2

Inflammation and Immunopathogenesis

of Tuberculosis Progression
Irina Lyadova
Central Tuberculosis Research Institute
Russia

1. Introduction
Approximately one third of the human population is infected with Mycobacterium
tuberculosis (Mtb). Most individuals establish latent infection. In approximately 10% of
infected individuals active disease develops (Raviglione, 2003). It is accepted that the
outcome of infection largely depends on the peculiarities of host immune reactivity that are
controlled genetically.
A lot of efforts have been made to elucidate immune mechanisms of TB defense. The studies
have identified immune cells, molecules and pathways essential for TB protection. It has
been demonstrated that protection depends primarily on the activity of Th1 lymphocytes
and macrophages (Schluger & Rom, 1998; Flynn & Chan, 2001; Boom et al., 2003; North &
Jung, 2004; Kaufmann, 2006). Th1 cells produce immune mediators, such as IFN- and TNF-
 that activate macrophages. Activated macrophages produce bactericidal molecules (e.g.,
reactive nitrogen and oxygen species) that kill mycobacteria. Both macrophages and T cells
secrete a wide range of soluble factors that promote migration of other immune cells to the
site of infection. At the site, immune cells settle to form granuloma that prevents
mycobacteria dissemination. Overall, immune protection depends on efficient pathogen
killing (i.e., antibacterial response) and efficient concentration of immune cells at the site of
infection (i.e., inflammatory response). Multiple studies have demonstrated that deficiency
in cells and molecules implicated in either of these responses results in extremely severe TB,
supporting a concept that TB develops as a result of immune deficiency. On the other hand,
since Koch’s studies, TB has been considered as an immunopathological disease. In this
concept, disease develops due to uncontrolled inflammatory reactivity of the host to the
pathogen. Direct evidences for this concept had not been available, but are now
accumulating, raising a general question on the role for immune deficiency and
hyperreactivity in the pathogenesis of tuberculosis.
As noted above, the outcomes of Mtb infection are very diverse. The diversity consists not
only in the establishment of latent infection vs progression to active disease, but also in a
great variability in the manifestations of active disease. These manifestations differ by the
type and the extent of lung tissue pathology, clinical disease characteristics, the rate of
disease progression, and patient’s responsiveness to treatment. Immune mechanisms
operating during the onset of Mtb infection and during active disease differ. In particular,

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20 Understanding Tuberculosis – Analyzing the Origin of Mycobacterium Tuberculosis Pathogenicity

inflammatory response is prerequisite for efficient control of Mtb at initial stages of the
infection, but may become deleterious at chronic stage of disease. While mechanisms of
initial TB control have been studied extensively, pathogenesis of TB progression is much
less understood.
This review summarizes recent studies on TB immunopathogenesis focusing on the role for
host inflammatory response in TB progression.

2. Mtb infection and host immune response in the lungs

2.1 Cellular immune responses to Mtb infection
Before considering processes ongoing during TB progression, it is important to summarize
current view of the onset of pulmonary Mtb infection.
Mycobacteria enter the lungs trough the respiratory tract. Following the inhalation, the
bacilli are phagocytosed by alveolar macrophages (AM) and airway dendritic cells (DC).
Infected cells migrate to distal sites of the lung and undergo necrosis allowing Mtb to enter
parenchyma and infect parenchymal phagocytes. Pattern recognition receptors (PRRs)
expressed by macrophages, DC and epithelial cells (both on the surface and within the cell)
interact with Mtb ligands (reviewed in detail in Kleinnijenhuis et al., 2001; van Crevel et al.,
2002; Dorhoi et al., 2011; Sasindran & Torrelles, 2011). The interaction drives host cells to
enhance the expression of adhesion molecules and produce inflammatory cytokines and
chemokines that recruit new immune cells (i.e., neutrophils, monocytes, lymphocytes) to the
infectious focus. The accumulating cells initiate formation of granuloma (reviewed in detail
in van Crevel et al., 2002; Russel et al., 2009; Flynn et al., 2011).
Infected DC assisted by neutrophils (Abadie et al., 2005; Blomgran & Ernst, 2011) migrate to
the lymph nodes and initiate T cell response. Due to a high production of IL-12, the response
is largely polarized towards a Th1 type. Th1 cells generated in the lymph nodes migrate to
the site of mycobacterial infection.
At the site, effector Th1 cells undergo functional maturation (Kapina et al., 2007) and
increase their production of chemokines and effector cytokines. Chemokines attract new
immune cells, amplifying local inflammatory DTH-type reaction and promoting
granuloma formation. The cytokines IFN- and TNF- activate adjacent macrophages
(Schluger & Rom, 1998; Flynn & Chan, 2001; Pearl et al., 2001). Activated macrophages
produce reactive nitrogen and oxygen intermediates (RNI, ROI), enhance surface
expression of MHC class II molecules and increase secretion of inflammatory mediators,
i.e. acquire ability to kill Mtb, enhance antigen presentation and propagate local
inflammation and granuloma formation.
Besides macrophages and CD4+ Th1 cells, other immune cells accumulate at the infectious
focus. CD8+ T cells produce IFN- and may exhibit cytotoxic effect against Mtb-infected cells
(Lalvani et al., 1998; Cooper, 2009); Th17 cells promote Th1 immunity and neutrophil
recruitment (Khader & Cooper, 2008); granulocytes phagocyte mycobacteria, mediate
bactericidal effect, and contribute to granuloma formation (Korbel et al., 2008; Rivas-
Santiago et al., 2008); B lymphocytes together with T cells form follicular structures (so-
called “tertiary lymphoid tissues”) that orchestrate immune response ongoing in the lungs

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Inflammation and Immunopathogenesis of Tuberculosis Progression 21

(Ulrichs et al., 2004). NK cells, unconventional T lymphocytes, regulatory T cells are also
attracted (Cooper, 2009).
Overall, TB protection is achieved by two major mechanisms: Mtb killing that, ideally, stops
the infection, and formation of granulomas that prevents Mtb dissemination. Both processes
depend upon proper functioning of sets of surface receptors and soluble factors that provide
immune cell activation, migration and effector activity. Factors essential for the current
review are briefly discussed below.

2.2 Molecular mediators of immune response

Innate immune cells recognize Mtb ligands by a set of PRRs that include Toll-like receptors
(TLRs), C-lectin type receptors (CLRs), scavenger receptors (SRs), immunoglobulin Fc
receptors (FcRs), NOD-like receptors (NLRs) (reviewed in detail in van Crevel et al., 2002;
Sasindran & Torrelles, 2011; Dorhoi et al, 2011). Ligation of PRRs induces gene expression,
primarily the expression of genes for early response cytokines IL-1, TNF-, IL-6. All, IL-1,
TNF- and IL-6 promote further activation of macrophages (Kishimoto, 2005). In addition,
IL-1 is highly chemotactic for T lymphocytes, stimulates CD4+ T cell proliferation and
IFN- production, controls early processes of granuloma formation, and stimulates the
generation and the recruitment of neutrophils (Hunninghake et al., 1987; Sugawara et al.,
2001; Miller et al., 2007; Oliveira et al., 2008; Ueda et al., 2009). TNF- is critical for the
continued organization of the granulomatous lesions (Kindler et al., 1989; Flynn et al., 1995;
Bean et al., 1999; Roach et al., 2002) and has immunoregulatory propereties (Orme &
Cooper, 1999; Motoo et al, 2009). IL-6 modulates T- cell response, is essential for antibody
formation, and stimulates hematopoiesis, in particularly, the myeloid lineage (Liu et al,
1997; Kishimoto, 2005; Walker et al., 2008). All three cytokines may cause severe pathology.
They have been implicated in microvascular thrombosis, capillary leak and neutrophilic
chemotaxis, produce organ dysfunction, systemic inflammation, acute-phase response,
cachexia and fever (Tracey et al., 1987; Hernandez-Pando et al., 1994; Chang & Bistrian,
1998; Bekker et al., 2000; Agriles et al., 2005; Oliveira et al., 2008).
Chemokines are secreted by macrophages, neutrophils, T lymphocytes, endothelial cells and
other local cells. CC chemokines CCL2, CCL3, CCL4, CCL5, and other attract monocytes,
lymphocytes, macrophages, DC, NK cells to the site of infection and favor Th1 response.
CXC chemokines CXCL10 (IP-10) and CXCL9 (MIG) are produced in response to IFN- and
attract predominantly T-lymphocytes and monocytes, propagating T cell response. CXC
chemokines CXCL8 (IL-8), CXCL2 (MIP-2) and CXCL1 (KC) are mainly chemotactic for
hematopoietic stem cells and granulocytes and are responsible for neutrophilic
inflammation at advanced stages of TB (Rhoades et al., 1995; Sasindran & Torrelles, 2011).
A separate set of molecules mediate Mtb killing. IFN- activates macrophage for Mtb killing.
Granzymes and perforin mediate cytotoxicity of CD8+ T cells and NK cells. ROI and RNI,
defensins, cathelicidin, proteases and other bactericidal molecules produced by IFN--
activated macrophages and by neutrophils mediate Mtb killing (Flynn & Chan, 2001; van
Crevel et al., 2002; Rivas-Santiago et al., 2008). Of note, these molecules are released not
only intracellularly but also extracellularly. Thus, extracellular milieu at the focus of the
infection becomes highly inflammatory containing multiple mediators that are not present
in healthy lungs and that potentially are highly deleterious. During active TB, cytokines,

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22 Understanding Tuberculosis – Analyzing the Origin of Mycobacterium Tuberculosis Pathogenicity

chemokines and other mediators released by immune cells, as well as activated immune
cells themselves, are found not only at the focus of the infection, but also in the
bronchoalveolar fluid (BAL) and in the circulation where they may mediate systemic
inflammatory response.

2.3 Granuloma in TB protection and pathology

It is generally assumed that formation of granuloma represents a host strategy to contain the
infection and limit pathogen dissemination. However, granulomatous response is observed
not only in individuals with latent infection, but also in TB patients, including patients with
extremely severe and rapidly progressing TB. Thus, it was suggested that a mere formation
of granuloma is not enough to prevent TB, rather it is important how “proper” granuloma is
functioning (Flynn et al., 2011).
In humans, granulomas observed during latent infection (“tuberculomas”) are usually
small, compact, solid and not numerous. They consist of macrophages and lymphocytes and
a small amount of neutrophils. A central core contains epithelioid macrophages and a few
neutrophils and multinucleated giant cells (Lin et al., 2009). The wall is well organized and
contains follicle-like structures, in which proliferating lymphocytes reside (Ulrichs &
Kaufmann, 2006). It is believed that such granulomas are able to control the infection and
keep Mtb in a dormant state (Flynn et al., 2011).
During active disease, the granuloma cannot contain the infection. Immune cells continue to
arrive, the granuloma grows and its organized structure disrupts (Ulrichs & Kaufmann,
2006; Russel et al., 2009; Cardona et al., 2011). Macrophages differentiate into epithelioid
cells. The neutrophil influx increases and the centrum of the granuloma necrotizes and then
caseates resulting in the formation of necrotizing and caseating granulomas. In necrotizing
granulomas the central area consists mainly of degenerating neutrophils; in caseating
granulomas it is presented by cell debris. The centrum is surrounded by a dense zone of
epithelioid macrophages, multinucleated giant cells and lymphocytes (Lin et al., 2009).
Eventually, the centrum caseous breaks into the bronchus, releasing bacteria into the
respiratory tract and resulting in the formation of cavities. Mtb replication goes out of
control. It has long been thought that the caseum represents a nutritional site for rapid Mtb
replication. However, recent data have shown that: (i) many necrotic areas are devoid of
Mtb (Ulrichs & Kaufmann, 2006), (ii) microbes located in the caseum resemble stationary-
phase organisms, whereas replicating Mtb are found in sputum and BAL, and in connection
with neutrophils (Eum et al., 2010). It is therefore suggested that Mtb replication does not
occur in the liquefying cavity, but rather starts upon the exit of the bacilli from that cavity
into the sputum.
Many questions regarding the functioning of granulomas remain unclear. What is an
association between caseation and TB activity? Caseation is often considered as a hallmark
of active disease. However, it has been reported that in non-human primates caseation
occurs very early in granuloma formation, shortly after macrophages in the lungs become
infected, i.e. during the very early, latent stage of the infection. In this model, caseating
granuloma could successfully contain the pathogen and did not necessarily proceed to
active TB (Lin et al., 2006), suggesting that it is probably the extent of caseation, but not the
caseation itself that determines disease activity. Next, caseous (tuberculous) pneumonia is

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Inflammation and Immunopathogenesis of Tuberculosis Progression 23

an example of active TB disease that is not accompanied by the formation of classical

granulomas. In this disease, extensive areas of parenchymal infiltration with multiple
necrotizing and caseating foci are observed, but these foci are not structured, instead they
extend contiguously in the lung parenchyma. Clinical manifestations of caseous pneumonia
are extremely severe with evident signs of severe systemic inflammation; but exact
pathways underlying the development of caseous pneumonia (vs caseating granulomas) are
poorly understood. Another important question is whether caseation (either during
pneumonia or in granulomas) represents host response to unlimited Mtb growth (i.e., is a
result of inefficient Mtb control) or whether it is a result of “improper” host reactivity to a
relatively small number of dormant Mtb persisting in early or mature granulomas. Several
recent reviews have discussed these questions and suggested hypotheses to explain the
development of active TB in non-immunosuppressed patients (Russel, 2009; Cardona, 2009;
2010; Flynn et al., 2011).

3. TB infection in hosts with immune deficiency

A role for immune deficiency in the pathogenesis of Mtb infection has been addressed in
multiple studies.
In mice, targeted mutations of PRR genes impaired host resistance to Mtb (Drennan et al.,
2004; Divangahi et al., 2008; Mayer-Barber et al., 2010). Deficiency on PRR adaptor
molecules, e.g., MyD88, CARD9, TIR8, resulted in extremely high susceptibility (Garlanda et
al., 2007; Dorhoi et al., 210; Mayer-Barber et al., 2010). Lack of “early response cytokines”
(i.e., IL-1, TNF-, IL-6) or their receptors impaired granuloma formation, cytokine and
chemokine synthesis and rendered mice extremely susceptible to Mtb infection. (Ladel et al.,
1997; Bean et al., 1999; Juffermans et al., 2000; Yamada et al., 2000; Roach et al., 2002;
Fremond et al., 2007).
Defects in acquired immunity also led to disease exacerbation. Mice deficient in T cells,
(especially, in CD4+ subset) and Th1 type cytokines (i.e., IL-12p40, IFN-) succumbed early
to Mtb infection with high bacterial loads (Cooper et al., 1993; Flynn et al., 1993; 1995;
Cooper et al., 1997; Mogues et al., 2001). Similar effects were observed in mice with defects
in enzymes involved in the generation of host bactericidal molecules (e.g., iNOS, p47phox
(MacMicking et al., 1997; Cooper et al., 2000; Scanga et al., 2001; Jung et al., 2002).
Observations in humans are in line with results obtained in mice. A role for TNF- in host
defense is supported by reactivation of TB in rheumatoid arthritis patients receiving anti-
TNF therapy (Keane et al., 2001). An essential role for CD4+ T cells in anti-TB defense is
evident from a high incidence of TB and altered histopathological characteristics of TB (i.e.,
diffuse necrotic lesions instead of structured granulomas) in humans co-infected with
immunodeficiency virus (Chaisson et al, 1987). Finally, humans with mutations in molecules
involved in Th1 immunity, i.e., the IL-12p40 subunit, the IL-12 receptor 1 chain, the IFN--
receptor ligand binding chain, STAT1, exhibit high susceptibility to mycobacterial infections
induced by Mtb, BCG or environmental mycobacteria (Altare et al., 1998; Dorman et al.,
2000; Casanova & Abel, 2002).
Altogether, multiple studies have associated severe Mtb infection with immune deficiency
and poor control of pathogen growth. This association explains why hosts with genetic or

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24 Understanding Tuberculosis – Analyzing the Origin of Mycobacterium Tuberculosis Pathogenicity

acquired immune deficiencies suffer from severe mycobacterial infections. However, it

cannot explain why active TB occurs in immunologically-competent hosts, or why TB
exhibits so many different clinical manifestations.

4. Inflammation and TB progression

Inflammation always accompanies infection and represents a critical component of host
immune defense. However, inflammatory reactions may also be deleterious and promote
disease exacerbation. The first indication of a damaging role of host immune response
during TB was obtained by Koch who described local and systemic reactions and disease
worsening following treatment of TB patients with Mtb extract (Koch, 1890, as cited in
Moreira et al., 2002). Thereafter, multiple observations have associated severe TB course
with high inflammatory reactions. However, it is usually very difficult to dissect whether
severe inflammation is a cause or a result of disease severity, i.e., whether it develops due to
intrinsic host hyperreactivity to the pathogen or whether it mirrors high pathogen load (i.e.
deficient Mtb control). Gene targeting approach is not very helpful with this respect as the
majority of factors mediating inflammation are prerequisite for the development of
protection and therefore their targeting or neutralization results in disease exacerbation and
masks potential pathological properties. Yet, several experimental settings made this
dissection possible. Detailed analysis of theses studies allows identifying immunological
features critical for TB progression.

4.1 Mtb infection in mice with deficiency in negative regulators of inflammation

Several studies examined the course of TB in mice with deficiency in negative regulators of
inflammation. TIR-8 (Toll/IL-1R), a member of the IL-1R family, is an inhibitor of
inflammation. The receptor functions by trapping of TNFR-associated factor 6 and IL-1R
associated kinase 1 and inhibiting activation of NF-kB induced by members of the IL-1/TLR
family (Polentarutti et al., 2003; Garlanda et al., 2007). In Mtb infected Tir-8-/- mice control of
mycobacteria growth and T cell responses were unimpaired. Nevertheless, the mice were
rapidly killed by low doses of Mtb. The disease was characterized by overwhelming
inflammatory response in the lungs that manifested as increased production of IL-1 and
TNF- and increased lung infiltration with neutrophils and macrophages. Blocking IL-1
and TNF- with a mix of anti-cytokine antibodies significantly prolonged survival of Tir-8-/-
mice supporting that their exaggerated mortality was associated with exacerbated
inflammation and tissue damage (Garlanda et al., 2007).
Similarly, mice lacking D6, a decoy and scavenger receptor for inflammatory CC
chemokines, had normal control of bacteria replication but responded to Mtb infection by
uncontrolled systemic inflammation and died from a fatal infection (Di Liberto et al., 2005).
WSX-1, a component of IL-27R complex, is another molecule that plays a regulatory role
during Mtb infection, mainly by dampening Th1 response. In the absence of WSX-1, Mtb
infection induced elevated production of the pro-inflammatory cytokines TNF- and IL-
12p40. This led to concomitant activation of CD4 T cells, increase in IFN- production and
macrophage effector functions. Bacterial loads were reduced, but mortality was accelerated,
which was attributed to chronic hyperinflammatory response (Holscher et al., 2005).

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Inflammation and Immunopathogenesis of Tuberculosis Progression 25

4.2 Mtb infection in mice with deficiency in positive regulators of inflammation

As discussed above, deficiency in molecules mediating inflammatory signals alters host
control of Mtb replication and exacerbates Mtb infection. Strikingly, even when
inflammatory pathways are altered, fatal infection is accompanied by overwhelming
inflammation, supporting a concept that TB progression and lethality are associated with
hyperinflammatory reactions.
Dorhoi and coauthors (Dorhoi et al., 2010) examined Mtb infection in mice that lack CARD9,
an adaptor molecule that collects signals from several PRRs. Mice developed a lethal
infection accompanied by uncontrolled Mtb replication, by besides that – by a severe
neutrophilic inflammation of the lung tissue and overproduction of factors involved in
granulocyte generation and chemoattraction (i.e., G-CSF, KC). Neutralization of G-CSF or
depletion of neutrophils reduced lung inflammation and prolonged host survival without
affecting bacterial burdens. Thus, dampening neutrophilic inflammation at advanced stage
of disease was enough to decrease disease severity.
Mice with a deficiency in IL-1R developed lethal infection characterized by extremely high
numbers of Mtb in their lungs. Of note, a characteristic feature of lethal infection was an
elevated (but not a deficient) production of major proinflammatory cytokines, e.g., IL-1,
IL-6, TNF- (Fremond et al., 2007).
Mice deficient in TNF- or TNF- receptor developed extremely severe disease due to
defects in granuloma formation (Bean et al.,1999). Of note, a characteristic feature of this
infection was a prominent infiltration of the lung tissue with neutrophils.
In humans, S180L polymorphism in TIRAP gene implicated in the TLR2- and TLR4-
mediated signaling, leads to the attenuation of inflammation and decreases the risk of TB
development (Castiblanco et al., 2008).

4.3 Anti-inflammatory treatment improves TB outcome

Several groups examined the possibility to improve TB outcome by limiting immune
inflammation. In patients with pulmonary TB, treatment with adjunctive corticosteroid
therapy together with antibiotics accelerated sputum culture conversion in comparison with
patients who received antibiotic treatment alone (Bilaceroglu et al., 1999). Adjunctive
treatment with etanercept, a soluble TNF-receptor, reduced time to sputum culture
conversion and improved clinical signs of TB in HIV infected patients (Wallis et al., 2004).
Thalidomide, an inhibitor of TNF- production, improved treatment outcome in patients
with pulmonary TB (Tramontano et al., 1995; Coral et al., 1996). Recently, an inhibitory
effect of CC-3052, an inhibitor of phosphodiesterase-4, on TNF- production was shown.
Co-treatment of Mtb infected rabbits and mice with isoniazid plus CC-3052 significantly
reduced the level of TNF- expression and the extent of disease (Koo et al., 2011; Subbian et
al., 2011). As mentioned above, simultaneous blocking of IL-1 and TNF- significantly
prolonged survival of Tir-8-/- mice, and neutralization of G-CSF or depletion of neutrophils
decreased disease severity in CARD9-/- mice (Garlanda et al., 2007; Dorhoi et al., 2010). In
contrast to anti-TNF treatment, treatment of mice with TNF- or BCG expressing TNF-
significantly increased lung tissue inflammation and resulted in accelerated mortality
without affecting the bacillary load (Moreira et al., 2002). Altogether, the studies show that

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26 Understanding Tuberculosis – Analyzing the Origin of Mycobacterium Tuberculosis Pathogenicity

dampening immune inflammation during TB may significantly ameliorate disease outcome

without affecting Mtb replication.

4.4 Mtb infection in hosts with genetic differences in the extent of inflammation
Studies reviewed above are largely based on the analysis of TB infection in hosts with
artificially altered or modulated immune responses. Such interventions may interfere with
processes naturally operating in the infected host. To elucidate whether the extent of
inflammation affects TB progression in a “normal” population, several groups have
compared immune responses in mice genetically resistant and susceptible to TB. In different
models, susceptible mice produced more proinflammatory cytokines and developed
stronger neutrophilic inflammation than resistant mice (Cardona et al., 2003; Eruslanov et
al., 2004; Eruslanov et al., 2005; Keller et al., 2006). To directly address an association
between inflammatory reactions and TB progression, we have recently analyzed TB severity
and immune reactivity in a panel of genetically heterogeneous (A/SnxI/St)F2 hybrid mice
(Lyadova et al., 2010). The hybrids originated from TB-highly-susceptible I/St and more
resistant A/Sn mice that following challenge with Mtb displayed different rates of TB
progression (Lyadova et al., 2000; Sanchez et al., 2003; Eruslanov et al., 2004). In F2 mice, the
rate of TB progression did not depend on lung Mtb loads or the levels of lung expression of
iNOS, IFN-, IL-12, or CCL5, i.e. genes controlling antibacterial response. Instead, it directly
correlated with high lung expression of inflammation-related factors, such as IL-1, IL-6, IL-
11, CXCL2, several metalloproteinases. Another characteristic feature of rapidly progressing
TB was the accumulation in the infected lungs of Gr-1-positive cells (see below for details).
Thus, similarly to gene-targeted mice, in F2 mice severe infection was characterized by: (i)
overexpression of proinflammatory factors and (ii) excessive infiltration of the lung tissue
with neutrophil-like cells. Further analysis suggested that these manifestations were a
consequence of increased transcription of proinflammatory factors in host macrophages and
were predetermined genetically (Lyadova et al., 2010).
A role for host genetic factors in the control of inflammation and TB progression was
directly demonstrated in the studies by Kramnik’s group (Pan et al., 2005; Yan et al., 2007).
The authors identified sst1 genetic loci on mouse chromosome 1 that controls progression of
pulmonary TB. Different susceptibility of sst1 congenic mice to Mtb infection was associated
with neither Th1 cell activation nor with iNOS/NO responses but was due to different host
capacity to mount necrotic lung inflammation and was mediated by macrophages.

4.5 T lymphocytes in TB exacerbation

T lymphocytes are responsible for efficient protection against mycobacteria. However, they
may also contribute to TB exacerbation. A series of recent studies performed in programmed
death-1 (PD-1) knockout mice has clearly demonstrated that (Lázár-Molnár et al., 2010;
Barbar et al., 2011).
PD-1 is an inhibitory receptor expressed on exhausting T cells; its engagement inhibits T cell
proliferation and cytokine secretion. PD-1-deficient mice infected with Mtb developed
unaltered or even increased CD4+ T cell and NO responses. Yet, they died because of severe
infection characterized by uncontrolled bacterial proliferation, increased lung tissue
pathology, neutrophilic infiltration, and high lung expression of proinflammatory cytokines

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Inflammation and Immunopathogenesis of Tuberculosis Progression 27

TNF-, IL-1, IL-6 and IL-17 (Lázár-Molnár et al., 2010; Barbar et al., 2011). Depletion of
CD4+ T cells ameliorated TB course, indicating that CD4+ T cells themselves drove the
increased bacterial loads and pathology seen in infected PD-1-deficient mice. In contrast to
Mtb infection, resistance to viral infections was increased in PD-1 deficient mice (Velu et al.,
2009). Thus, in TB imbalanced T cell responses are more deleterious than during other
infections.
Our observations made in F2 model support the involvement of T cells in TB exacerbation
(Lyadova et al., 2010). In this model, susceptible mice displayed first signs of TB progression
(i.e., wasting) on day 16 post-challenge and died on days 26-35 post-challenge. Mice that had
not succumbed to infection by the end of week 5 survived for as long as 140 days (the time
of observation). It is well established that Mtb–specific Th1 response appears at week 2 and
reaches its plateau at week 4 post-challenge. Thus, the most susceptible F2 mice succumbed
to Mtb infection at a time when T cell response started to operate; mice that survived this
period, lived for a long time. We believe that the onset (or a sudden increase, as in Koch’s
studies) of T cell response represents a risk factor that may provoke disease exacerbation.
The underlying mechanism likely involves T-cell dependent propagation of inflammation
mediated by innate immune cells.
The role for T cells in hyperinflammatory reactions and TB exacerbation is also supported
by the immune restoration syndrome (IRS) observed in patients co-infected with HIV-1 and
Mtb and initiating highly active antiretroviral therapy. The syndrome is characterized by the
exacerbation of granulomatous lesions and massive inflammatory and Th1 cytokine storm.
The syndrom has been associated with a sudden restoration of immune competence, i.e. an
increase in the numbers of activated tuberculin-specific effector memory CD4 T cells
(Autran et al., 2009).

4.6 Infection induced by imp Mtb mutants

Recently, several mutant Mtb strains bearing immunopathology (imp) phenotype have been
generated. The mutants have unaltered capacity to grow and persist in mouse lungs, but
induce poor inflammation and attenuated disease. TB-susceptible DBA/2 mice challenged
with SigC mutant had decreased mortality associated with lower numbers of neutrophils
and reduced levels of TNF-, IL-1, IL-6 and IFN- in their lungs (Khairul-Bariah et al.,
2008). Similar results were obtained when SCID mice were challenged with SigC mutant.
whiB3 Mtb mutant induced milder disease than wild type Mtb strain due to reduced
granulomatous inflammation in the lungs (Steyn et al., 2002 ). SigH Mtb mutant produced
high bacterial counts in the lungs, but recruited fewer CD4+ and CD8+ T cells and was
nonlethal in TB-susceptible C3H mice (Kaushal et al., 2002).
Thus, peculiarities of infecting Mtb strain represent another factor that determines TB
outcome by affecting inflammatory reactions.

4.7 Inflammatory responses in patients with pulmonary TB

In TB patients, severe infection is also associated with excessive inflammatory reactions.
Patients with pulmonary TB have higher levels of proinflammatory cytokines IL-1, IL-6,
TNF-, IL-8, and their inhibitors TNFRI, IL-1Ra and TGF- in sera and BAL fluid than

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28 Understanding Tuberculosis – Analyzing the Origin of Mycobacterium Tuberculosis Pathogenicity

healthy controls and TB contacts (Zhang et al., 1995; Tsao et al., 1999; Tsao et al., 2000;
Nemeth et al., 2011). Among TB patients, serum levels of TNF- and TGF- are significantly
higher in patients with advanced TB compared to patients with mild-moderate TB (Fiorenza
et al., 2005). In involved sites of TB, spontaneous release of IL-1, IL-6 and TNF- is
significantly higher than in uninvolved sites and in miliary TB (Law et al., 1996). Patients
with large TB cavity have much higher concentrations of TNF- and IL-1 than patients
who have small or no cavity. Importantly, the ratios of TNF- to sTNF-RI and IL-1 to IL-
1RA in the BAL fluids are also higher in patients with large cavity. Thus, a role for the
relative abundance of TNF- and IL-1 in tissue necrosis and cavity formation was
suggested (Tsao et al., 2000).
Besides high levels of proinflammatory factors, a characteristic feature of progressing
pulmonary TB is high numbers of granulocytic cells in the BAL fluid (Law et al., 1996; Barry
et al., 2008). It was demonstrated that in sputum and BAL fluids of patients with pulmonary
TB neutrophils are more abundant and contain more intracellular bacilli than macrophages
(Eum et al., 2010).
In summary, hyperinflammatory reaction is a characteristic feature of progressing
pulmonary TB in both humans and experimental animals. The reaction manifests as high
expression of proinflammatory cytokines and prominent neutrophilic influx to the lung
tissue. These manifestations develop irrespectively on exact pathways that have led to
severe TB (e.g., defects in host capacity to control Mtb growth, host hyperreactivity to
pathogen-derived signals, or peculiarities of infecting Mtb strain).
Mechanisms whereby proinflammatory cytokines mediate their pathological activity have
been studied during different pathological conditions and reviewed in detail elsewhere
(Chang & Bistrian, 1998; Thacker, 2006; Mootoo et al., 2009; Argiles et al., 2005). In contrast,
data on the role for neutrophils in TB pathogenesis are contradictory and require special
consideration.

5. Neutrophils
Physiological activities of neutrophils involve adhesion, migration to the site of
inflammation, phagocytosis, degranulation, and release of inflammatory mediators. We will
briefly review activities related to TB and discuss the controversial results of the studies that
addressed the role of these cells in tuberculosis.

5.1 Functional activities

Neutrophils are among the first cells that arrive at the inflammatory focus (Appelberg &
Silva, 1989). The process involves adhesion of circulating neutrophils to the endothelial cells
and migration through the endothelial barrier and within the inflamed tissues. Neutrophils’
migration is driven by the inflammatory cytokines IL- and TNF-, the chemokines IL-8,
CXCL2, CXCL1, bacteria products and molecules released by dying cells, i.e. it occurs in
response to inflammation and tissue injury (reviewed in Witko-Sarsat et al., 2000).
At the site of infection, neutrophils phagocytoze IgG- and complement-opsonized targets
and exhibit bactericidal activity. The later is mediated by the production of ROI and release

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Inflammation and Immunopathogenesis of Tuberculosis Progression 29

of bactericidal molecules stored in neutrophils’ granules. ROI include: (i) superoxide anion
and hydrogen peroxide generated by NADPH-dependent oxidase; (ii) hypochlorus acid and
chloramines, generated by neutrophil-specific enzyme metalloperoxidase. Granule-
associated bactericidal molecules are numerous and include short bactericidal peptides (e.g.,
human neutrophil peptides (HNPs) 1–3, cathelicidin LL-37, lipocalin 2); lactoferrin; serine
proteases; metalloproteinases (Witko-Sarsat et al., 2000; Fu, 2003; Martineau, et al. 2007;
Rivas-Santiago et al., 2008). Macrophages utilize neutrophil bactericidal peptides to increase
their antibacterial activity: they phagocyte apoptotic neutrophils and deploy neutrophils'
bactericidal peptides to combat intracellular Mtb (Tan et al., 2006).
An additional bactericidal mechanism is formation of extracellular traps (NETs) - a web of
chromatin fibers that contain serine proteases and can trap and kill extracellular microbes
(Brinkmann et al., 2004).
Neutrophils are involved in the formation of granuloma (Seiler et al., 2003) and in the
initiation of T cell response: they were shown to transport live mycobacteria from
peripheral tissues to the lymphoid organs and to deliver mycobacterial antigens to DC in a
form that makes DC more effective initiators of naïve CD4+ T cell activation (Abadie et al.,
2005; Blomgran et al., 2011).
An important activity of neutrophils is a secretion of inflammatory mediators and their
inhibitors. The list includes proinflammatory cytokines IL-1 and TNF-, the major
neutrophil attracting chemokines IL-8 and CXCL2, growth factors GM-CSF and VEGF,
several metalloproteinases, IL-1Ra, TGF- (McColl et al., 1992; Cassatella, 1995; Riedel &
Kaufamm, 1997; Petrofsky et al., 1999; Scapini et al., 2000; Matzer et al., 2001; Sawant &
McMurray, 2007; Lyadova et al., 2010). The secretion is not high, but when neutrophils
accumulate in high numbers, it may represent an important source of inflammatory factors.
Interestingly, many neutrophils contain intracellular IFN-. This was shown during Mtb
infection (our unpublished observations) and also in other models (Terri & Beaman, 2002).
Neutrophils not only produce proinflammatory cytokines by themselves, but also stimulate
proinflammatory activity of macrophages (Persson et al., 2008).
An important issue is that factors produced by neutrophils are the major positive
regulators of their activity: TNF- and IL-1 enhance neutrophils’ migration,
degranulation, oxidative and secretory activities; IL-8 and CXCL2 are the major
neutrophil-attracting chemokines; IFN- promotes secretory activity; metalloproteinases
degrade extracellular matrix facilitating cell migration within the inflamed tissue. Thus,
neutrophilic inflammation is under an autocrine regulation. The major inhibitors of
cytokine production by neutrophils are IL-10, IL-4, and IL-13 (Witko-Sarsat et al., 2000),
but they are poorly produced during TB.
Neutrophils release bactericidal molecules and enzymes not only into the phagosome, but
also into the extracellular milieu. This allows killing extracellular microbes, but on the other
part is detrimental: serine proteinases degrade almost all components of extracellular matrix
and a variety of plasma proteins; collagenase (MMP8) and gelatinase (MMP9) cleave
different types of collagen; ROI and chlorinated oxidants inactivate inhibitors of proteinases,
activate metalloproteinases and may mediate direct cytotoxic effect (Weiss, 1989; Witko-
Sarsat et al., 2000)

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30 Understanding Tuberculosis – Analyzing the Origin of Mycobacterium Tuberculosis Pathogenicity

The only way to resolve neutrophilic inflammation is to clear the infection: in this case
emigration of new neutrophils stops; neutrophils that had migrated to the inflamed sites
undergo apoptosis and are phagocytosed by macrophages. During chronic infections,
neutrophilic inflammation becomes uncontrolled.

5.2 Neutrophils during Mtb infection

5.2.1 Antimycobacterial activity of neutrophils and TB prevention
Neutrophils are among the first cells that migrate to the focus of lung Mtb infection, and
they progressively accumulate at the infectious site during the chronic stage of disease.
Human and mouse neutrophils efficiently phagocyte mycobacteria (Kisich et al., 2002;
Eruslanov et al., 2005), but their capacity to kill mycobacteria is disputable.

Denis and Andersen reported that human neutrophils stimulated with IFN- failed to kill
Mtb (Denis & Andersen, 1991). In line with this, in our previous studies mouse neutrophils
displayed low antimycobacterial activity that could not be enhanced by the addition of
exogenous IFN- (Eruslanov et al., 2005). In a recent study by Eum and coauthors (Eum et
al., 2010), neutrophils present in the sputum and BAL fluids of patients with active
pulmonary TB contained Mtb that exhibited signs of replication. Based on these
observations, it is concluded that neutrophils have poor antimycobacterial activity and
during TB act by hiding Mtb from macrophages and permitting Mtb replication (Eruslanov
et al., 2005; Eum et al., 2010).

In other studies, neutrophils were shown to kill Mtb. The effect was mediated by -
defensins, LL37 and lipocalin and promoted by TNF- (Kisich et al., 2002). Of note, IFN-
did not enhance killing, which may explain a failure to detect neutrophil-mediated Mtb
killing in the studies described above (Denis & Andersen, 1991; Eruslanov et al., 2005).
Recently, an association between low plasma levels of HNP1-3 and the development of
multi-drug resistant TB has been demonstrated (Zhu et al., 2011), supporting the
involvement of neutrophils in TB protection. In line with this, it has been demonstrated that
black African participants (known to have a relatively high susceptibility to TB) have lower
counts of neutrophils and lower concentrations of circulating HNP1–3 and lipocalin 2 than
white participants; in TB contacts, the counts of peripheral blood neutrophils inversely
correlated with risk of TB development (Martineau et al., 2007). Thus, multiple studies
suggest a role for neutrophils in TB prevention.

5.2.2 Neutrophils and TB progression

In contrast to early stages of Mtb infection, at which neutrophils are not numerous and may
contribute to Mtb control, during active disease neutrophils become more abundant and
may cause severe pathology. In humans, high numbers of neutrophils in BAL fluids have
been associated with disease activity and lung tissue cavitation (Barry et al., 2009;
Sutherland et al., 2009). In mice, neutrophils (Gr-1-positive cells) accumulate abundantly in
the lungs of susceptible mice (e.g., I/St, DBA/2) but are less numerous in resistant mice
(Eruslanov et al., 2005; Keller et al., 2006). It is believed that neutrophils contribute to disease
progression by amplifying local inflammatory reactions and mediating tissue injury.

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Inflammation and Immunopathogenesis of Tuberculosis Progression 31

An important question is whether the propensity to develop extensive neutrophilic

inflammation is a primary cause of host susceptibility to the infection. In some studies,
granulocytes from susceptible mice were shown to have intrinsically high capacity for
migration in response to inflammatory stimuli (Keller et al., 2006). However, neutrophilic
infiltration is a characteristic future of severe TB in hosts of different genetic backgrounds,
e.g., in DBA/2, C3H, I/St, 129Sv mice. It is unlikely that initial mechanisms of TB
susceptibility operating in these mice are identical. Rather, at early stages of infection the
disease is driven via different pathways. Such pathways may include defects in host
ability to restrict Mtb growth, intrinsic hyperreactivity of host macrophages to Mtb
derived ligands resulting in overproduction of neutrophil-activating factors, or high
reactivity of neutrophils to inflammatory stimuli. Ultimately, different pathways converge
to induce uncontrolled inflammation, characterized by high local production of
proinflammatory factors and extensive neutrophilic infiltration. These inflammatory
reactions become a hallmark and an important pathogenic mechanism of TB progression.
It would be interesting to know whether “inflammatory” neutrophils (i.e., neutrophils
residing in highly inflammatory conditions) retain their antibacterial activity and can, at
least in part, mediate Mtb control, or whether at this stage of disease they exhibit only
inflammatory functions.

5.2.3 Neutrophil depletion experiments

To directly address a role for neutrophils in anti-TB defense, several groups examined how
neutralization of granulocytes affected Mtb infection in mice.
Pedrosa and colleagues (Pedrosa et al., 2000) found that depletion of neutrophils from TB-
resistant BALB/c mice during the first week of Mtb infection worsened disease and
increased bacillary growth. The effect was due to a decreased production of IFN- and NO,
i.e. was mediated indirectly. Depletion of neutrophils at late stages of the infection did not
have a significant effect on the growth of Mtb in the lungs. Appelberg and coauthors
(Appelberg et al., 1995) performed studies in B6 and beige mice. Beige mice bear mutation
that affects function of leukocytes, including granulocytes, and renders mice susceptible to
M. avium. Transfusion of beige mice with B6 granulocytes at the early stage of infection
increased host resistance. In contrast, depletion of neutrophils from B6 mice increased host
susceptibility. Seiler and coauthors (Seiler et al., 2003) reported that early depletion of
granulocytes from B6 mice did not affect host survival or Mtb burden, but impaired
granuloma formation.
In the study by Ehlers’ group (Keller et al., 2006), depletion of granulocytes from TB
resistant B6 or BALB/c mice did not affect the course of Mtb infection. In contrast, in TB-
susceptible DBA/2 mice depletion of granulocytes had beneficial effect and prolonged mice
survival. In CARD9-/- mice, depletion of neutrophils on days 8-14 post-challenge
significantly prolonged mice survival. The effect was due to a reduced inflammation, and
was not associated with changes in bacterial burdens (Dorhoi et al., 2010).
The results of these studies are usually interpreted as contradictory. In fact, they are
compatible and can be explained by (i) the differential role for neutrophils at early and late
stages of Mtb infection; (ii) different strength of neutrophilic inflammation in genetically
different hosts. We suppose that at the early stage of the infection, when neutrophils are not

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32 Understanding Tuberculosis – Analyzing the Origin of Mycobacterium Tuberculosis Pathogenicity

numerous and neutrophil-activating proinflammatory cytokines are not abundant,

neutrophils contribute to Mtb control. At the late stage of the disease, the action of
neutrophils depends on the strength of local inflammation: if neutrophils accumulate in
high numbers and are in highly inflammatory milieu (conditions usually observed in TB-
susceptible mice), they become deleterious. Thus, depletion of neutrophils reduced Mtb
control and worsened disease in resistant mice, but dampened inflammation and
ameliorated disease course in susceptible mice.

5.2.4 Not all Gr-1/Ly-6G-positive cells accumulating in the lungs at the advanced
stage of Mtb infection are neutrophils
To address a role for granulocytes in TB progression, we have recently used our F2 model of
Mtb infection (Lyadova et al., 2010). In this model, (A/SnxI/St)F2 mice challenged with Mtb
display different rates of TB progression. We examined the accumulation of cells expressing
Gr-1 marker (marker expressed by granulocytes and to a less extent – by monocytes) and
Ly-6G molecules (molecules thought to be expressed exclusively by granulocytes) in the
lungs of F2 mice at advanced stage of disease (day 24 post-infection). We found that the
population of Gr-1-positive cells infiltrating Mtb-infected lungs, was not homogeneous, and
consisted of two different subsets, Gr-1hi and Gr-1dim. Similarly, Ly-6G-positive cells
contained Ly-6Ghi and Ly-6Glow subsets. In mice with slowly progressing TB all Gr-1/Ly-
6G-positive cells were Gr-1hi/Ly-6Ghi. In contrast, in mice with severe infection a vast
majority of Gr-1/Ly-6G-positive cells were Gr-1dim/Ly-6Gdim, whereas Gr-1hi/Ly-6Ghi cells
were almost undetectable. Further analysis showed that Gr-1hi/Ly-6Ghi cells were
granulocytes: they expressed F4-80negCD11bhi phenotype and had segmented nuclei. Gr-
1dim/Ly-6Gdim cells exhibited characteristics of immature myeloid cells: they had F4-
80lowCD11bhi phenotype that could be attributed nor to mature granulocytes nor to
monocytes. Analysis of nuclear morphology showed that these cells had un-segmented or
low-segmented nuclei. At advanced stage of Mtb infection, Ly-6Gdim cells appeared and
accumulated not only in the lungs, but also in the bone marrow (Tsiganov E.N., Lyadova
I.V., manuscript in preparation), suggesting that hematopoiesis was altered in mice with
progressing TB and that the accumulation of Gr-1dim/Ly-6Gdim cells in the lungs was a result
of this alteration.
In connection with these data, two points should be discussed.
First, Gr-1 and even Ly-6G expressing cells accumulating in the lungs of Mtb-infected mice
do not necessarily represent mature neutrophils. Experimental studies in which neutrophils
were identified based on their Gr-1/Ly-6G-positivity should be revised to take into account
the level of Gr-1/Ly-6G expression. Similarly, several studies identified neutrophils based
on the expression of myeloperoxidase. This enzyme is, indeed, synthesized be granulocytes,
but also - by their myeloid precursors.
Second, our data suggest that severe TB is accompanied by hematopoietic shifts that result
in a progressive accumulation of immature myeloid cells and gradual disappearance of
mature neutrophils from Mtb-infected lungs. It will be interesting to examine, whether the
substitution of neutrophils by immature cells may underlie inability of “neutrophils” to
control Mtb infection at the advanced stages of TB disease.

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Inflammation and Immunopathogenesis of Tuberculosis Progression 33

6. Conclusion
Inflammation plays a dual role in host immune response to mycobacteria. On the one part, it
is prerequisite for successful pathogen elimination. On the other part, it mediates tissue
injury and disease progression. At the onset of the infection, inflammatory reactions are
largely protective; during active disease, the deleterious effect of inflammation prevails,
making inflammation a paramount pathogenic factor of TB progression.
Irrespectively on genetic factors and molecular pathways that have lead to severe TB (that
are different in genetically different hosts), pathogenetic mechanisms operating during
advanced stage of disease are common. They include overproduction of proinflammatory
factors and excessive infiltration of the lung tissue with neutrophils (or their precursors). A
positive feedback loop between these reactions exists (proinflammatory factors promote
neutrophilic inflammation; neutrophils produce proinflammatory factors; both induce tissue
injury, Mtb dissemination, and another round of inflammation) making the regulation of the
ongoing inflammation difficult. An additional and a new component of TB progression is
alteration of host hematopoiesis that results in the generation of immature myeloid cells,
their emigration and prominent accumulation in the periphery. The role for these cells in TB
progression is yet to be determined.
The fact that mechanisms mediating TB progression are common has an important practical
outcome: there is no need to search for exact cause that has driven severe disease in each
individual; it might be possible to slow down disease progression by interfering with any of
the pathways involved in hyperinflammatory response. With this respect, co-treatment of
host with anti-Mtb and anti-inflammatory drugs opens new perspectives for efficient TB
therapy (Koo et al., 2011).

7. Acknowledgement
This work was supported by the Central Tuberculosis Research Institute of the Russian
Academy of Medical Sciences, and by NIH grant AI078899 and Russian Federation of Basic
Research grant # 10-04-01128.

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 Understanding Tuberculosis - Analyzing the Origin of
Mycobacterium Tuberculosis Pathogenicity
Edited by Dr. Pere-Joan Cardona

ISBN 978-953-307-942-4
Hard cover, 560 pages
Publisher InTech
Published online 24, February, 2012
Published in print edition February, 2012

Mycobacterium tuberculosis in an attempt to understand the extent to which the bacilli has adapted itself to the
host and to its final target. On the other hand, there is a section in which other specialists discuss how to
manipulate this immune response to obtain innovative prophylactic and therapeutic approaches to truncate the
intimal co-evolution between Mycobacterium tuberculosis and the Homo sapiens.

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