Tubercle bacillus Koch 1882
Mycobacterium tuberculosis is a species of pathogenic bacteria in the
Mycobacteriaceae and the causative agent of tuberculosis.
First discovered in 1882 by Robert Koch, M. tuberculosis has an
unusual, waxy coating on its cell surface primarily due to the
presence of mycolic acid. This coating makes the cells impervious to
Gram staining, and as a result, M. tuberculosis can appear either
Gram-negative or Gram-positive. Acid-fast stains such as
Ziehl-Neelsen, or fluorescent stains such as auramine are used instead
to identify M. tuberculosis with a microscope. The physiology of M.
tuberculosis is highly aerobic and requires high levels of oxygen.
Primarily a pathogen of the mammalian respiratory system, it infects
the lungs. The most frequently used diagnostic methods for
tuberculosis are the tuberculin skin test, acid-fast stain, culture,
and polymerase chain reaction.
The M. tuberculosis genome was sequenced in 1998.
2.1 Strain variation
4.1 Co-evolution with modern humans
5 Host genetics
9 See also
11 External links
M. tuberculosis is part of a complex that has at least 9 species: M.
tuberculosis sensu stricto, M. africanum, M. canetti, M. bovis, M.
caprae, M. microti, M. pinnipedii, M. mungi, and M. orygis. It
requires oxygen to grow, does not produce spores, and is
nonmotile. M. tuberculosis divides every 15–20 hours. This is
extremely slow compared with other bacteria, which tend to have
division times measured in minutes (
Escherichia coli can divide
roughly every 20 minutes). It is a small bacillus that can withstand
weak disinfectants and can survive in a dry state for weeks. Its
unusual cell wall is rich in lipids such as mycolic acid and is likely
responsible for its resistance to desiccation and is a key virulence
Other bacteria are commonly identified with a microscope by staining
them with Gram stain. However, the mycolic acid in the cell wall of M.
tuberculosis does not absorb the stain. Instead, acid-fast stains such
as Ziehl-Neelsen stain, or fluorescent stains such as auramine are
used. Cells are curved rod-shaped and are often seen wrapped
together, due to the presence of fatty acids in the cell wall that
stick together. This appearance is referred to as cording, like
strands of cord that make up a rope. M. tuberculosis is
characterized in tissue by caseating granulomas containing Langhans
giant cells, which have a "horseshoe" pattern of nuclei.
M. tuberculosis can be grown in the laboratory. Compared to other
commonly studied bacteria, M. tuberculosis has a remarkably slow
growth rate, doubling roughly once per day. Commonly used media
include liquids such as Middlebrook 7H9 or 7H12, egg-based solid media
such as Lowenstein-Jensen, and solid agar-based such as Middlebrook
7H11 or 7H10. Visible colonies require several weeks to grow on
agar plates. It is distinguished from other mycobacteria by its
production of catalase and niacin. Other tests to confirm its
identity include gene probes and MALDI-TOF.
Humans are the only known reservoirs of M. tuberculosis. A
misconception is that M. tuberculosis can be spread by shaking hands,
making contact with toilet seats, sharing food or drink, sharing
toothbrushes, or kissing. It can only be spread through air droplets
originating from a person who has the disease either coughing,
sneezing, speaking, or singing.
When in the lungs, M. tuberculosis is phagocytosed by alveolar
macrophages, but they are unable to kill and digest the bacterium. Its
cell wall prevents the fusion of the phagosome with the lysosome,
which contains a host of antibacterial factors. Specifically, M.
tuberculosis blocks the bridging molecule, early endosomal autoantigen
1 (EEA1); however, this blockade does not prevent fusion of vesicles
filled with nutrients. Consequently, the bacteria multiply unchecked
within the macrophage. The bacteria also carry the UreC gene, which
prevents acidification of the phagosome. In addition, production
of the diterpene isotuberculosinol prevents maturation of the
phagosome. The bacteria also evade macrophage-killing by
neutralizing reactive nitrogen intermediates.
Protective granulomas are formed due to the production of cytokines
and upregulation of proteins involved in recruitment. Granulotomatous
lesions are important in both regulating the immune response and
minimizing tissue damage. Moreover, T cells help maintain
Mycobacterium within the granulomas.
The ability to construct M. tuberculosis mutants and test individual
gene products for specific functions has significantly advanced the
understanding of its pathogenesis and virulence factors. Many secreted
and exported proteins are known to be important in pathogenesis.
Aerolysin is a virulence factor of the pathogenic bacterium Aeromonas
hydrophila. Resistant strains of M. tuberculosis have developed
resistance to more than one TB drug, due to mutations in their genes.
Typing of strains is useful in the investigation of tuberculosis
outbreaks, because it gives the investigator evidence for or against
transmission from person to person. Consider the situation where
person A has tuberculosis and believes he acquired it from person B.
If the bacteria isolated from each person belong to different types,
then transmission from B to A is definitively disproved; however, if
the bacteria are the same strain, then this supports (but does not
definitively prove) the hypothesis that B infected A.
Until the early 2000s, M. tuberculosis strains were typed by pulsed
field gel electrophoresis (PFGE). This has now been superseded by
variable numbers of tandem repeats (VNTR), which is technically easier
to perform and allows better discrimination between strains. This
method makes use of the presence of repeated
DNA sequences within the
M. tuberculosis genome.
Three generations of VNTR typing for M. tuberculosis are noted. The
first scheme, called exact tandem repeat, used only five loci, but
the resolution afforded by these five loci was not as good as PFGE.
The second scheme, called mycobacterial interspersed repetitive unit,
had discrimination as good as PFGE. The third generation
(mycobacterial interspersed repetitive unit – 2) added a further
nine loci to bring the total to 24. This provides a degree of
resolution greater than PFGE and is currently the standard for typing
M. tuberculosis. However, with regard to archaeological remains,
additional evidence may be required because of possible contamination
from related soil bacteria.
Antibiotic resistance in M. tuberculosis typically occurs due to
either the accumulation of mutations in the genes targeted by the
antibiotic or a change in titration of the drug. M. tuberculosis
is considered to be multidrug-resistant (MDR TB) if it has developed
drug resistance to both rifampicin and isoniazid, which are the most
important antibiotics used in treatment. Additionally, extensively
drug-resistant M. tuberculosis (XDR TB) is characterized by resistance
to both isoniazid and rifampin, plus any fluoroquinolone and at least
one of three injectable second-line drugs (i.e., amikacin, kanamycin,
M. tuberculosis (stained red) in tissue (blue)
Cording M. tuberculosis (
H37Rv strain) culture on the luminescent
The genome of the
H37Rv strain was published in 1998. Its size is
4 million base pairs, with 3,959 genes; 40% of these genes have had
their function characterised, with possible function postulated for
another 44%. Within the genome are also six pseudogenes.
The genome contains 250 genes involved in fatty acid metabolism, with
39 of these involved in the polyketide metabolism generating the waxy
coat. Such large numbers of conserved genes show the evolutionary
importance of the waxy coat to pathogen survival. Furthermore,
experimental studies have since validated the importance of a lipid
metabolism for M. tuberculosis, consisting entirely of host-derived
lipids such as fats and cholesterol.
Bacteria isolated from the lungs
of infected mice were shown to preferentially use fatty acids over
carbohydrate substrates. M. tuberculosis can also grow on the
lipid cholesterol as a sole source of carbon, and genes involved in
the cholesterol use pathway(s) have been validated as important during
various stages of the infection lifecycle of M. tuberculosis,
especially during the chronic phase of infection when other nutrients
are likely not available.
About 10% of the coding capacity is taken up by the PE/PPE gene
families that encode acidic, glycine-rich proteins. These proteins
have a conserved N-terminal motif, deletion of which impairs growth in
macrophages and granulomas.
Nine noncoding sRNAs have been characterised in M. tuberculosis,
with a further 56 predicted in a bioinformatics screen.
In 2013, a study on the genome of several sensitive, ultraresistant,
and multiresistant M. tuberculosis strains was made to study
antibiotic resistance mechanisms. Results reveal new relationships and
drug resistance genes not previously associated and suggest some genes
and intergenic regions associated with drug resistance may be involved
in the resistance to more than one drug. Noteworthy is the role of the
intergenic regions in the development of this resistance, and most of
the genes proposed in this study to be responsible for drug resistance
have an essential role in the development of M. tuberculosis.
The M. tuberculosis complex evolved in Africa and most probably in the
Horn of Africa. The M. tuberculosis group has a number of
members that include M. africanum, M. bovis (Dassie's bacillus), M.
caprae, M. microti, M. mungi, M. orygis, and M. pinnipedii. This group
may also include the M. canettii clade.
The M. canettii clade — which includes M. prototuberculosis — is a
group of smooth-colony
Mycobacterium species. Unlike the established
members of the M. tuberculosis group, they undergo recombination with
other species. The majority of the known strains of this group have
been isolated from the Horn of Africa. The ancestor of M. tuberculosis
appears to be M. canettii, first described in 1969.
The established members of the M. tuberculosis complex are all clonal
in their spread. The main human-infecting species have been classified
into seven spoligotypes: type 1 contains the East African-Indian
(EAI), the Manila family of strains and some Manu (Indian) strains;
type 2 is the
Beijing group; type 3 consists of the Central Asian
(CAS) strains; type 4 of the
Haarlem (H/T), Latin
Mediterranean (LAM) and X strains; types 5 and 6 correspond to
M. africanum and are observed predominantly and at very high frequency
in West Africa. A seventh type has been isolated from the Horn of
Africa. The other species of this complex belong to a number of
spoligotypes and do not normally infect humans.
Types 2, 3 and 4 had the most common ancestor and all share a unique
duplication event. Types 2 and 3 are more closely related to each
other than to the other types. Types 5 and 6 are most closely aligned
with the species that do not normally infect humans. Type 3 has been
divided into two clades: CAS-Kili (found in Tanzania) and CAS-Delhi
India and Saudi Arabia).
Type 4 is also known as the Euro-American lineage. Subtypes within
this type include Latin American Mediterranean, Uganda I, Uganda II,
Haarlem, X, and Congo.
The most recent common ancestor of the M. tuberculosis complex evolved
between 40,000 and 70,000 years ago. The most recent common
ancestors of the EAI and LAM strains have been estimated to be 13,700
and 7,000 years ago, respectively. The Beijing- CAS strains diverged
about 17,100 years ago. All types of the M. tuberculosis began their
current expansion about 5000 years ago—a period that coincides with
the appearance of M. bovis. The
Beijing strain appears to have been
the most successful with around a 500-fold increase in effective
population size (Ne) since its expansion began. The least successful
of the main lineages appears to have been those limited to Africa,
where they have undergone an Ne increase of only five-fold. Since its
initial evolution, M. bovis has undergone an expansion of Ne of about
Co-evolution with modern humans
Much evidence suggests the different strains of the obligate human
pathogen M. tuberculosis have co-evolved, migrated, and expanded with
their human hosts. This well-supported theory is consistent with
the bacterium’s phylogeny and phylogeography. With the
global spread of M. tuberculosis, studies have examined whether
geographically defined human populations are especially susceptible to
the transmission of a particular lineage or strain of M. tuberculosis.
They have found that even when transmission of M. tuberculosis occurs
in an urban center outside the region of origin, a human host’s
region of origin is predictive of which TB strain they carry and that
genetically differentiated populations of M. tuberculosis do indeed
preserve stable associations with host populations from their
geographic region. The fact that all six principle
phylogeographic lineages are found in Africa combined with the belief
that ancestral mycobacteria may have impacted early hominids in East
Africa as early as three million years ago, once again point to the
theory of M. tuberculosis originating in Africa and expanding
alongside the human migration out of East Africa. The significant
correlation of increased frequency of tuberculosis-resistant alleles
with the duration of a human population’s urban settlement similarly
points to an extensive co-evolutionary relationship. Some of the
most compelling data concerning the co-expansion of M. tuberculosis
with modern humans come from a study that compared M. tuberculosis
phylogeny to human mitochondrial genomes and found impressive
similarities in the patterns and geographical locations of branching
and divergence events. The match between M. tuberculosis and human
mitochondrial phylogenies supports an extended relationship between M.
tuberculosis and its host, while the clear expansion of this bacterial
pathogen during the
Neolithic Demographic Transition
Neolithic Demographic Transition (around 10,000
years ago) suggests that M. tuberculosis was able to adapt to changing
human populations and that the historical success of this pathogen was
driven at least in part by dramatic increases in human host population
The nature of the host-pathogen interaction between humans and M.
tuberculosis is considered to have a genetic component. A group of
rare disorders called Mendelian susceptibility to mycobacterial
diseases was observed in a subset of individuals with a genetic defect
that results in increased susceptibility to mycobacterial
Early case and twin studies have indicated that genetic component are
important in host susceptibility to M. tuberculosis. Recent
genome-wide association studies (GWAS) have identified three genetic
risk loci, including at positions 11p13 and 18q11. As is
common in GWAS, the variants discovered have moderate effect sizes.
As an intracellular pathogen, M. tuberculosis is exposed to a variety
of DNA-damaging assaults, primarily from host-generated antimicrobial
toxic radicals. Exposure to reactive oxygen species and/or reactive
nitrogen species causes different types of
DNA damage including
oxidation, depurination, methylation, and deamination that can give
rise to single- and double-strand breaks (DSBs).
DnaE2 polymerase is upregulated in M. tuberculosis by several
DNA-damaging agents, as well as during infection of mice. Loss of
DNA polymerase reduces the virulence of M. tuberculosis in
mice. DnaE2 is an error-prone repair
DNA repair polymerase that
appears to contribute to M. tuberculosis survival during infection.
The two major pathways employed in repair of DSBs are homologous
recombinational repair (HR) and nonhomologous end joining (NHEJ).
Macrophage-internalized M. tuberculosis is able to persist if either
of these pathways is defective, but is attenuated when both pathways
are defective. This indicates that intracellular exposure of M.
tuberculosis to reactive oxygen and/or reactive nitrogen species
results in the formation of DSBs that are repaired by HR or NHEJ.
However deficiency of DSB repair does not appear to impair M.
tuberculosis virulence in animal models.
Main article: History of tuberculosis
M. tuberculosis, then known as the "tubercle bacillus", was first
described on 24 March 1882 by Robert Koch, who subsequently received
Nobel Prize in Physiology or Medicine
Nobel Prize in Physiology or Medicine for this discovery in 1905;
the bacterium is also known as "Koch's bacillus".
Tuberculosis has existed throughout history, but the name has changed
frequently over time. In 1720, though, the history of tuberculosis
started to take shape into what is known of it today; as the physician
Benjamin Marten described in his A Theory of Consumption, tuberculosis
may be caused by small living creatures transmitted through the air to
The BCG vaccine, which was derived from M. bovis, has had limited
success in preventing tuberculosis.
Philip D'Arcy Hart
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