the host cell, which is converted into a foamy macrophage, appears to maximize the survival potential of Mtb. Intracellular Mtb utilizes host cholesterol and fatty acids as its primary carbon source. This metabolic interplay can be demonstrated with bacterial mutants defective in carbon assimilation pathways, by live cell imaging and tracking of fluorescently-tagged lipid substrates, and through the identification of small molecule inhibitors that limit bacterial survival in a host cell environment. A large, unbiased screen of 340,000 compounds for those toxic to intracellular bacilli identified cholesterol degradation and propionyl-CoA flux as major points of effective intervention against intracellular Mtb.
In sub-Saharan Africa HIV remains the most significant risk factor for active tuberculosis, even following extended treatment by ART. Recent studies indicate that in areas of high TB transmission the majority of co-infections are due to new, and not reactivated TB infections. Experimental co-infections of Mtb and HIV in culture demonstrated synergy at the level of the infected macrophage implying it extends beyond loss of CD4 surveillance. We recently developed a FISH-based detection protocol for identification of HIV at the single cell level in HIV-infected individuals. Analysis of the cells in the airway recovered by broncho-alveolar lavage demonstrated the following: (1) HIV was readily detectable in the alveolar macrophages (AM) of HIV-infected individuals. (2) Despite extended ART treatment, which removed peripheral viremia, viral message was still detectable in AM. (3) The presence of HIV in AM preceded both sero-conversion, and the establishment of peripheral viremia. The potential of HIV-infected AM as a portal for infection by respiratory pathogens, such as Mtb, will be discussed.