TB and AIDS
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
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