TB and AIDS
AIDS in HIV-infected individuals (e.g., low CD4+ T cells) is one of the most important contributors to the develop-ment of TB in co-infected individuals in many parts of the world, including the United States. The low CD4+ T cell counts translate into suboptimal macrophage activation and an inability to mount a protective response. HIV-co-infection is the greatest single risk factor for progres-sion from M. tuberculosis infection to dis-ease. The risk of developing disease after infection with M. tuberculosis in an HIV-co-infected person is about 5 to 15 percent per year, compared with a lifetime risk of developing active TB after infection of about 10 percent in immunocompetent individuals. Furthermore, the inability to mount an effective adaptive immune response leads to a more progressive course of TB in HIV-infected individuals. Miliary TB, a highly disseminated form of TB that can affect multiple organs, is also more frequent in AIDS patients. Fur-thermore, some evidence suggests that the interaction might be reciprocal, since active TB might stimulate viral replication, thereby accelerating the onset of AIDS, perhaps through tumor necrosis factor-alpha (TNF-α,) which induces viral tran-scription, and/or activation of the CD4+ T cells that support viral replication. Cur-rent estimates indicate that there are about 11 million individuals co-infected with HIV and M. tuberculosis worldwide. A recent study found that of an estimated 1.8 million deaths from TB, 12 percent were attributable to HIV, and similarly, TB was responsible for 11 percent of all deaths due to AIDS in adults.
The emergence of drug-resistant strains of M. tuberculosis is another important fac-tor modifying the current TB epidemic. A strain is considered multidrug resistant (MDR) if it is resistant to at least isonia-zid and rifampicin, the two most effective drugs for TB. Rapidly spreading MDR M. tuberculosis strains, that are resistant to all four first-line TB drugs, including isonia-zid, rifampin, pyrazinamide, and etham-butol, have already emerged. According to WHO estimates, around 5 percent of all active TB cases worldwide are caused by MDR strains.
The Tubercle Bacillus
Mycobacterium tuberculosis belongs to the class Actinobacteria, order Actinomyce-tales, suborder Corynebacterineae, family Mycobacteriaceae. The suborder Coryne-bacterineae encompasses other high G+C gram-positive bacteria including members of the Nocardia, Rhodococcus, and Cory-nebacterium families. M. tuberculosis bacilli are nonmotile rod-shaped bacteria with general dimensions ranging from 1 to 4 μm in length and 0.3 to 0.6 μm in diameter. Though M. tuberculosis requires oxygen for growth, it can grow at low oxygen ten-sions and even survive complete oxygen deprivation.
Mycobacteria are notorious for being very slow growers. M. smegmatis, a fast-growing innocuous mycobacterial sap-rophyte used as a surrogate to study M. tuberculosis, has a division time of about 3 hours in axenic culture and takes 3–4 days to form a colony on agar. M. tubercu-losis has a doubling time of about 20 hours in culture and formation of a colony on agar requires 18–21 days. One of the most
striking features of mycobacterial cells is their tremendously complex lipid-rich envelope, which comprises half of the cell’s dry weight. This property causes mycobac-terial cells to aggregate into clumps in cul-ture, making their experimental manipula-tion difficult. Limited studies suggest that mycobacterial cells might be relatively less permeable to hydrophilic substrates due to the presence of mycolic acids and myco-sides; this impermeability could prevent transport of hydrophilic substrates into the cell. This lipid “shield,” which causes M. tuberculosis to retain carbol fuchsin dye despite acid treatment (“acid fastness”), plays an important protective function from physical and chemical stress, and accumulating evidence indicates that its components mediate complex interac-tions with the host immune response. These properties might also limit the abil-ity of certain drugs to efficiently enter the cell.
In 1998, Cole and colleagues were the first to sequence an M. tuberculosis genome – that of virulent laboratory strain H37Rv. A recent clinical isolate, termed CDC1551, was sequenced shortly after, and a third clinical isolate (strain 210) has also been completed. This wealth of information has uncovered unique aspects about mycobac-terial biology. The constant G+C content of around 65 percent throughout mycobacte-rial genomes suggests the absence of hori-zontally acquired pathogenicity islands, which are widespread in other pathogenic bacteria. The most salient characteristic of the M. tuberculosis and other mycobacterial genomes is the presence of lots of genes dedicated to lipid metabolism (more than 8 percent of the M. tuberculosis genome); considering that nearly 40 percent of the dry weight of the mycobacterial cell wall is made up of lipids, it is reasonable to conclude that lipid metabolism plays a major role in the biology of mycobacteria.