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ANNUAL
REVIEWS Further
Tuberculosis Pathogenesis
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Top cited articles Jennifer A. Philips and Joel D. Ernst
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Our comprehensive search Division of Infectious Diseases, Department of Medicine; Department of Pathology;
and Department of Microbiology; New York University School of Medicine, New York,
New York 10016; email: Jennifer.Philips@nyumc.org, Joel.Ernst@med.nyu.edu
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Annu. Rev. Pathol. Mech. Dis. 2012. 7:35384 Keywords


First published online as a Review in Advance on Mycobacterium tuberculosis, granuloma, phagosome maturation, innate
October 31, 2011
immunity, acquired immunity, immune evasion
The Annual Review of Pathology: Mechanisms of
Disease is online at pathol.annualreviews.org
Abstract
This articles doi:
10.1146/annurev-pathol-011811-132458
Despite the development of potentially curative chemotherapy, tuber-
culosis (TB) continues to cause increasing worldwide morbidity and is
Copyright  c 2012 by Annual Reviews.
All rights reserved
a leading cause of human mortality in the developing world. Recent
advances in bacterial molecular genetics, immunology, and human ge-
1553-4006/12/0228-0353$20.00
netics have yielded insight into the molecular determinants of virulence,
the immune responses that are essential for restricting progressive dis-
ease, and the determinants of immunopathology in TB. Despite these
advances, a large knowledge gap still exists that limits the development
and testing of new interventions, including novel drugs and efcacious
vaccines. This review focuses on our current knowledge of TB patho-
genesis and immunity that has been derived from in vitro and in vivo
studies. In addition, it highlights topics that need to be better under-
stood to provide improved means of controlling TB worldwide.

353
PM07CH15-Ernst ARI 15 December 2011 7:46

INTRODUCTION Robert Koch identied M. tuberculosis as the


causative agent of TB nearly 130 years ago, and
In most people, infection with Mycobacterium
since then, enormous progress has been made.
Bacillus Calmette- tuberculosis is characterized by a lifelong stand-
Guerin (BCG): However, we remain unable to answer many
off: Bacterial replication is kept at bay, there is
attenuated strain of M. key questions regarding TB pathogenesis and
no evidence of disease, and the only indication
bovis that is widely used immunity, and these fundamental biological
of infection is the presence of immune respon-
as a vaccine strain, questions have important practical implica-
although it confers siveness to mycobacterial antigens. This clinical
tions. The existing TB vaccine, Mycobacterium
limited protection situation, termed latent infection, is thought to
against pulmonary bovisbacillus Calmette-Guerin (BCG), was
exist in approximately one-third of the worlds
tuberculosis in adults rst used in humans 90 years ago and has
population. In a small fraction (510%) of in-
Dendritic cells been administered to an estimated 3.5 billion
fected individuals, the stalemate is broken and
(DCs): myeloid cells people; unfortunately, it does not reliably pre-
active disease ensues; this is a clinical state in
that migrate from vent pulmonary disease in adults. An effective
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

which the bacterial burden is high and trans-


peripheral tissues to vaccine could change the face of the current
lymph nodes and mission can occur. Even though only a small
TB epidemic, but without a fundamental un-
specialize in antigen fraction of infected individuals develop active
presentation derstanding of disease pathogenesis, the path
disease, the vast reservoir of latently infected
toward a successful vaccine remains uncertain.
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CLRs: C-type lectin people causes an estimated 1.7 million deaths


receptors per year, more than from any other single bac-
terial pathogen. This global health problem MYCOBACTERIAL ENTRY
is compounded by human immunodeciency INTO HOST CELLS
virus (HIV) infection, which dramatically in- After it is inhaled as respiratory droplets and
creases the risk of active disease, and drug- deposited in the distal alveoli, M. tuberculosis
resistant bacteria, which seriously hamper the is presumed to rst encounter and be in-
ability to treat tuberculosis (TB). gested by alveolar macrophages. Most re-
The ongoing global TB epidemic presents search on phagocytic receptors has focused on
important questions in terms of bacterial macrophages, although various phagocytic cells
pathogenesis and host immunity. How do recruited to the infected lung, including neu-
the bacteria establish infection? What are the trophils, monocyte-derived macrophages, and
determinants of a successful immune response dendritic cells (DCs), also ingest bacteria and
that, in the majority of individuals, restricts probably play an important role in the outcome
bacterial replication and prevents active disease of the infection. In fact, in aerosol-infected
and transmission? Why does the immune mice, the dominant infected population in lungs
response fail to sterilize infection? What causes and draining lymph nodes are myeloid DCs (1).
the balance to shift in favor of the pathogen in Numerous receptors expressed in phagocytic
those individuals who develop active disease? cells bind mycobacteria (reviewed in Reference
This review describes the progress that has been 2); these receptors include C-type lectin re-
made in addressing these central questions in ceptors (CLRs), scavenger receptors (SRs), and
TB pathogenesis. We focus on M. tuberculosis, complement receptors (CRs) (Table 1). The
and not on opportunistic mycobacteria, which ability to infect macrophages appears to be an
are important pathogens in immunocom- important determinant of bacterial spread and
promised hosts. M. marinum, a close genetic dissemination, and M. tuberculosis has no short-
relative of M. tuberculosis, causes granulomatous age of entry routes. However, the complex-
disease in ectotherms. It shares genetic deter- ity of uptake mechanisms has made it difcult
minants of pathogenicity with M. tuberculosis, to demonstrate the contribution of individual
so we consider M. marinum in cases in which receptors in primary cells and in vivo.
it has provided valuable insight into TB Several CLRs are implicated in the binding
pathogenesis. and uptake of mycobacteria; these CLRs

354 Philips Ernst


PM07CH15-Ernst ARI 15 December 2011 7:46

Table 1 Receptors implicated in Mycobacterium tuberculosis uptake in phagocytic cells


Receptor M. tuberculosis ligand(s) Comment
Nonopsonic
C-type lectin (transmembrane)
Mannose receptor ManLAM, PIMs, arabinomannan, Thought to be anti-inammatory and to inhibit delivery of
(CD207) mannans, mannoproteins mycobacteria to the lysosome
DC-SIGN (CD209) ManLAM, PIMs, arabinomannan, Major uptake receptor in human DCs; thought to be
lipomannan, 19-kD antigen anti-inammatory and inhibit DC maturation. There are
seven paralogs in mice (SIGNR15, SIGNR7, SIGNR8)
Dectin-1 Unknown Recognizes fungal -glucan in cooperation with TLR2.
M. tuberculosis ligand is unknown
Integrin family
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

Complement receptor 3 LAM, PIMs, antigen 85C Has a lectin domain and mediates opsonic and nonopsonic
(CD11b/CD18) uptake of M. tuberculosis
SRs
Class A (SR-A1, MARCO) Unknown SRs display broad ligand-binding ability; ligands include
Class B (CD36, SR-B1) lipoproteins, polyanionic molecules, gram-positive and
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gram-negative bacteria
Opsonic
CRs
CR1, CR3 Host iC3b CR3 is the major complement receptor involved in
(CD11b/CD18) complement-opsonized M. tuberculosis uptake;
M. tuberculosis activates the alternative complement
pathway and is opsonized by C3b and iC3b
Collectins (soluble C-type lectins)
Surfactant protein A ManLAM; lipomannan, a 60-kD Agglutinates M. tuberculosis and enhances macrophage
glycoprotein; the glycoprotein Apa internalization
Surfactant protein D ManLAM Agglutinizes M. tuberculosis and delays macrophage
phagocytosis
Mannose-binding lectin ManLAM, PIMs Human studies suggest that low levels confer protection
from tuberculosis
Fc receptor
FcR Host IgG Uptake through Fc receptors may direct M. tuberculosis to
the lysosome

Abbreviations: DC, dendritic cell; IgG, immunoglobulin G; LAM, lipoarabinomannan; ManLAM, mannose-capped liparabinomannan;
PIM, phosphatidylinositol mannan; SR, scavenger receptor; TLR, Toll-like receptor.

include the macrophage mannose receptor (see the section titled Innate Immunity to
(MMR), DC-specic intracellular adhesion M. tuberculosis, below). MMR and DC-SIGN
molecule 3grabbing nonintegrin (DC-SIGN), recognize the abundant mycobacterial cell wall
and Dectin-1. The MMR was the rst CLR to lipoglycan, mannose-capped liparabinoman- Mannose-capped
be associated with recognition of M. tuberculo- nan (ManLAM), whereas the M. tuberculosis liparabinomannan
sis, and along with DC-SIGN, it is implicated ligand for Dectin-1 is unknown. ManLAM (ManLAM):
in the phagocytosis of M. tuberculosis. In addi- has been extensively investigated as a potential an abundant cell wall
lipoglycan in
tion to their proposed role in bacterial uptake, virulence factor because LAM is mannosylated pathogenic
MMR and DC-SIGN are thought to inuence in pathogenic mycobacteria, whereas in the mycobacteria
phagosome maturation and cytokine signaling cell wall of environmental mycobacteria, LAM

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PM07CH15-Ernst ARI 15 December 2011 7:46

is capped by arabinose (AraLAM) or inositol mediates opsonic and nonopsonic uptake of


phosphate (3). Thus, engagement of MMR and M. tuberculosis, but here too, disease outcome in
DC-SIGN by ManLAM was hypothesized to knockout mice infected with M. tuberculosis was
Phosphatidylinositol
mannan (PIM): a be important in bacterial virulence. However, similar to controls (14). To add to this complex-
mycobacterial cell wall mice lacking the MMR are equivalent to wild- ity, along with the receptors mentioned above,
component type controls in terms of their ability to control opsonic uptake of bacteria may be mediated
Trehalose M. tuberculosis (4). Inhibitor studies showed that by surfactant receptors, immunoglobulin G Fc
dimycolate (TDM): DC-SIGN is the major mycobacterial receptor receptors, and CR1.
a mycobacterial in human DCs, but in mice there are seven A prominent hypothesis has been that up-
glycolipid historically
paralogs, which has made it difcult to dene take via distinct receptors dictates the intracel-
known as cord factor
the murine DC-SIGN homolog and evaluate lular fate of the bacteria. For example, uptake
Esx-1: type VII
the loss of function phenotype (reviewed in via the MMR is thought to allow the bacteria
secretion system that is
Reference 5). Surprisingly, BCG and M. to resist phagosome maturation, whereas up-
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

deleted in BCG and


critical for marinum mutants that do not add mannose take mediated by DC-SIGN or Fc receptors
M. tuberculosis caps to LAM are not attenuated during in vitro is thought to result in lysosomal delivery of the
pathogenesis infection of macrophages or in vivo infection of bacteria (15, 16). However, because many of the
mice (6). Given that DC-SIGN also recognizes relevant receptors are coexpressed on the same
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other mannosylated cell wall components, cells, uptake of M. tuberculosis in vivo is likely
particularly hexamannosylated phosphatidyli- to occur through cooperation of several recep-
nositol mannan (PIM6 ), bacterial mutants tor types. Thus, in contrast to pathogens that
defective in both ManLAM and PIM6 were have devised strategies to avoid uptake into host
recently examined; no phenotype could be as- phagocytic cells, M. tuberculosis takes advantage
cribed to these mutants (7), which suggests that of multiple routes to intrude into and, as dis-
there are additional ligands in the mycobac- cussed below, exploit host phagocytic cells.
terial cell wall that can engage DC-SIGN and
other receptors. Macrophage-inducible C-type
lectin (Mincle) is essential for recognition of the
mycobacterial glycolipid, trehalose dimycolate INTRACELLULAR BACTERIAL
(TDM, historically known as cord factor) TRAFFICKING
(8, 9). Mincle plays an important role in The long-held dogma is that M. tuberculosis
cytokine signaling in response to TDM, but prevents the normal maturation of the phago-
a role in mycobacterial uptake has not been some into a degradative and microbicidal
reported. Thus, numerous CLRs and their compartment and, instead, resides in a com-
ligands are implicated in bacterial binding, partment that resembles an early endosome.
uptake, and signaling, but their individual con- Numerous investigators have described the
tributions have been difcult to demonstrate long-term residence of M. tuberculosis in such
with mycobacterial or mouse mutants. a compartment. More recently, the idea that
In addition to CLRs, inhibitor studies sug- the bacteria also grow in the cytoplasm has
gested that SRs also play a role in mycobac- gained recognition (17, 18). First, we describe
terial binding and uptake (10). Class B SRs the well-documented phagosomal location
can mediate mycobacterial uptake, as was ini- of the bacteria and then discuss more recent
tially demonstrated by studies in Drosophila (11). results describing the role of the Esx-1 locus
However, no defect in M. tuberculosis uptake was in mediating phagosomal damage and the role
observed in mouse macrophages from animals of autophagy in modulating the mycobacterial
decient in the class B SRs, CD36 and SR-B1 phagosome. In sum, these observations suggest
(4, 12, 13). Similarly, defects in the class A SRs, that M. tuberculosis probably inhabits various
MARCO and SR-A, did not signicantly alter intracellular niches (Figure 1), and the relative
the outcome of infection (4). CR3, an integrin, distribution of bacilli is likely to depend upon

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M. tuberculosis

Possible bacterial
survivalandgrowth
withtransmission

Rab5 Membrane
Escape
a LowPI3P
Rab5 damage b c
Esx1
dependent
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

Rab7 Ub Ub
IFN/vitamin D
Bacterial growth Adaptor
and transmission
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e f g d
Ub Ub
Phagolysosomes
Autolysosome Resequestration

Bacterial Possiblebacterial Bacterial death


death survivalorgrowth or restricted growth

Figure 1
Possible fates of intracellular Mycobacterium tuberculosis. (a) M. tuberculosis can prevent phagosome maturation
and grow in an early endosomelike compartment by inhibiting phosphatidylinositol 3-phosphate (PI3P)
generation on the phagosome and impairing the recruitment of active, GTP-bound Rab7 while retaining
Rab5. (b) The Esx-1 system permeabilizes the phagosomal membrane, allowing direct cytosolic access.
(c) In some cases, this process may result in the escape of the bacteria into the cytosol. The extent of cytosolic
growth may depend upon cell type. (d ) At least in the case of M. marinum, the cytosolic bacteria are
recognized by the host ubiquitin system and are resequestered in a membrane-bound compartment. (e) Some
ingested bacteria fail to prevent phagosome maturation, and they are delivered to the lysosome, where their
replication is curtailed. ( f ) However, in certain contexts, they may be able to grow in lysosomes.
( g) Interferon (IFN)- and vitamin D can overcome the early endosomelike arrest of M. tuberculosis,
thereby promoting delivery of bacteria to autolysosomes, where growth is curtailed.

the type of host cell that has been infected and diminished or absent. The latter markers in-
the stimuli that cell has experienced. clude the v-ATPase, which causes a failure of
Altered trafcking of the mycobacterial M. tuberculosis phagosomes to fully acidify. This
phagosome was discovered because bacteria early endosomelike arrest is thought to allow
avoid colocalization with ferritin-labeled lyso- the bacteria to acquire nutrients, such as iron via
somes (19), but it has since been described recycling endosomes, while avoiding the acidic,
through various molecular markers. The degradative environment of the lysosome (20).
M. tuberculosis phagosome is characterized by Numerous mycobacterial lipid and protein
the prolonged retention of early endosomal effectors modulate phagosome maturation (21).
markers that are normally cleared from the Phagosome maturation requires the conver-
maturing phagosomal surface, and numer- sion of Rab5 to active, GTP-bound Rab7
ous late endosomal or lysosomal markers are and the production of phosphatidylinositol

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PM07CH15-Ernst ARI 15 December 2011 7:46

Compared with phagosomes containing


latex beads or dead mycobacteria, live my-
cobacterial phagosomes exhibit diminished
M. tuberculosis
PI3P. The class III phosphatidylinositol 3-
kinase Vps34 generates PI3P, which can recruit
proteins containing the FYVE [which stands
for conserved in Fab1, YOTB, Vac1, and early
endosome antigen 1 (EEA1)], Phox homology,
Rab5 or Pleckstrin homology domain. Diminished
PI3P on the mycobacterial phagosome has
NdkA
been demonstrated by decreased colocalization
Vps34 with FYVE and Phox homology domain
chimeras, as well as by direct measurement
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

Rab7-GTP GDP

PI3P
X on puried phagosomes (2426). Exactly how
M. tuberculosis impairs PI3P generation on the
Phagolysosomes phagosome is not clear. The M. tuberculosis
PtpA cell wall component, ManLAM, may disrupt
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a calcium-dependent calmodulin signaling


Figure 2 pathway that acts upstream of PI3P production
Model of how Mycobacterium tuberculosis arrests phagosome maturation. (27). PI3P may be degraded by SapM, a PI3P
Mycobacteria remain in a Rab5-positive phagosome, blocking the generation phosphatase secreted by M. tuberculosis that can
of phosphatidylinositol 3-phosphate (PI3P) and GTP-bound Rab7 on the
block phagosome-late endosome fusion in an
phagosome membrane. The precise mechanisms underlying the disruption of
PI3P generation are not clear, although there is evidence for impaired in vitro system (24); however, a BCG mutant
recruitment of the lipid kinase Vps34 arising from altered calcium signaling in that lacks SapM is unaffected in arresting
the cell. There is also evidence that the bacterial effectors PtpA and NdkA phagosome maturation (28). Consistent with
interfere with Rab7 activation. In particular, PtpA can dephosphorylate the nding that there is less PI3P on the
Vps33B, a component of the homotypic fusion and protein sorting complex,
mycobacterial phagosome, two cellular PI3P-
which converts Rab7 to its GTP-bound, active form. In concert, NdkA can
enhance the guanosine triphosphatase activity of Rab7, enhancing conversion binding proteins, EEA1 and hepatocyte growth
back to GDP-Rab7. Other effectors that are implicated in blocking phagosome factorregulated tyrosine kinase substrate, are
maturation are not shown but are discussed in Reference 21. also diminished. The absence of these PI3P
effectors, as well as downstream effectors such
as the endosomal sorting complex required for
3-phosphate (PI3P) on the phagosomal mem- transport, may account for the arrest of phago-
brane, both of which are impaired on the some maturation (26, 29, 30). Because PI3P
mycobacterial phagosome (Figure 2). Two is also required for autophagy, by disrupting
secreted M. tuberculosis effectors, PtpA and PI3P generation the bacteria could impair
NdkA, may be responsible for the failure of their clearance by this mechanism as well (31).
the mycobacterial phagosome to contain Rab7. In addition to the bacterial proteins de-
PtpA, a tyrosine phosphatase, dephosphory- scribed above, other effectors also appear to
lates host Vps33B, a component of the ho- play a role in arresting phagosome maturation;
motypic fusion and protein sorting complex, these effectors include PknG, LpdC, Zmp1,
which is critical for Rab7 activation (22). NdkA and numerous factors identied in several for-
acts as a guanosine triphosphatase (GTPase)- ward genetic screens. Their exact role, or how
activating protein and may directly catalyze these activities are coordinated, is not clear.
the conversion of GTP to GDP on Rab7 Some may affect the mycobacterial cell wall,
PI3P:
to render it inactive (23). Thus, both of as cell wall components such as ManLAM and
phosphatidylinositol
3-phosphate these proteins could impair Rab7 activation on TDM can inhibit phagosome maturation (32,
phagosomes. 33). TDM has a profound immunomodulatory

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PM07CH15-Ernst ARI 15 December 2011 7:46

effect mediated by Mincle (8, 9), although family (termed Esx-AW). These secreted
whether the effect of TDM on phagosome effectors are approximately 100 amino acids in
maturation is mediated by Mincle remains length and have a characteristic hairpin bend
TSSS: type VII
to be determined. The existence of multiple formed by a Trp-Xaa-Gly (W-X-G) motif. secretion system(s)
M. tuberculosis effectors that can modulate M. tuberculosis encodes more than 20 such
phagosome maturation seems to indicate proteins, whose functions are ill dened. The
considerable redundancy, although because best-studied TSSS is Esx-1, which is deleted
many of them are necessary for full virulence, in the vaccine strain BCG; its absence largely
they must not have completely overlapping accounts for why BCG is attenuated (3739).
functions. One possibility is that the primary Esx-1 plays a central although incompletely
defect of some of these M. tuberculosis mutants understood role in M. tuberculosis pathogenesis
is the ability to survive in macrophages, and that includes effects on innate and adaptive
as a secondary consequence, they are delivered immune responses.
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

to a lysosome. Moreover, lysosomal delivery Recent work suggests that Esx-1 mediates
may not always result in impaired bacterial damage to the mycobacterial phagosomal
replication; M. tuberculosis can grow in at membrane, which appears to enable the bacte-
least some acidic, vacuolar compartments. For ria to replicate in the cytosol. In M. marinum,
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example, Armstrong & Hart (34) showed that if mutants defective in the Esx-1 secretion system
M. tuberculosis is coated with immune serum, are impaired in cytolytic activity, cell-to-cell
which results in uptake via Fc receptors, it is spreading, and phagosome escape (40, 41). In
delivered to a lysosome and grows unhindered human macrophages and DCs, Esx-1 promotes
in this compartment. Similarly, certain bacte- escape of M. tuberculosis from the phagosome
rial mutants that are aberrantly delivered to a (18), although the degree to which this process
lysosomal compartment can still replicate intra- occurs in other cell types and the balance of
cellularly. The degree to which M. tuberculosis phagosomal versus cytoplasmic growth remain
is acid resistant in vitro depends upon the com- to be determined. Two effectors secreted by the
position of the media, and it seems likely that in Esx-1 system, Esx-A/ESAT-6 and Esx-B/CFP-
vivo M. tuberculosis resists both phagosome mat- 10, are implicated in mediating membrane
uration and killing in some acidic phagolyso- damage. Together, they form a stable het-
somes (reviewed in Reference 35). Our current erodimer that lacks the structural features that
understanding is probably limited by the way would suggest a pore-forming complex, but
in which we identify lysosomes, which fails to Esx-A alone exhibits membranolytic activity in
capture their diversity or antimicrobial activity. vitro (38, 41, 42). One hypothesis is that Esx-A
dissociates from Esx-B in the acidic conditions
of the phagosome, where it promotes the
PHAGOSOMAL MEMBRANE escape of M. tuberculosis into the cytoplasm
DAMAGE AND BACTERIAL (42). The Esx-1 system may play additional
ESCAPE roles in phagosome maturation. Certain Esx-1
The M. tuberculosis genome encodes ve mutants fail to arrest phagosome maturation,
separate type VII secretion systems (TSSS), although exactly why is unclear. This defect
which are specialized protein secretion systems may reect the activity of particular secreted
that enable mycobacteria to transport virulence Esx-1 effectors or a more general defect in cell
factors across their complex and impermeable wall composition, which has been described
cell envelope (reviewed in Reference 36). for Esx-1 mutants (4346). Also, damage to the
Each of the ve loci encoding a secretion phagosome may activate autophagic clearance
apparatus (Esx-15) contains genes coding for of the bacteria, but a direct examination of
components of the secretion machinery as well the role of Esx-1 in autophagy has not been
as secreted proteins belonging to the WXG100 reported.

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PM07CH15-Ernst ARI 15 December 2011 7:46

By damaging the phagosomal membrane, or as more recently described, intracellular


the Esx-1 machinery also allows innate immune microbes (in this case, the process is termed
receptors in the cytoplasm to gain access to xenophagy). The double-membrane autopha-
M. tuberculosis constituents. For example, the gosomes that capture cellular content undergo
mycobacterial cell wall component N-glycolyl- maturation into autolysosomes by fusing with
muramyl dipeptide stimulates the cytosolic lysosomal organelles. Autophagosome forma-
sensor nucleotide oligomerization domain 2 tion depends upon two protein-protein and
(NOD2) to produce type I interferons (IFNs) protein-lipid conjugation systems (Atg5/Atg12
only if the Esx-1 system is intact. NOD2 and Atg8/LC3), which are controlled by
activation can be restored to bacteria lacking signaling pathways that respond to nutrient
Esx-1 by an alternative membranolytic factor limitation, stress inputs, and immune media-
(4749). Similarly, Esx-1 is required for the tors. Autophagy sequesters bacteria that access
bacteria to activate the inammasome in the the host cell cytosol, which can promote both
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

host cytoplasm (50, 51). bacterial eradication and antigen presentation.


The Esx-1 secretion system plays important The cytosolic bacteria are decorated with ubiq-
roles in pathogenesis beyond its effect on uitin and are enclosed in a double-membrane
phagosome integrity. Esx-A appears to be compartment that then matures to an autolyso-
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important in optimal recruitment of unin- some. The targets of ubiquitination, and even
fected macrophages to foci of infection by whether they are bacterial or host derived, are
inducing matrix metalloproteinase 9 (MMP-9) not clear, but adaptor proteins such as p62 and
by nearby nonhematopoietic cells (52). In Ndp52 are thought to recognize the ubiquiti-
addition, Esx-1 is also important in adaptive nated bacteria and link them to the autophagy
immune responses, as Esx-A and Esx-B are machinery. Bacteria that are adapted to repli-
prominent antigens recognized by both CD4+ cate in the cytosol, such as Listeria and Shigella,
and CD8+ T cells (53). Less is known about inhibit autophagy to survive intracellularly.
the other TSSS. The Esx-3 secretion apparatus Similar to what has been described for
is important in bacterial iron acquisition, and other bacteria that enter the host cytosol, in
its secreted effectors (Esx-H/TB10.4 and Esx- the case of M. marinum, bacteria that escape
G/TB9.8) are also important T cell antigens the phagosome become ubiquitinated and then
(54, 55), whereas in M. marinum, the Esx-5 are sequestered into membrane structures that
locus is required for transport of many proteins resemble autophagosomes. However, this pro-
from two gene families found uniquely in cess does not appear to require LC3 or Atg5, so
mycobacteria. These proteins are termed PE it may proceed via an autophagy-independent
and PPE proteins [named for their conserved pathway (58). Although M. tuberculosis also
proline and glutamic acid (PE) and proline damages the phagosome and accesses the
prolineglutamic acid (PPE) motifs] (56). cytosol in human cells several days after
infection, it is unclear in this context whether
these bacteria are cleared by autophagy, have
The Role of Autophagy mechanisms to inhibit autophagy, or are
in Bacterial Trafficking sequestered in an autophagy-independent
Recent work has demonstrated the importance manner that is analogous to what was described
of autophagy in eukaryotic cells in resistance for M. marinum. Many experiments examin-
to viral and bacterial pathogens (reviewed in ing the role of autophagy in mycobacterial
Reference 57). Macroautophagy is a process by infection have used BCG, mouse cells, or early
which double-membrane organelles, termed time points postinfection, when there may be
autophagosomes, capture and degrade cyto- limited access of the bacteria to the cytosol.
plasmic components. These components may Under these conditions, basal autophagy does
be protein aggregates, damaged organelles, not appear to make a major contribution to

360 Philips Ernst


PM07CH15-Ernst ARI 15 December 2011 7:46

bacterial clearance, but autophagy is antimicro- murine macrophages with IFN- prior to
bial when activated by multiple different stim- infection with M. tuberculosis activates cells to
uli, including starvation and rapamycin, as well kill a signicant fraction of the subsequently
as by immune mediators such as IFN-, vitamin added bacteria by activating expression of
D, Toll-like receptor 4 (TLR4), and TLR7 (31, nitric oxide synthase 2 and production of
5962). One way in which autophagy promotes reactive nitrogen intermediates (RNI) (68).
bacterial clearance is by causing the production IFN- also enhances phagosome maturation
of peptide-ubiquitin conjugates that have an- in a manner dependent upon the immunity-
timycobacterial activity; these conjugates can related GTPases (69, 70). Consistent with the
be delivered to the bacterial phagosome when idea that the intracellular bacterial niche is
it fuses with autolysosomes (63, 64). Consistent altered by treatment with IFN-, bacterial
with a role for autophagy in controlling bac- access to iron and carbon sources becomes
terial replication in unactivated macrophages limited. The bacteria respond by inducing
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

as well, a high-throughput RNA interference iron-scavenging systems and subsisting on


screen in human THP-1 cells found that host cholesterol as a primary carbon source
several negative regulators of autophagy are (7173). As mentioned above, at least one way
required for intracellular bacterial growth (65). in which IFN- promotes lysosomal delivery
by University of Sussex on 05/26/12. For personal use only.

Although the intracellular pathways of of mycobacteria is by activating autophagy.


mycobacterial survival noted above are well Surprisingly, given the observation that IFN-
characterized in macrophages, less informa- enhances phagosome maturation, IFN-
tion is available on the intracellular fate of actually impairs the initial rate of phagosome-
M. tuberculosis in other host cells, especially in lysosome fusion for latex-bead phagosomes,
myeloid DCs, which harbor M. tuberculosis in which causes diminished hydrolytic and pro-
humans and mice (1). The transcriptional pro- teolytic activity of the phagosome (74, 75).
le of M. tuberculosis is signicantly different This defect may be advantageous to the host,
when the bacteria are inside DCs as compared as it would enhance antigen presentation by
with macrophages (66), which indicates that macrophages, although whether this delay in
comparative studies of the intracellular trafck- phagosome-lysosome fusion also occurs in the
ing and fate of M. tuberculosis in macrophages context of mycobacterial pathogen-associated
and DCs are likely to yield valuable information molecular patterns has not been determined.
about the life cycle of the pathogen. In contrast to the situation in murine
macrophages, it has been difcult to determine
the extent to which human macrophages
Intracellular Killing of M. tuberculosis use RNI to kill M. tuberculosis. Instead, a
by Activated Macrophages separate line of investigation has implicated
Whereas virulent strains of M. tuberculosis activation of human macrophages by 1,25-
clearly survive and replicate within so-called dihydroxyvitamin D3 [1,25(OH)2 D3] in
resting macrophages, exposure of murine and mediating intracellular killing of M. tuberculosis
human macrophages to specic cytokines and (76, 77). In cultured human macrophages,
other factors, such as IFN-, tumor necrosis 1,25(OH)2 D3 induces transcription of the
factor (TNF), and vitamin D, can activate nuclear vitamin D receptor, which in turn
these cells to kill M. tuberculosis. IFN- is ab- mediates transcription of the gene encod-
solutely essential for control of M. tuberculosis ing cathelicidin, the precursor of LL-37, a
in humans and mice (67). After the onset of protein that can directly kill M. tuberculosis
acquired immunity, macrophages are activated and selected other bacteria (77, 78). In ad-
by IFN-, mainly from T lymphocytes, which, dition, activation of human macrophages
among other effects, activates macrophage with TLR2 ligands, in the presence of serum
antimicrobial mechanisms. Treatment of containing physiological concentrations of

www.annualreviews.org TB Pathogenesis and Immunity 361


PM07CH15-Ernst ARI 15 December 2011 7:46

25(OH)D3, can induce expression of the nu- by newly recruited, previously uninfected
clear vitamin D receptor and cathelicidin (76). phagocytic cells. A recent study of M. marinum
Both IFN- and 1,25(OH)2 D3 may promote in zebrash embryos revealed that once the
intracellular bacterial clearance by a common bacteria replicate to high density within the
mechanism, as recent work demonstrates initially infected cell, they recruit uninfected
that, like IFN-, 1,25(OH)2 D3 activates macrophages. Bacteria that are released from
autophagy. 1,25(OH)2 D3-dependent expres- the rst cell infect an average of more than
sion of cathelicidin activates transcription of two previously uninfected cells, amplifying the
autophagy-related genes; in addition, LL-37 number of infected cells in vivo (Figure 3)
is directly recruited to autophagosomes and is (86). Optimal recruitment of uninfected
required for 1,25(OH)2 D3-dependent delivery macrophages requires Esx-A-dependent induc-
of bacteria to autophagosomes (59). Vitamin D tion of MMP-9 from nearby nonhematopoietic
deciency is frequently associated with active cells (52), although the mechanism whereby
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

TB in humans; taken together, current evidence MMP-9 mediates macrophage recruitment


indicates that vitamin D may play an important remains to be dened.
role in human innate immunity to TB.
TNF is essential for control of M. tuber- HOST CELL DEATH PATHWAYS
by University of Sussex on 05/26/12. For personal use only.

culosis in humans and in experimental animals IN TUBERCULOSIS


(79); although TNF is a pleiotropic cytokine,
Increasing evidence indicates that (a) necrosis
its predominant activities in immunity to TB
of M. tuberculosisinfected cells is more fa-
are to contribute to activation of macrophages
vorable to the pathogen than apoptosis is and
for killing of intracellular mycobacteria and to
(b) manipulation of cell death is a virulence
modulate apoptosis of infected cells (80, 81). In
property of M. tuberculosis. First, studies in
particular, TNF can act in concert with IFN-
cultured macrophages revealed that apop-
to activate macrophages for optimal control of
totic cells release fewer viable mycobacteria
M. tuberculosis growth. However, excess TNF
compared with those recovered from necrotic
also contributes to the immunopathology of
cells (87). Second, attenuated variants of
TB (82, 83), which indicates that optimal
M. tuberculosis are associated with macrophage
immunity with minimal tissue damage is an im-
apoptosis, whereas virulent strains inhibit
portant element of the biology of TNF in TB.
apoptosis, promote necrosis, and grow more
M. tuberculosis has also developed specic mech-
efciently in human macrophage monolayers
anisms to manipulate TNF to its advantage,
(88). Third, several single-gene mutant strains
most notably by expressing a secreted adenylate
of M. tuberculosis that promote macrophage
cyclase that modulates macrophage production
apoptosis are attenuated in vivo (89, 90), which
of TNF (84) and enhances virulence and
indicates that an antiapoptotic phenotype is ad-
lung inammation in experimentally infected
vantageous to the bacteria. Fourth, apoptosis is
mice.
widely thought to promote cross-presentation
of mycobacterial antigens for recognition by
CELL-TO-CELL SPREAD OF CD8 T cells, thereby providing an additional
VIRULENT MYCOBACTERIA pathway to development of host-protective
Mycobacteria that replicate in host phagocytes adaptive immune responses.
must spread to additional host cells to promote Recent research in zebrash embryos, mice,
disease and to be transmitted to new hosts. and humans has converged to provide espe-
Although evidence exists for actin-driven cially valuable insights into host determinants
cytoplasmic motility of M. marinum as a mode exploited by virulent mycobacteria to optimize
of cell-to-cell transmission (85), most studies their in vivo success. Comparison between
have focused on release of mycobacteria from an avirulent strain (H37Ra) and a virulent
apoptotic or necrotic cells, followed by uptake strain (H37Rv) of M. tuberculosis revealed that
362 Philips Ernst
PM07CH15-Ernst ARI 15 December 2011 7:46

Initially Erratum
infected
cell

Pronecrotic Proapoptotic
M. tuberculosis M. tuberculosis
(high LXA4, (low LXA4,
suboptimal TNF) optimal TNF)
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

Viable M. tuberculosis Some M. tuberculosis


are released, ingested are killed; fragments
by newly recruited and antigens are
phagocytes acquired by
dendritic cells
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Bacterial population Dendritic cells


expands by growth present antigens
and further directly or by
cell-cell spread cross-presentation
to CD4 and
CD8 T cells,
which limit the
spread of infection

Figure 3
Alternative cell death pathways for Mycobacterium tuberculosisinfected cells. Inhibition of apoptosis is a virulence determinant in
M. tuberculosis; distinct strains exhibit quantitative differences in terms of their ability to inhibit apoptosis and promote necrosis.
Antiapoptotic/pronecrotic bacteria are released by dying cells and ingested by surrounding macrophages, neutrophils, and/or dendritic
cells that have been recruited by active mechanisms dictated by the bacteria. Uptake by these additional cells provides replicative niches
for the bacteria and allows their growth, population expansion, and transmission. Proapoptotic bacteria are partially killed in apoptotic
cells; their cellular constituents and antigens can be taken up by dendritic cells and presented to nave and effector T lymphocytes,
which arrest the progression of infection. Abbreviations: TNF, tumor necrosis factor; TXA4, thromboxane A4.

they stimulate production of distinct arachi- zebrash that were hypersusceptible to


donate products: H37Ra induced synthesis M. marinum. The mutation in this line of
of proapoptotic prostaglandin E2 (PGE2), sh inactivates the gene encoding leukotriene
whereas H37Rv induced production of lipoxin A4 hydrolase (LTA4H); lack of activity of
A4 (LXA4) (91). Further study revealed that this enzyme resulted in overproduction of
mice lacking the gene encoding 5-lipoxygenase LXA4 and a hypersusceptible phenotype,
(Alox5/ ), which is required for the produc- along with accelerated necrosis of infected
tion of LXA4, are more resistant to infection macrophages and release of large numbers of
with M. tuberculosis H37Rv and have enhanced viable mycobacteria, which were at least in
antigen-specic CD8 T cell responses (92); part due to decient production of TNF. Of
this nding indicates that excessive production particular interest is that there is an association
of LXA4 is detrimental to the host. between human polymorphisms of the LTA4H
Other investigators performed a forward gene and susceptibility to TB and survival of
genetic screen to identify a line of mutant TB meningitis (83); in this case, heterozygosity

www.annualreviews.org TB Pathogenesis and Immunity 363


PM07CH15-Ernst ARI 15 December 2011 7:46

for specic single-nucleotide polymorphisms in human and murine TB and are frequently
(SNPs) provided protection, whereas homozy- associated with necrotic regions of granulomas
gosity for either allele was disadvantageous. (98). In vitro, mycobacterial lipids, especially
MGCs:
multinucleated giant Because certain SNPs are associated with oxygenated mycolic acids such as ketomycolic
cells higher production of leukotriene B4 (93), acids, can trigger differentiation of human
the heterozygous advantage was interpreted blood monocytes into foamy macrophages
as evidence that optimal outcomes in human (98). In murine macrophages, foamy cells can
TB depend on balanced production of spe- be induced by infection with BCG, through
cic arachidonate metabolites and associated a process that depends on TLR2 (99). Direct,
production of TNF. Together, these studies quantitative analysis of the lipids that predom-
provide strong evidence that bacterial manip- inate in foamy macrophages has not yet been
ulation of host cell death pathways is a major performed in the case of TB, but the obser-
determinant of virulence in TB (Figure 3). vation that foamy macrophages contain large
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

numbers of lipid bodies, together with analo-


gies to foam cells in atherosclerotic lesions,
GRANULOMAS has led to the prevalent belief that host lipids
Granulomas are the classical histopathologi- such as cholesterol and cholesteryl esters pre-
by University of Sussex on 05/26/12. For personal use only.

cal lesions in TB; this close association has dominate in foamy macrophages. This model
prompted considerable interest in the cellu- is indirectly supported by the observations that
lar composition of granulomas and the mecha- M. tuberculosis depends on lipids as carbon and
nisms of their formation and maintenance. As energy sources during chronic infection (72),
might be expected in a chronic infection, there that M. tuberculosis phagosomes are found ad-
is evidence that granulomas benet both the jacent to lipid bodies in cultured macrophages
host and the pathogen. (98), and that cholesterol import is required
for full virulence of M. tuberculosis in mice
(72, 73).
Cellular Composition of Granulomas Recent research using an in vitro culture
The sine qua non of granulomas is an organized system has provided substantial insight into the
aggregate of macrophages (94). Granuloma molecular mediators of formation of MGCs.
macrophages exhibit several phenotypes, in- First, the formation of MGCs is associated with
cluding mature macrophages, differentiated or virulent but not avirulent mycobacteria (e.g.,
epithelioid macrophages, foamy macrophages, M. smegmatis), and the early stages of MGC
and multinucleated (or Langhans) giant cells formation can be reproduced using specic
(MGCs), which form by fusion of the plasma mycobacterial glycolipids: PIMs, lipomannan
membranes (but not the nuclei) of multiple (LM), and TDM promote MGC formation,
macrophages (95). Real-time observations of whereas phosphatidylinositol and ManLAM
granuloma formation in transparent zebrash do not. The MGC-promoting mycobacterial
embryos infected with M. marinum at a devel- glycolipids are exposed on the exterior of the
opmental stage prior to the appearance of T bacilli, and LM-mediated MGC formation
lymphocytes have revealed that macrophages requires the host pattern-recognition molecule
are sufcient for the initiation of granulo- TLR2 (95). This is not a universal response
mas (96). Likewise, an in vitro system that to TLR2 stimulation, however, as a synthetic
utilizes human peripheral blood cells and triacylated bacterial lipoprotein analog did not
M. tuberculosis has conrmed that macrophages stimulate MGC formation. Downstream of
are sufcient for the early stages of granuloma TLR2, MGC formation depended on 1 inte-
and MGC formation (97). grin expression, as well as on expression of the
Foamy macrophages, which contain large disintegrin and metalloproteinase domain fam-
amounts of lipid, are observed in granulomas ily member ADAM9. The dependence on both

364 Philips Ernst


PM07CH15-Ernst ARI 15 December 2011 7:46

1 integrins and ADAM9 suggests that the In addition to macrophages of various phe-
mechanism underlying fusion of macrophages notypes, human and murine TB granulomas
to form MGCs resembles the homotypic fusion also contain DCs (Figure 4), which are myeloid
of macrophages mediated by fusion-regulatory cells that resemble macrophages but are special-
protein 1 (also known as CD98). Once MGCs ized for antigen presentation to T lymphocytes
form, they exhibit functional properties that are and, unlike macrophages, can migrate from
analogous to those of mature DCs in that they peripheral tissues, including the lungs, to sec-
phagocytose particles with low efciency and ondary lymphoid tissues such as lymph nodes.
express high levels of major histocompatibility One molecular marker of human myeloid DCs
complex (MHC) class II molecules (100). The is the C-type lectin DC-SIGN; M. tuberculosis
observation that MGCs are poorly phagocytic has been detected on DC-SIGN-expressing
in vitro is consistent with the nding that cells in biopsies of human tissues (101).
they rarely contain bacteria in tuberculous M. tuberculosis has also been found in myeloid
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

granulomas. DCs after aerosol infection of mice, in which,


by University of Sussex on 05/26/12. For personal use only.

Multinucleated
giant cell

Neutrophil M. tuberculosis CD4 T cell

Dendritic cell
Macrophage B cell CD8 T cell

Figure 4
The cellular composition of a representative Mycobacterium tuberculosis granuloma. Individual granulomas
can exhibit diverse morphologies, including striking areas of central caseous necrosis. The cells depicted
have been identied in human granulomas, as well as in those of experimentally infected animals. A
characteristic nding is that a small minority of the macrophages and dendritic cells in granulomas are
infected by M. tuberculosis.

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PM07CH15-Ernst ARI 15 December 2011 7:46

10 days postinfection and beyond, infected unique insight into the initiation of granulomas
myeloid DCs outnumbered infected alveolar formation through real-time analysis under
macrophages (1). DCs have been localized video microscopy. Studies performed with this
to murine TB granulomas by immunohisto- model have revealed that after administration
chemistry (102). Because DCs are required of a low inoculum of M. marinum, the bacteria
for transport of M. tuberculosis from the lungs replicate freely in macrophages, and that many
to the local draining lymph nodes for antigen uninfected macrophages are actively recruited
presentation to nave T cells (103), and because to the area surrounding the initially infected
indirect evidence indicates that DC trafcking cell (96). Recruitment of macrophages results
from lung granulomas occurs at a lower rate in their aggregation and organization and
during later stages of infection than in early represents the initial step to commitment of
stages of infection (1), further characterization granuloma formation. Following replication
of the dynamics of DCs in TB granulomas of mycobacteria in the initial macrophage,
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

is likely to yield valuable insight into the bacteria are released into the extracellular space
regulation of antigen presentation during the through the death of the macrophage and are
course of infection. then rapidly ingested by the surrounding
Although they are not essential for macrophages, which the bacteria exploit to
by University of Sussex on 05/26/12. For personal use only.

initiation of granuloma formation, T lym- further expand the pathogen population (86).
phocytes are present in mature granulomas in As noted above, a major effect of TNF in this
M. tuberculosisinfected humans (104) and mice system is to restrict growth of the bacteria
(Figure 4) (105), and their contributions are within macrophages, which has secondary
essential for the maintenance of organized consequences on limiting the spread of the in-
granulomas and the control of mycobacterial fection (81). In addition, during the early stages
progression after the acute phase of infection. of granuloma formation, a fraction of infected
In human TB granulomas, T lymphocytes macrophages depart from the nascent granu-
[typically 6070% CD4+ (104)] either may be loma and initiate infection at distant sites (86).
diffusely distributed among other cells or may In this system, experiments are performed at
be found as a discrete band of cells at the periph- an embryonic stage that precedes the develop-
ery of granulomas (105). In most strains of mice ment of T or B lymphocytes; such experiments
infected with M. tuberculosis, T lymphocytes are have not yet been extended to later stages,
diffusely distributed among other cells in the which could provide insight into the genera-
granulomas (105), and in contrast to the classic tion, trafcking, and maintenance of adaptive
belief that granulomas wall off the site of in- immune cells in mycobacterial granulomas.
fection, real-time imaging studies indicate that Even though inanimate particles can re-
T cells can readily trafc throughout mycobac- sult in (foreign-body) granulomas, several
terial granulomas, at least in the liver (106). B mycobacterial components make major con-
cells are also found in human and murine TB tributions to generation of granulomas. The
granulomas (105). Although their role, and that protein Esx-A/ESAT-6, secreted by the Esx-1
of antibodies, in TB is incompletely dened, virulence locus described above, directly acts
there is emerging evidence that they play on zebrash embryo epithelial cells to induce
an important immunoregulatory role during expression of MMP-9 in order to optimize
chronic infection with M. tuberculosis (102). recruitment of uninfected macrophages for ex-
pansion of the bacterial population (52). The in
vitro system using human blood mononuclear
Mechanisms of Granuloma Initiation cells to examine early events in granuloma
The recent development of a novel model using formation (described above) has revealed that,
transparent zebrash embryos and uorescent in addition to the glycolipids that can mediate
proteinexpressing M. marinum has provided formation of MGCs (LM, PIMs, and TDM),

366 Philips Ernst


PM07CH15-Ernst ARI 15 December 2011 7:46

ManLAM and AraLAM can mediate early that M. tuberculosis granulomas can be hypoxic
aggregation of mononuclear cells, mimicking in guinea pigs, rabbits, and nonhuman primates
the initial stage of granuloma formation (95). (109), but not in commonly used strains of mice
The active participation of both a secreted (105). These ndings provide potential leads
mycobacterial protein and multiple glycolipids for the development of new drugs and vaccines.
that are unique to mycobacteria (that is, are
absent from pyogenic bacteria) indicates that Effects of Human Immunodeficiency
mycobacteria clearly communicate to the host Virus and Tumor Necrosis Factor
to generate granulomas. Antagonists on Tuberculosis
Granulomas
Biological Benefits of Granulomas Coinfection with HIV profoundly alters the
Because granulomas contain both persistent host response to M. tuberculosis (detailed be-
infection and accumulation of immune cells, low), which inuences the formation, mainte-
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

they represent a stalemate between the host nance, and appearance of granulomas. Because
and the pathogen, implying a benet to both, HIV infection increases the frequency of ex-
as opposed to the classical model in which trapulmonary TB, much of the knowledge of
granulomas are interpreted as walling off the TB granulomas in coinfected patients has been
by University of Sussex on 05/26/12. For personal use only.

infection. Recent evidence strongly supports derived from lymph node samples (110), al-
the idea that early granuloma formation ben- though granulomas in the lungs are similarly
ets the bacteria by recruiting macrophages affected and exhibit fewer lymphocytes and ep-
that serve as additional sanctuaries for bac- ithelioid macrophages, poorer cellular organi-
terial growth and population expansion (86). zation, and large areas of necrosis compared
Whether later granulomas also provide bene- with TB granulomas in non-HIV-infected in-
ts to the pathogen, or whether later granu- dividuals (111). In addition, a larger number of
lomas are the cost of the early benet to the acid-fast bacilli may be found in granulomas of
pathogen, remains to be determined. For the HIV-TB-coinfected individuals than in those
host, granulomas represent sites for optimal in- of non-HIV-infected people (111). The latter
teractions between pathogen-infected antigen- observation contrasts with the lower frequency
presenting cells, such as macrophages and DCs, of sputum smear positivity observed in people
in close apposition to effector T lymphocytes, with HIV-TB coinfection compared with non-
to allow for immune control of mycobacterial HIV-infected controls (112), which suggests
infection. That the host response is sufcient that M. tuberculosis occupies a distinct cellular
to arrest, but not eradicate, the bacteria (or al- or tissue niche in people with HIV coinfection.
ternatively, that the bacteria have mechanisms Advances in the treatment of certain
with which to evade or resist elimination by host autoimmune and inammatory diseases with
responses) translates into the establishment and TNF antagonists has markedly improved
persistence of granulomas. the outcome of diseases such as rheumatoid
A feature of granulomas that has been the arthritis and Crohns disease, although this
focus of recent investigation is the state of improvement has come at the cost of increased
oxygenation at the site where mycobacteria frequency of certain infections. In particular,
reside. Although the fact that M. tuberculosis TNF antagonists such as monoclonal anti-
can shift its metabolism in response to low bodies (iniximab and adalimumab) or soluble
oxygen tension has been known for several receptors (etanercept) have been found to
decades, recent work has identied specic markedly increase the frequency of TB (re-
transcriptional responses to hypoxia (107, 108). viewed in Reference 79). Although a pleiotropic
Moreover, additional research using a chemical cytokine such as TNF contributes to immunity
probe that forms covalent adducts in the to TB by multiple mechanisms, a clinical effect
presence of low oxygen tension has revealed of TNF blockade is to cause the disorganization

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PM07CH15-Ernst ARI 15 December 2011 7:46

or absence of granulomas (113). However, this M. tuberculosis have been well characterized, and
is not a universal nding, as patients treated the importance of these responses in the control
with TNF antagonists can also exhibit typical of infection is exemplied by the early mortal-
granulomas in the context of TB (114). ity and high bacterial burdens observed in spe-
cic gene-deleted mice. Although innate im-
mune responses are clearly essential for defense
Granuloma Unknowns against progressive infection with M. tuberculo-
Although granulomas have been recognized sis, they are insufcient for the long-term con-
as characteristic lesions in TB for well over trol and prevention of active disease. In the case
100 years, many aspects of granuloma biology, of TB, the primary roles of innate immunity
especially in TB, remain poorly understood. appear to be in (a) optimizing the development
One such clinical observation is that within a and regulation of adaptive immune (T cell) re-
host, TB granulomas may exhibit discordant sponses and (b) regulating inammation.
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

and/or dyssynchronous behavior in which one


or more granulomas progress and expand in
size while others remain unchanged (115). This Toll-Like Receptors
nding suggests either that the behavior of bac- M. tuberculosis expresses multiple agonists for
by University of Sussex on 05/26/12. For personal use only.

terial populations at one site is independent of TLRs. In particular, the M. tuberculosis genome
that at other sites or that the efcacy of host im- is predicted to encode 99 putative lipoproteins
munity to TB is determined locally rather than (117), which are potent and abundant TLR2
systemically. agonists. Mycobacterial lipoproteins activate
In addition, the dynamics of bacterial macrophages to produce proinammatory cy-
growth and death at sites of stable (i.e., latent) tokines such as TNF, and this activity is strictly
granulomas remains controversial. Latent TB dependent on TLR2 (118). M. tuberculosis PIMs
was long believed to represent a state in which also serve as TLR2 agonists (119), indicating
bacteria are dormant and not replicating, but that mycobacteria have evolved unique TLR2
recent evidence indicates that, at least in some agonists that are not shared by other bacte-
models of persistence, a subpopulation of bac- ria. In addition to its diverse TLR agonists,
teria are actively replicating (116). M. tuberculosis genomic DNA is a potent agonist
Although latent TB granulomas have long for TLR9, and TLR2/TLR9 double-knockout
been considered stable lesions with long-lived mice are more susceptible to M. tuberculosis in-
cellular populations, it is unlikely that the same fection than either of the single-gene knockout
cells inhabit a granuloma for decades. Because mice (120). Because genetic association stud-
our understanding of the events that allow ies have identied human TLR2 and TLR9
latent TB to reactivate and progress to active polymorphisms that are associated with differ-
disease is incomplete, it will be important to ential susceptibility to TB (121), both of these
determine the rate of turnover of myeloid pattern-recognition molecules appear to be im-
cells (macrophages and DCs), as well as of portant for sensing M. tuberculosis infection.
antigen-specic CD4 and CD8 T cells, given Mice lacking the adaptor protein MyD88,
that variations in egress, death, generation, and which is a downstream signaling adaptor for all
recruitment of cells to the site of infection may members of the TLR family, are even more sus-
contribute to the stability or progression of TB. ceptible to M. tuberculosis than are TLR2/TLR9
double-knockout mice. Although this nding
could imply an important role for additional
INNATE IMMUNITY TO TLRs in response to M. tuberculosis, the ex-
M. tuberculosis treme susceptibility of MyD88-decient mice
Multiple pathways of recognition and sig- is closely mimicked in mice lacking interleukin
naling for innate immune responses to (IL)-1 or the IL-1 receptor (122), which also

368 Philips Ernst


PM07CH15-Ernst ARI 15 December 2011 7:46

signals through MyD88. Therefore, a molecule susceptible to M. tuberculosis infection than are
that coordinates signals through multiple up- NLRP3-sufcient mice (126). In contrast, mice
stream sensors is especially crucial in innate im- lacking the adaptor protein PYCARD/ASC,
mune responses. which links several distinct NLRs to inam-
masome activation, are highly susceptible to
M. tuberculosis infection and exhibit early
NOD2 and NOD-Like Receptors mortality, high bacterial burdens, and poorly
NOD2 is a cytoplasmic pattern-recognition formed granulomas (126). Thus, PYCARD/
receptor that mediates responses to bacterial ASC is clearly an adaptor for at least one
cell wall peptidoglycan and its core subunit, additional upstream sensor that is important
muramyl dipeptide. NOD2 is required for for innate immunity to M. tuberculosis.
optimal macrophage cytokine (e.g., TNF,
IL-6, Il-12p40) responses to mycobacteria, and
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

NOD2-decient mice exhibit earlier lethality C-Type Lectin Receptors


and higher bacterial burdens after infection Multiple CLRs recognize M. tuberculosis; some
with M. tuberculosis compared with wild-type of them mediate phagocytosis (see above), some
mice (123), although the latter nding is not initiate selected signal transduction pathways,
by University of Sussex on 05/26/12. For personal use only.

universal (124). Of considerable interest is that and some may mediate both. Here, we discuss
in mycobacteria, including M. tuberculosis, the their role in cytokine signaling.
peptidoglycan is modied such that the core There is evidence that engagement of
subunit muramyl dipeptide is N-glycolylated the MMR by M. tuberculosis or its complex
(rather than N-acylated) due to the action lipoglycan, ManLAM, activates a regulatory
of mycobacterial N-acetyl-muramic acid pathway involving the nuclear receptor PPAR-
hydroxylase (NamH). This modication makes (peroxisome proliferatoractivated receptor
mycobacterial peptidoglycan a more effective ) and thereby modulates proinammatory
agonist for NOD2 compared with peptido- cytokine production (127), although the mech-
glycan from other bacteria (49). Although anisms of signal transduction remain unclear.
this nding may indicate that efcient recog- However, as mentioned above, MMR-decient
nition of peptidoglycan by NOD2 confers a mice are equivalent to wild-type controls in
pathogenic advantage to mycobacteria, it is terms of the ability to control growth of
unlikely that it has driven its evolutionary se- M. tuberculosis in the lungs and to survive for
lection, given that NamH and glycolylated mu- as long as 23 weeks postinfection (4). Another
ramyl dipeptide are present in nonpathogenic CLR, DC-SIGN, is expressed largely on
mycobacterial species such as M. smegmatis. human DCs, where it has been implicated in
binding a broad array of pathogens, including
M. tuberculosis. The cytoplasmic domain of
Inflammasomes DC-SIGN contains sequence motifs that
Recent investigation of the mechanism of mediate its internalization and uptake of
IL-1 activation and secretion has revealed bound particles and direct them to mature
the involvement of a multiprotein complex phagolysosomes. Engagement of DC-SIGN
termed the inammasome (125). Whereas by ManLAM activates the serine/threonine
inammasomes share caspase-1 as a terminal kinase Raf-1 and induces secretion of IL-10,
effector that cleaves pro-IL-1, the initiators of indicating that this ligand-receptor interaction
inammasome activation are distinct members leads to an anti-inammatory response (128).
of the NOD-like receptor (NLR) protein Genetic association studies of polymorphisms
family. Although NLRP3 mediates activation in the DC-SIGN gene and susceptibility to TB
of caspase-1 in response to M. tuberculosis have so far yielded conicting results and re-
(126), NLRP3-decient mice are no more quire study in additional populations. Further

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PM07CH15-Ernst ARI 15 December 2011 7:46

understanding of the overall roles of DC- protein in mediating innate immune responses
SIGN in TB is complicated by the absence of to M. tuberculosis was recently demonstrated
a clear DC-SIGN ortholog in mice, although with the nding that Card9-decient mice suc-
T helper 17 (Th17)
cells: CD4+ T helper murine SIGNR3 binds the same spectrum of cumb rapidly (approximately four weeks) after
cells that secrete the mannosylated and fucosylated ligands as hu- aerosol infection with M. tuberculosis (135).
cytokine interleukin man DC-SIGN, and SIGNR3-decient mice This early mortality was associated with
(IL)-17, with or are less able to control growth of M. tuberculosis defects in secretion of TNF, IL-6, CCL5,
without other
early after a high-dose infection, although IL-1, and IL-12p40 in cultured macrophages
cytokines including
IFN- and/or IL-22 they are equivalent to wild-type controls at stimulated with M. tuberculosis, although sig-
later time points (129). Further investigation nicant deciencies in these were not found in
is clearly necessary to understand the unique the lungs or serum of M. tuberculosisinfected
roles of DC-SIGN in immunity to TB. Card9/ mice. Instead, M. tuberculosisinfected
A third member of the CLR family, Dectin- Card9/ mice exhibited exuberant neu-
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

1, recognizes both -glucan carbohydrate trophilic inammation associated with higher


structures and M. tuberculosis, even though levels of granulocyte colonystimulating factor
these bacteria lack -glucans. Engagement of (G-CSF) and KC, a neutrophil-attracting
Dectin-1 by M. tuberculosis induces expression chemokine; neutralization of G-CSF or de-
by University of Sussex on 05/26/12. For personal use only.

of IL-12p40 (130) and causes DCs to drive CD4 pletion of neutrophils prolonged survival of
T cells toward T helper 17 (Th17) differentia- the infected mice. These results indicate that
tion (131, 132). Whereas Dectin-1/ mice are CARD9 coordinates signals from multiple
highly susceptible to infection with the fungus upstream sensor molecules and plays an es-
Aspergillus fumigatus (133), they are no more sential role in regulating inammation during
susceptible to M. tuberculosis infection than are infection with M. tuberculosis. Notably, these
wild-type controls (134). Card9/ mice did not have defects in devel-
Another CLR, Mincle, is essential for recog- opment of antigen-specic T cell responses to
nition of the mycobacterial glycolipid TDM M. tuberculosis. Although humans with a null
(8, 9). TDM activates macrophages to produce mutation in CARD9 are decient in Th17
TNF and the chemokine macrophage inam- cells and suffer from chronic mucocutaneous
matory protein 2, and it directs DC-dependent candidiasis, studies of CARD9 polymorphisms
Th1 and Th17 polarization of CD4 T lympho- in human TB have not yet been reported.
cytes. Injection of TDM induces inammatory
cell recruitment and formation of granulomas;
these activities are abolished in the absence of Vitamin D in Innate Immunity
Mincle. Although Mincle-decient mice can- to Tuberculosis
not control infection with the yeast Candida As noted above, treatment of cultured hu-
albicans, no reports have yet appeared regarding man (but not mouse) macrophages with
their ability to control M. tuberculosis infection 1,25(OH)2 D3 can activate these cells to kill
in vivo. intracellular M. tuberculosis, which indicates
that this pathway may operate as an innate
immune mechanism against TB. Additional
Caspase Recruitment studies lend credence to the hypothesis that
DomainContaining Protein 9 vitamin D contributes to the control of TB in
The CLRs Dectin-1 and Mincle share a signal humans. First, multiple clinical studies have
transduction pathway that depends on the Fc found that individuals with active pulmonary
receptor chain, the tyrosine kinase Syk, and TB have lower serum levels of 25(OH)D3
the adaptor protein CARD9. CARD9 has also than do healthy controls (136, 137). Second,
been indirectly implicated in signaling down- epidemiological studies have revealed that
stream of NOD2. The essential function of this dark-skinned individuals, who have lower

370 Philips Ernst


PM07CH15-Ernst ARI 15 December 2011 7:46

serum levels of 25(OH)D3 due to less photoac- gene expression in unstimulated whole-blood
tivation of vitamin D in skin, have increased leukocytes in which the most prominent
frequencies of TB when they move to regions transcript signature in subjects with active TB
with less intense sunlight; this nding indicates was of IFN-regulated genes, including those
that in the presence of marginal levels of vita- regulated by type I IFNs (142). More work will
min D, a further decrease can increase the risk be required to determine the signicance of the
of progression to active TB disease. Together, type I IFN signature in human TB, especially
these observations have led to several clinical whether it contributes to the pathogenesis and
trials to determine whether the addition of progression of the infection.
vitamin D to multidrug chemotherapy for TB
enhances the clearance of the bacteria from
sputum, and results from two of these trials Innate Lymphocytes in Tuberculosis
have been reported. A placebo-controlled trial Natural killer (NK) cells recognize endogenous
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

of intermittent vitamin D3 added to rst-line host molecules with altered expression due to
TB chemotherapy in Guinea-Bissau found no cellular stress through a combination of stim-
difference in the rate of clinical improvement ulatory and inhibitory receptors. Although the
or clearance of M. tuberculosis from the sputum roles of NK cells in viral infections, tumors, and
by University of Sussex on 05/26/12. For personal use only.

(138), whereas a similar study in London found organ transplantation tolerance and rejection
that addition of vitamin D3 accelerated the rate are increasingly well understood, their roles in
of clearance of M. tuberculosis from the sputum, TB remain to be dened. Human NK cells
but only in subjects with a specic polymor- recognize M. tuberculosisinfected macrophages
phism of the vitamin D receptor gene (139). via the activating receptor NKp46 and can lyse
M. tuberculosisinfected cells in vitro (143). Hu-
man NK cells express the protein granulysin,
Type I Interferons in Tuberculosis which has direct antimycobacterial activity, but
Although type I IFNs are widely known for understanding its contribution to the overall
their antiviral activities, they also possess response to M. tuberculosis infection has been
important immunomodulating activities, and hindered by the absence of a mouse homolog.
recent research in TB has brought some of NK cells are an essential source of IFN- in T
these activities to light. Infection of mice with a celldecient mice infected with M. tuberculo-
strain of M. tuberculosis from the Beijing family sis (144), and there is evidence for both activa-
is more virulent in mice than are other clinical tion and depletion of NK cells in the peripheral
isolates or the commonly used H37Rv strain; blood of patients with active TB.
this greater virulence correlates with greater Natural killer T (NKT) cells, especially in-
induction of type I IFN expression by the more variant NKT (iNKT) cells, which express NK
virulent Beijing strain, and intranasal adminis- cell markers in addition to an invariant (mouse,
tration of type I IFNs further increased growth V18; J18) or semi-invariant (human, V24)
of the Beijing strain in the lungs (140). Further- T cell antigen receptor (TCR) chain, and
more, treatment of mice with a potent inducer recognize microbial or self lipids bound to
of type I IFN results in increased lung bacterial the antigen-presenting molecule CD1d, are in-
loads after aerosol infection with M. tuberculosis creasingly being considered for potential roles
and accelerates the animals mortality, which is in TB immunity. In response to lipid anti-
attributable to the increased CCR2-dependent gen recognition, iNKT cells secrete selected
recruitment of a specic monocytic cell subset cytokines and modulate the activities of NK
that is especially permissive for intracellular cells and B and T lymphocytes, as well as
growth of M. tuberculosis in vivo (141). Evidence macrophages and DCs. iNKT cells are acti-
for a role for type I IFN activity in human vated in people with active TB (145), which
TB was recently obtained in a study proling indicates either that M. tuberculosis produces

www.annualreviews.org TB Pathogenesis and Immunity 371


PM07CH15-Ernst ARI 15 December 2011 7:46

a lipid antigen recognized by iNKT cells or of the known antigens presented by CD1 group
that TB induces the expression or exposure 1 are derived from M. tuberculosis or M. bovis.
of an endogenous lipid antigen. In mice, ac- They include didehydroxymycobactin (CD1a);
tivation of iNKT cells with the synthetic lipid mycolic acid, glucose monomycolate, PIM,
-galactosylceramide prior to or during infec- and LAM (CD1b); and mannosyl--1-
tion with M. tuberculosis results in enhanced phosphoisoprenoid (CD1c) (151). Unlike
IFN- secretion by CD4 and CD8 T cells, CD1d-restricted iNKT cells, CD1 group 1
reduced bacterial burdens, and prolonged sur- restricted T cells exhibit diverse TCRs. CD1
vival (146, 147). Finally, coating BCG with - group 1restricted T cells characteristically
galactosylceramide activates iNKT cells in vivo, secrete Th1 cytokines, and some can lyse
signicantly increases the maturation of DCs, M. tuberculosisinfected cells. So far, it has been
and when used to immunize mice, results in difcult to establish the role of CD1 group
the enhanced priming of antigen-specic CD8 1restricted T cells in protective immunity
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

T cells and improved control of TB infection to M. tuberculosis, at least in part because the
compared with unmodied BCG (148). genes encoding them are absent from the
Mucosal-associated invariant T cells mouse genome. Studies of their trafcking
(MAITs) are a recently characterized subset and memory properties are likely to reveal
by University of Sussex on 05/26/12. For personal use only.

of T cells that are enriched at mucosal sites insight into their roles in human TB. Table 2
such as the gut and the airways, express an summarizes the interactions and functions of
invariant TCR chain (human, V7.2; mouse, specic lymphocyte subsets in TB.
V19), and recognize unidentied antigens
bound to the highly conserved MHC class I
related molecule MR1. MAITs that react with ADAPTIVE IMMUNITY TO
M. tuberculosisinfected DCs in vitro are M. tuberculosis
abundant in the blood of tuberculin skin Studies of adaptive immunity to M. tuberculo-
testnegative individuals and are present in sis have emphasized T lymphocytes rather than
lower numbers in the blood and enriched in B cells and antibodies. Although the roles of B
the lungs of people with active TB (149, 150). cells and antibodies are presently subjects of ac-
MAIT clones that recognize M. tuberculosis tive investigation, in this review we focus on the
infected DCs also recognize DCs infected with roles of CD4 and CD8 T cells.
Staphylococcus aureus or Salmonella typhimurium A notable feature of the adaptive immune
(but not Listeria monocytogenes), suggesting response in TB is that, compared with the time
that such clones recognize a highly conserved required to develop immune responses to other
bacterial antigen or that bacterial infection pathogens, initiation of M. tuberculosis antigen
of cells induces the expression, modication, specic CD4 T cell responses is delayed in both
or exposure of a self-antigen. Further work is humans (152) and mice; in the latter species,
necessary to identify the epitopes recognized this delay is due to a long lag between the
by MAITs and to understand their roles in time of initial infection and the migration of
innate immunity to TB. M. tuberculosisinfected DCs from the lungs
CD1 group 1 molecules are structurally to the local lymph node, where they can be
related to human leukocyte antigen (HLA) recognized by nave antigen-specic CD4 T
class I molecules, but unlike classical class I cells (103). Because this delay allows the bac-
molecules, they exhibit very little sequence terial population to expand markedly in the
diversity in human populations. CD1 group lungs, it gives the bacteria an advantage over
1 molecules present a diverse array of lipids, the host, and elucidating the molecular basis of
lipopeptides, and glycolipids to CD4, CD8, or this delay will be crucial to understanding how
CD4 CD8 human T cells. A large proportion M. tuberculosis evades host immunity.

372 Philips Ernst


PM07CH15-Ernst ARI 15 December 2011 7:46

Table 2 Lymphocyte subsets in immunity to Mycobacterium tuberculosis


Antigen-
presenting Roles in control of
Lymphocyte subset molecule Epitopes recognized Effector functions M. tuberculosis
Natural killer cells Classical MHC Specic self-molecules Cytokine (especially Depletion without
class I molecules induced by cellular stress IFN-) secretion; striking effect in T
are inhibitory cytolysis cellsufcient mice
Invariant natural CD1d -Galactosylceramide; Cytokine (especially Ligand activation
killer T cells possible M. tuberculosis IFN-) secretion enhances control of
ligand(s) infection in mice
Mucosal-associated MHC class Unknown conserved pathogen Cytokine secretion Respond to stimulation;
innate T cells Irelated molecule or altered self roles in TB in vivo not
molecule yet established
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

CD4 ( T cell MHC (HLA) Bacterial peptides Cytokine (IFN-, Essential in humans and
receptor) T cells class II TNF, IL-2, mice; distinct
lymphotoxin, IL-17) cytokine-producing
secretion subsets (Th1, Th17,
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Tregs) contribute to TB
immunity through
distinct mechanisms
CD8 ( T cell MHC (HLA) Bacterial peptides Cytokine secretion; Found in humans;
receptor) T cells class I cytolysis (Fas ligand, essential in mice during
TRAIL, or chronic stage of infection
perforin-granzyme
dependent)
CD1a-, CD1b-, or CD1a, CD1b, or Dideoxymycobactin (bound to Cytokine secretion; Present in humans and
CD1c-restricted T CD1c CD1a); mycolic acid, glucose cytolysis guinea pigs; absent in
cells (CD4+ , CD8+ , monomycolate, mice; roles in protection
or CD4 CD8 ) phosphatidylinositol mannan, in TB under
or lipomannan (bound to investigation
CD1b); mannosyl--1-
phosphoisoprenoid (bound to
CD1c)
T cells CD1c, other (?) Mycobacterial Secretion of cytokines Present, but unclear roles;
phosphoantigens; (IFN-, IL-17) deletion in mice has no
stress-induced effect on the course of
self-recognition through TB in vivo
natural killer cell receptors
B cells Not applicable Diverse protein and Antibody production; Regulatory in mice; under
nonprotein (lipid and regulatory cytokines investigation in mice and
glycolipid) (e.g., IL-10) humans
Abbreviations: HLA, human leukocyte antigen; IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; TB, tuberculosis; Th,
T helper cell; TNF, tumor necrosis factor; TRAIL, TNF-related apoptosisinducing ligand; Treg, regulatory T cell.

CD4 T Cells essential role for CD4 T cells in humans de-


rives from studies of HIV-infected individuals.
CD4 T cells, which recognize peptide anti-
HIV infection increases the rate of progression
gens bound to MHC/HLA class II molecules,
from latent to active TB by 5- to 10-fold, and
are clearly essential for protective immunity to
only modest reductions in CD4 T cell counts
TB in humans and in mice. Evidence for an

www.annualreviews.org TB Pathogenesis and Immunity 373


PM07CH15-Ernst ARI 15 December 2011 7:46

are sufcient to increase the incidence of TB vaccine in mice (159) and are essential for ma-
(112). Moreover, reconstitution of CD4 T cells ture granuloma formation in BCG-inoculated
by treatment of HIV with antiretroviral therapy mice (160). In contrast, IL-17 is implicated
decreases the incidence of TB, although not to in pathological inammatory responses to
the same level as in HIV-uninfected individu- mycobacterial infection, including in cattle
als (112). In mice, deciency of CD4 T cells, ei- infected with M. bovis (161), mice lacking the
ther by deletion of MHC class II or by antibody inhibitory costimulatory receptor PD-1 (162),
depletion, results in poorer control of infec- and mice with a selective deciency of IFN-
tion, higher bacterial burdens, and accelerated receptors on nonhematopoietic cells (157).
mortality (153). Additional investigation is needed to dene the
Substantial evidence indicates that circumstances that determine whether IL-17
M. tuberculosis possesses several mechanisms for and Th17 cells contribute to protection or
inhibiting MHC/HLA class II antigen presen- immunopathology, especially in humans with
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

tation and stimulation of CD4 T cells. These TB.


mechanisms include downregulation of antigen Regulatory T cells (Tregs), whose devel-
gene expression by the bacteria, inhibition of opment depends on the cytokine transforming
IFN- induction of MHC/HLA class II expres- growth factor and the transcription factor
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sion, and interference with MHC/HLA class FoxP3, are also emerging as important contrib-
II peptide loading and trafcking to the cell utors to TB immunity. In mice infected with
surface (154). Additional work is needed to pre- M. tuberculosis, Tregs develop with kinetics sim-
cisely identify the steps in MHC class II antigen ilar to that of effector T cells, and in contrast
processing and presentation that are targeted to other systems studied, wherein Tregs recog-
by M. tuberculosis, as well as to identify the nize self-peptides on antigen-presenting cells,
molecules that serve as the bacterial effectors. Tregs can recognize at least one bacterial pep-
Several subsets of CD4 T cells are impor- tide epitope (163). Depletion of Tregs in mice
tant in immunity to M. tuberculosis. The best results in reduction of the bacterial burden in
characterized are Th1 cells, which depend on the lungs, which indicates that Tregs help im-
the cytokine IL-12 and the transcription factor pose a ceiling on the efcacy of effector T
T-bet for their development and maintenance cells in TB. However, Tregs also clearly pre-
(155, 156). The canonical cytokine secreted by vent excessive inammation, so understanding
Th1 cells is IFN-, although Th1 cells can also their expansion, trafcking, and regulation is
secrete TNF, IL-2, lymphotoxin, and certain likely to illuminate important aspects of the bal-
CCL chemokines, and IFN- can be secreted ance between protection and pathology in TB.
by CD8 T cells as well as by innate T cells. In Tregs are found at high frequencies in humans
addition to its role in augmenting the antimi- with active TB disease (164) and are more fre-
crobial capacity of macrophages (see above), quent in tissue sites in miliary TB than in pleu-
IFN- activates macrophages to express MHC ral TB (165), although it is not known whether
class II and acts on nonhematopoietic cells to this greater frequency is the cause or the conse-
regulate IL-17-mediated inammation at the quence of widespread infection in miliary TB.
site of infection (157). Despite the requirement
for IFN- in immunity to TB, its secretion by
CD4 T cells is a poor correlate of protection in CD8 T Cells
humans infected with M. tuberculosis (158). Classically restricted CD8 T cells recognize
Th17 cells, whose canonical cytokine is peptide epitopes bound to MHC/HLA class
IL-17, have recently been recognized for Ia molecules (HLA-A, -B, or -C in humans).
their contributions to TB immunity, although In mice, CD8 T cells contribute to protection
their roles are still being dened. Th17 cells against rapidly progressive M. tuberculosis
augment responses to a protein subunit TB infection; infected CD8 T celldecient mice

374 Philips Ernst


PM07CH15-Ernst ARI 15 December 2011 7:46

succumb earlier than wild-type controls but antigenspecic CD8 T cells. Doing so may
later than CD4 T celldecient mice (153). confer improved protection against TB.
In a nonhuman primate model, CD8 T cells
also contribute to the control of M. tuberculosis
infection. In humans, evidence that CD8 T FUTURE DIRECTIONS IN
cells are essential for immunity to TB is not yet UNDERSTANDING
available, although the nding that administra- TUBERCULOSIS PATHOGENESIS
tion of antibodies to TNF depletes a subset of AND IMMUNITY
CD8 T cells in people with rheumatoid arthri- Despite signicant advances in our understand-
tis and predisposes to progression of latent TB ing of the biology of TB, much remains to be
to active TB provides the strongest association explained. For example, despite considerable
available to date (166). M. tuberculosis antigen effort, investigators have not yet identied a
specic CD8 T cells produce cytokines such as clear correlate of protective immunity against
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

IFN- in response to stimulation and can lyse M. tuberculosis infection or active TB. Finding
M. tuberculosisinfected antigen-presenting such a correlate is important because the devel-
cells (167). In addition to classically restricted opment of more efcacious vaccines depends
CD8 T cells, human CD8 T cells can also on the ability to compare relevant immune re-
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recognize peptide antigens presented by the sponses that are valid correlates of protection
nonpolymorphic class Ib molecule HLA-E in individuals who receive novel or established
(168, 169), and the aforementioned MAITs vaccines. At the same time, correlates of im-
can express CD8. munopathology in TB need to be dened both
The pathways that deliver M. tuberculosis to enable interventions to limit the morbidity of
peptides for class I presentation to CD8 T cells active TB and to evaluate vaccine candidates so
have been the focus of considerable investi- as to minimize the likelihood that a vaccine will
gation. Despite early observations that M. tu- worsen the pathologic outcome in recipients
berculosis can escape phagosomes (17), recent who are subsequently infected by M. tuberculo-
attention has concentrated on apoptosis and sis. Further studies in appropriate animal mod-
cross-presentation pathways in which directly els, followed by studies in well-dened subjects
infected cells provide apoptotic vesicles con- at risk for TB, are needed, and such studies must
taining bacterial antigens to uninfected DCs be informed, but not biased, by existing knowl-
that can process the antigens for presentation to edge. In addition, an improved understanding
CD8 T cells on MHC/HLA class I (Figure 3). of the virulence determinants in M. tuberculo-
Recent research in mice has clearly shown that sis, along with their host targets, will be essen-
enhancing apoptosis of M. tuberculosisinfected tial for directing new drug development with
cells in vivo results in more robust expansion a goal toward interventions that will shorten
and stimulation of CD8 T cells (92), which the treatment course for TB and benet HIV-
lends strong support to a role for apoptosis and infected, immunodecient individuals. Finally,
cross-presentation in immunity to TB. How- more analysis of genetic variation in both the
ever, the recent revival of interest in phagosome pathogen and the host are needed to under-
escape by M. tuberculosis (18) is likely to prompt stand why certain individuals have mild, indo-
additional investigation of pathways that pro- lent TB disease while others have rapidly pro-
mote direct presentation of antigens from cy- gressive, destructive, and highly transmissible
tosolic bacteria via MHC/HLA class I. disease. The worldwide burden of TB warrants
Although this topic is beyond the scope of aggressive efforts to improve the knowledge of
this review, there is considerable interest in de- the pathogen, the host, and their interactions so
veloping TB vaccines that stimulate the ex- as to intervene with and reverse the progressive
pansion and differentiation of M. tuberculosis worsening of the TB epidemic.

www.annualreviews.org TB Pathogenesis and Immunity 375


PM07CH15-Ernst ARI 15 December 2011 7:46

SUMMARY POINTS
1. M. tuberculosis occupies various cellular (macrophage, DC, neutrophil) and subcellular
(immature phagosome, cytoplasm, autophagolysosome) niches.
2. Multiple host receptors mediate the uptake of M. tuberculosis into macrophages, which
promotes bacterial growth, population expansion, and transmission.
3. M. tuberculosis exhibits dynamic responses to the host environment that promote its
survival, replication, and transmission.
4. Determinants of M. tuberculosis virulence, including secreted proteins and biologically
active lipids, interact with the host to contribute to the long-term success of the bacteria
by modulating intracellular bacterial trafcking, host cell death pathways, and granuloma
Annu. Rev. Pathol. Mech. Dis. 2012.7:353-384. Downloaded from www.annualreviews.org

formation.
5. Granulomas, which both contain persistent M. tuberculosis and accumulate immune cells,
represent a stalemate between host and pathogen, implying a benet to both. Our un-
derstanding of the molecular and cellular determinants that maintain this stalemate is
by University of Sussex on 05/26/12. For personal use only.

developing.
6. Multiple molecular components from M. tuberculosis are recognized by elements of host
innate immune responses. Innate immune responses are essential for defense against
progressive infection with M. tuberculosis; however, they are insufcient for long-term
control and prevention of active disease.
7. M. tuberculosis induces antigen-specic CD4 and CD8 T cell responses, as well as re-
sponses by innate lymphocytes, but these mechanisms are usually unsuccessful in elimi-
nating the bacteria.

DISCLOSURE STATEMENT
The authors are not aware of any afliations, memberships, funding, or nancial holdings that
might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS
We apologize to all the investigators whose research could not be appropriately cited due to
space limitations. Our work is supported in part by grants from the Doris Duke Charitable Trust
( J.P.), the IDSA Education and Research Foundation and the National Foundation for Infectious
Diseases ( J.P.), and the National Institutes of Health (R01 AI051242, AI084041, and AI090928
to J.E. and R01 AI087682 to J.P.). We appreciate the insightful comments of Drs. Christopher
Sassetti and Eric Rubin on an early version of the manuscript.

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384 Philips Ernst


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Annual Review of
Pathology:
Mechanisms of
Disease

Contents Volume 7, 2012


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Instantiating a Vision: Creating the New Pathology Department


at Stanford Medical School
David Korn p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
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The Life and Death of Epithelia During Inammation:


Lessons Learned from the Gut
Stefan Koch and Asma Nusrat p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p35
The Cell Biology of Phagocytosis
Ronald S. Flannagan, Valentin Jaumouille, and Sergio Grinstein p p p p p p p p p p p p p p p p p p p p p p p p61
Human Microbiome in Health and Disease
Kathryn J. Pughoeft and James Versalovic p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p99
Merkel Cell Carcinoma: A Virus-Induced Human Cancer
Yuan Chang and Patrick S. Moore p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 123
Molecular Pathogenesis of Ewing Sarcoma: New Therapeutic
and Transcriptional Targets
Stephen L. Lessnick and Marc Ladanyi p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 145
Mechanisms of Function and Disease of Natural
and Replacement Heart Valves
Frederick J. Schoen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 161
Pathology of Demyelinating Diseases
Bogdan F.Gh. Popescu and Claudia F. Lucchinetti p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 185
Molecular Mechanisms of Fragile X Syndrome:
A Twenty-Year Perspective
Michael R. Santoro, Steven M. Bray, and Stephen T. Warren p p p p p p p p p p p p p p p p p p p p p p p p p p 219
Pathogenesis of NUT Midline Carcinoma
Christopher A. French p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 247
Genetic Variation and Clinical Heterogeneity in Cystic Fibrosis
Mitchell L. Drumm, Assem G. Ziady, and Pamela B. Davis p p p p p p p p p p p p p p p p p p p p p p p p p p p p 267

v
PM07-FrontMatter ARI 15 December 2011 8:19

The Pathogenesis of Mixed-Lineage Leukemia


Andrew G. Muntean and Jay L. Hess p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 283
ATM and the Molecular Pathogenesis of Ataxia Telangiectasia
Peter J. McKinnon p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 303
RNA Dysregulation in Diseases of Motor Neurons
Fadia Ibrahim, Tadashi Nakaya, and Zissimos Mourelatos p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 323
Tuberculosis Pathogenesis and Immunity
Jennifer A. Philips and Joel D. Ernst p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 353
Psoriasis
Gayathri K. Perera, Paola Di Meglio, and Frank O. Nestle p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 385
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Caveolin-1 and Cancer Metabolism in the Tumor Microenvironment:


Markers, Models, and Mechanisms
Federica Sotgia, Ubaldo E. Martinez-Outschoorn, Anthony Howell,
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Richard G. Pestell, Stephanos Pavlides, and Michael P. Lisanti p p p p p p p p p p p p p p p p p p p p p p p 423


Pathogenesis of Plexiform Neurobroma:
Tumor-Stromal/Hematopoietic Interactions in Tumor Progression
Karl Staser, Feng-Chun Yang, and D. Wade Clapp p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 469

Indexes

Cumulative Index of Contributing Authors, Volumes 17 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 497


Cumulative Index of Chapter Titles, Volumes 17 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 500

Errata

An online log of corrections to Annual Review of Pathology: Mechanisms of Disease articles


may be found at http://pathol.annualreviews.org

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