REVIEW ARTICLE
Survival mechanisms of pathogenic Mycobacterium
tuberculosis H
37
Rv
Laxman S. Meena and Rajni
Institute of Genomics and Integrative Biology, Delhi, India
Introduction
Five decades of tuberculosis (TB) control programs
using potentially efficacious drugs have failed to reduce
prevalence of infection by the causative organism,
Mycobacterium tuberculosis, in most parts of the world
[1]. A large number of individuals (more than three
billion) have been vaccinated with Bacillus Calmette-
Gue
´
rin (BCG), but TB still kills more than 50 000
people every week and approximately one-third of the
world’s population is asymptomatically infected by
M. tuberculosis [2]. It is estimated that 200 million
people will display symptoms and that 35 million will
die of TB between 2000 and 2020 if control and pre-
ventive measures are not strengthened (World Health
Organization Annual Report, 2000). TB accounts for
32% of the deaths in HIV infected individuals [3]. The
situation is exacerbated by the emergence of multi-
drug-resistant TB [4] and the catastrophic nexus
between AIDS and TB [5,6]. A prerequisite for effec-
tive control is an understanding of the host–pathogen
interaction and its contribution to the development of
diseases. Our knowledge about how M. tuberculosis

effective in internalizing and clearing most of the bacteria, M. tuberculosis
H
37
Rv has evolved a number of very effective survival strategies, including:
(a) the inhibition of phagosome–lysosome fusion; (b) the inhibition of
phagosome acidification; (c) the recruitment and retention of tryptophan-
aspartate containing coat protein on phagosomes to prevent their delivery
to lysosomes; and (d) the expression of members of the host-induced repeti-
tive glycine-rich protein family of proteins. However, the mechanisms by
which M. tuberculosis H
37
Rv enters the host cell, circumvents host defenses
and spreads to neighboring cell are not completely understood. Therefore,
a better understanding of host–pathogen interaction is essential if the glo-
bal tuberculosis pandemic is ever to be controlled. This review addresses
some of the pathogenic strategies of the M. tuberculosis H
37
Rv that aids in
its survival and pathogenicity.
Abbreviations
BCG, Bacillus Calmette-Gue
´
rin; LAM, lipoarabinomannan; PE-PGRS, a repetitive glycine-rich protein family; TACO, tryptophan-aspartate
containing coat protein; TB, tuberculosis.
2416 FEBS Journal 277 (2010) 2416–2427 ª 2010 The Authors Journal compilation ª 2010 FEBS
vaccine candidates for the treatment of the disease.
A variety of mechanisms have been suggested to con-
tribute towards the survival of Mycobacterium within
macrophages. These mechanisms are shown as a sche-
matic representation in Fig. 2. The present review aims

Phagosome
Lysosome
Inhibition of fusion of phagosome harbouring
Mycobacteria with lysosome
TACO protein on phagosome
harbouring mycobacteria
TACO
Proton ATPase-
Pump
Virulence
Proteins
Expression of virulence proteins of
PE-PGRS family
Inhibition of acidification of phagosome
harbouring Mycobacteria
Protection from reactive oxidative radicals
Fusion
H
+
O
2
–
.
OH.
H
2
O
2
NO.
AD

[14]. Using whole genome transpositional mutagenesis
techniques, 30 mutants of M. tuberculosis were selected
from a total screen of approximately 2500 mutants
that showed reduced growth. Seven of these mutants
had insertion within a locus involved in the synthesis
of phthiocerol dimycocerosate, an abundant compo-
nent of cell wall biosynthesis [15]. Phthiocerol dimyco-
cerosate was subsequently shown to help entry of
Mycobacterium leprae into peripheral nerve cells by
binding to nerve cell laminin protein [16]. The majority
of exported proteins and protective antigens of
M. tuberculosis are a triad of related gene products
called the antigen 85 complex, each having fibronectin
binding capacity and thus an important role in disease
pathogenesis [17].
LAM is also a major constituent of mycobacterial
cell wall and has been shown to induce tumor necrosis
factor release from the macrophages [18], which plays
a prominent role in bacterial killing. Studies have
shown that LAM acts at several levels and that it can
scavenge potentially cytotoxic oxygen free radicals,
inhibit protein kinase C activity and block the tran-
scriptional activation of gamma interferon inducible
genes in human macrophages such as cell lines, and
hence contribute to the persistence of mycobacteria
within mononuclear phagocytes [19].
Host cell surface receptors
M. tuberculosis appears to gain entry into macrophages
via cell surface molecules, including those of the inte-
grin family CR1 and CR3 complement receptors [20]

and CR4, mannose receptor, lung surfactant protein
receptors, CD14, scavenger receptors and Fc receptors,
in the intracellular fate and survival of M. tuberculosis
is still far from being understood [24]. Successful
pathogens (e.g. Salmonella typhi) appear to survive in
phagosomes by entering a receptor-mediated pathway
that is not coupled to the activation of macrophage
antimicrobial mechanisms, such as the production of
reactive oxygen or nitrogen intermediates [27]. How-
ever, to date, it is not yet clear how mycobacteria use
the advantage of selective receptor-mediated intracellu-
lar survival as a pathogenic strategy. It is possible that
the distinct routes of entry of M. tuberculosis result in
different cytokine secretion responses or different
downstream activation signals in the host macrophages,
leading to the differential survival of this pathogenic
bacteria.
Inhibition of phagosome–lysosome fusion
Both inhibition of growth and killing of intracellular
pathogens within the host cell of the mononuclear
phagocyte lineage are considered to be dependent on
phagosome–lysosome fusion [28]. Immediately after
engulfment by macrophages, most tubercle bacilli are
directed to phagolysosomes [29]. Subsequently, how-
ever, individual M. tuberculosis bud out from the fused
phagolysosomes into vacuoles that fail to fuse to the
secondary lysosomes and thus escape lysosomal killing.
Thus, temporary residence within a phagolysosome
Survival strategies of mycobacteria in host L. S. Meena and Rajni
2418 FEBS Journal 277 (2010) 2416–2427 ª 2010 The Authors Journal compilation ª 2010 FEBS

natural resistance-associated macrophage protein 1
has been demonstrated [36] in directly promoting
H
+
-ATPase-dependent acidification of Mycobacterium
bovis BCG phagosomes in peritoneal macrophages.
Maturation of phagosomes
M. tuberculosis residing within host phagosomes modi-
fies the maturation of the phagosomal compartment
and enhances intracellular survival. This maturation
leads to the inhibition of phagolysosomal fusion.
Moreover, the aberrant expression of Rab5 on the
phagosomes containing M. tuberculosis causes the mat-
uration arrest of these phagosomes at the early
endosomal stage [37]. Phagosomes containing inert
particles or avirulent bacteria transiently display Rab5,
whereas phagosomes containing virulent M. tuberculosis
exhibit a persistent display of Rab5 [37].
Recruitment and retention of tryptophan-aspartate
containing coat protein (TACO) on phagosome wall
Recruitment and retention of the host protein TACO
to phagosomes harboring mycobacteria prevents
bacterial delivery to lysosomes [38]. TACO⁄ coronin-1
is an actin binding protein known to associate with
cholesterol within the plasma membrane [39]. Reten-
tion of TACO on the phagosomal wall allows the
mycobacteria to escape the bactericidal action of
macrophages [38]. Vitamin D
3
and retinoic acid down-

PE-PGRS produced M. marinum strains that were
incapable of replication in macrophages. The strains
exhibited decreased persistence in granulomas, thereby
suggesting a direct role for PE-PGRS proteins in
mycobacterial virulence. Hypoxia was also observed to
be a major factor in inducing the nonreplicating persis-
tence of tubercle bacilli [43].
Protection against oxidative radicals
The macrophages offer a hostile environment to intra-
cellular bacteria by producing a vast array of chemi-
cals such as reactive oxygen and nitrogen radicals.
However, the virulent Erdman strain of M. tuberculosis
overexpresses a protein that cyclopropanates mycolic
acid double bonds, resulting in a ten-fold lower suscep-
tibility to peroxide [44]. Also, the oxyR (i.e. a sensor
L. S. Meena and Rajni Survival strategies of mycobacteria in host
FEBS Journal 277 (2010) 2416–2427 ª 2010 The Authors Journal compilation ª 2010 FEBS 2419
of oxidative stress and a transcriptional activator that
induces the expression of detoxifying enzymes such
as catalase ⁄ hydroperoxidase) of M. tuberculosis has
numerous deletions and frameshift mutations giving
the appearance of a pseudogene [45]. Perhaps the pro-
tection afforded by cyclopropanated cell wall compo-
nents has rendered oxyR superfluous in pathogenic
mycobacteria. Superoxide dismutases play an impor-
tant role in protection against oxidative stress and so
contribute to the pathogenicity of many bacterial
species [46].
Virulence genes of M. tuberculosis
Initial efforts aimed at identifying the genes involved

using genomic DNA from M. tuberculosis and electro-
porated into M. smegmatis [53]. The transformants
were used to infect the human macrophages cell line
U-937, and one transformant (eis) was isolated that
showed an enhanced survival over a period of 48 h
compared to the wild-type M. smegmatis [53]. The eis
gene, which encodes a 42 kDa protein, confers
M. smegmatis with the ability to resist killing by host
macrophages. The function of the Eis protein is still
unknown. It has been suggested that the secreted pro-
teins of mycobacteria have a profound influence on its
pathogenicity. It was found that the disruption of an
erp gene of M. tuberculosis encoding a secretory pro-
tein effects the survival of M. tuberculosis in host mac-
rophages [54].
In many Gram-negative bacteria, iron-regulated
genes are essential for the expression of full virulence
[55]. It is likely that the acquisition of iron by M. tuber-
culosis is also essential for growth and survival during
the course of infection. M. tuberculosis synthesizes two
distinct iron-regulated siderophores: the cell surface-
associated mycobactin and the excreted siderophore,
exochelin [56]. The mbtB gene, which is involved in the
biosynthesis of siderophores, was disrupted in
M. tuberculosis and the resulting mutant was observed
to have a restricted growth in iron-depleted conditions
[57]. The mutant also exhibited stunted growth pattern
in human monocyte cell line THP-1, suggesting a role
for siderophores in virulence.
M. tuberculosis and other mycobacterial species also

Survival strategies of mycobacteria in host L. S. Meena and Rajni
2420 FEBS Journal 277 (2010) 2416–2427 ª 2010 The Authors Journal compilation ª 2010 FEBS
the Src family of protein tyrosine kinases. These kinas-
es result in the increased tyrosine phosphorylation of
multiple macrophage proteins and the activation of
phospholipase D [82]. Activation of protein tyrosine
kinases appears to enhance stimulation of phospholi-
pase D activity and the associated increase in phospha-
tidic acid. Phosphatidic acid may trigger a number of
downstream processes that are necessary for membrane
remodeling during phagocytosis and the intracellular
survival of M. smegmatis in host cells [83]. Further-
more, LAM from the virulent species of M. tuberculo-
sis possesses the ability to modulate signaling
pathways linked to bacterial survival by phosphoryla-
tion of an apoptotic protein in the phosphatidylinositol
3-kinase-dependent pathway in THP-1 cells [84].
Many regulatory proteins or enzymes commonly
known as G-proteins play a vital role in cell signaling by
binding and hydrolyzing GTP to GDP [85]. Despite
their common biochemical function of GTP hydrolysis,
these proteins are associated with diverse biological
functions. In eukaryotes, G-proteins are classified into
three main groups: Ras and its homologs; the transla-
tion elongation factors [86], Tu and G; and the a
subunits of heterotrimeric G-proteins. All members of
this group share a common structural core, suggesting a
common evolutionary origin for these proteins. The
members of G-protein superfamily are known to play a
complex array of functions in eukaryotes, such as, hor-

[76]
17 Pks2 Rv3825c Polyketide synthase PKS2 [77]
18 fadE28 Rv3544c Acyl-coenzyme A dehydrogenase [78]
19 nuoG Rv3151 NADH dehydrogenase I (chain G)
NADH-ubiquinone oxidoreductase chain G
[61]
20 phoP Rv0757 Positive regulator for the phosphate regulon,
required for intracellular growth
[79]
21 plcA Rv2351c Phospholipase c 1 plca (mtp40 antigen) [80]
22 plcB Rv2350c Membrane-associated phospholipase c 2 plcb [80]
23 plcC Rv2349c Intracellular survival, by the alteration of cell
signaling events or by direct cytotoxicity ⁄
phospholipase c 3 plcc
[80]
24 plcD Rv1755c Intracellular survival, by the alteration of cell
signaling events or by direct cytotoxicity ⁄
phospholipase c 4 (fragment) plcd.
[80]
25 mmpL8 Rv3823c Considered to be involved in the transport of
lipids and shown to be required in the
production of a sulfated glycolipid, sulfolipid-1
[81]
L. S. Meena and Rajni Survival strategies of mycobacteria in host
FEBS Journal 277 (2010) 2416–2427 ª 2010 The Authors Journal compilation ª 2010 FEBS 2421
Recent studies have shown that bacterial GTPases con-
trol vast arrays of function, such as the regulation of
ribosomal function and the cell cycle, the modulation
of DNA partitioning and DNA segregation [87]. The
best known prokaryotic small GTP-binding protein is

transcription factors. Homologs of the Ras family of
GTP-binding proteins have also been shown to
contribute to morphology and virulence in several
pathogenic fungi [101].
LepA is another member of GTP-binding protein
family; however, its exact function is still not clear.
Helicobacter pylori resides in the gastric mucus layer,
where the pH is in the range 4.5–5.0; therefore, to per-
sist in the hostile acidic environment of the stomach, it
must survive acid shock and grow at acidic pH. Inacti-
vation of an ortholog of the E. coli LepA in H. pylori
resulted in the inability of mutant to grow at pH 4.8,
suggesting that LepA is essential for the growth of
H. pylori under acidic conditions and that it might
play a critical role in infection by this pathogen [103].
Microbial pathogens such as mycobacteria have sus-
tained a long lasting association with their host
because they have evolved sophisticated mechanisms to
interfere with the macrophage signaling process and
eventually affect the overall phagocytosis process.
Keeping in view the importance of G-proteins, one
approach to help understand this mechanism would
involve looking for the presence of such G-proteins in
M. tuberculosis, which might interfere with the cell sig-
naling and might be specifically expressed under
growth of bacteria in macrophage.
Keeping in mind the importance of members of
G-proteins in diverse functions such as bacterial
growth, survival, stress management and virulence, we
investigated the complete genome sequence of

M. tuberculosis are likely to mediate specific signal
transduction events with host pathways. Protein kinas-
es G and F may comprise key molecules that change
the phosphorylation pattern of host proteins upon
infection, thereby promoting bacterial survival [107].
Inhibitors of protein kinases have also been shown to
prevent the uptake of M. leprae by peritoneal macro-
phages of mice [108]. This suggests that the protein
kinases of M. tuberculosis may be involved in modify-
ing the host phosphorylation pattern to promote their
establishment and survival within the host cells.
Survival strategies of mycobacteria in host L. S. Meena and Rajni
2422 FEBS Journal 277 (2010) 2416–2427 ª 2010 The Authors Journal compilation ª 2010 FEBS
A major anti-phosphotyrosine reactive protein is
present only in strains belonging to M. tuberculosis
complex [109]. Thus, protein phosphorylation may
play an important role in the pathogenesis of myco-
bacteria. It has been shown that M. tuberculosis has
two functional tyrosine phosphatases that are secreted
into the culture supernatant, and that they may inter-
fere within the host cells [110].
Recently, a new transporter family (mmpL) was
shown to transport lipid molecules into host cells [9],
where they may interact with specific host cellular tar-
gets and serve to modulate the host-signaling network.
Mycobacterial lipids can be found in host cytoplasm
without a mycobacterial presence within the host cells
[111]. Stress-induced p38 mitogen-activated protein
kinase is a component of M. tuberculosis phagosome
arrest. The uptake of Mycobacterium stimulates p38

hydrolytically active phagolysosome, and also avoids
the development of localized, productive immune
responses against M. tuberculosis in the host.
Acknowledgements
We thank Rajesh S. Gokhale for making this work
possible. We also thank Hemant Khanna (University
of Michigan, Flint, MI, USA) for providing valuable
suggestions. The authors acknowledge financial sup-
port from GAP0050 of the Department of Science and
Technology and Council of Scientific & Industrial
Research.
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