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Review Article
Immunology of Tuberculosis
Competing interests: The authors have declared that no competing interests exist.
Abstract. MTB ranks as the first worldwide pathogen latently infecting one third of the population
and the second leading cause of death from a single infectious agent, after the human
immunodeficiency virus (HIV). The development of vigorous and apparently appropriate immune
response upon infection with M. tuberculosis in humans and experimental animals conflict with
failure to eradicate the pathogen itself and with its ability to undergo clinical latency from which it
may exit. From a clinical standpoint, our views on MTB infection may take advantage from
updating the overall perspective, that has quite changed over the last decade, following remarkable
advances in our understanding of the manipulation of the immune system by M. tuberculosis and of
the role of innate components of the immune response, including macrophages, neutrophils,
dendritic cells and NK cells in the initial spread of MTB and its exit from latency. Scope of this
review is to highlight the major mechanisms of MTB escape from immune control and to provide a
supplementary translational perspective for the interpretation of innate immune mechanisms with
particular impact on clinical aspects.
Introduction. Mycobacterium tuberculosis (MTB) about one third of the world population having been in
may be regarded as the most successful intracellular contact and latently infected.1,2
bacterium worldwide, in view of its world prevalence Since its first characterization by Robert Koch at the
and distribution. MTB ranks as the second leading end of the 19th century,3 intense efforts have led to the
cause of death from a single infectious agent, after the characterization of the manifold interactions of M.
human immunodeficiency virus (HIV). Indeed, about tuberculosis with the immune system, to a renewed
8.7 million incident cases of pulmonary tuberculosis study of its metabolism for the identification of new
(TB) (range, 8.3 million to 9 million), equivalent to specific pathways subject to inhibition by new drugs, to
125 cases per 100,000 population, were registered the discovery of the mechanisms it uses to divert host
globally in 2011.1 Despite availability of defences and to the understanding of the broad
antituberculous drugs for the last 50 years Mth is spectrum of soluble factors and cells involved in its
responsible for 1.5 million deaths every year with control.
disease. Also in this case TST and IGRA do not help of smoldering infection, prophylaxis of true latency
discriminate different clinical courses. and avoiding unnecessary toxicity for eradicated
The ability to identify those individuals with latent infection.
TB who are at risk of reactivation would help target
preventative therapy and devise individualized target Timing of Immune Responses and Granuloma
treatment thereby increasing adherence and minimizing Formation. Following the establishment of M.
toxicity and costs. Using transcriptional profiling of tuberculosis infection in the airways and lung
leukocytes in whole peripheral blood by microarray parenchyma, the bacilli are believed to be
analysis, a characteristic neutrophil-driven IFN- phagocytosed by the alveolar macrophages15 and are
inducible 393 transcript-signature has been identified taken up by neutrophils16 and dendritic cells (DCs).17
in patients with active TB.13 This transcript signature Over time, cells progressively assemble in a compact,
disappears by 2 months of effective treatment and organized aggregate of mature macrophages
correlates with the extent of radiographic involvement. surrounded by fibroblasts and interspersed with
Interestingly, 10-20% of patients with TB latency have neutrophils, DCs, Natural Killer cells, B cells, CD4+
a transcript signature similar to those with active and CD8+ T cells. This structure is a granuloma and
disease. Although not proven yet, these patients might has been historically and until recently considered to
represent the minority of latent TB who will eventually represent a concentrated effort of the immune system
progress to active TB years later. Leukocyte or purified to sequester, wall off and eradicate M.tuberculosis.18,19
cell population transcriptional analysis - also in other Recent evidences have however subverted the classic
areas of chronic infections including HCV14 - is likely view that the granuloma is a host-protective structure.
to become a useful future tool to identify the subset of Indeed, different stages of the immune response to M.
patients with true latency who will develop post- tuberculosis can be recognized, and granulomas are
primary reactivation and for whom chemoprophylaxis - dynamic structures that are initially exploited by the
or rather treatment - may be mandatory. The precise bacterium to subvert the immune response, replicate
labelling of patients with different types of latency and spread at other locations.
using molecular or immunological tools represents one Innate immune phase-granuloma dynamics. Upon
of the main future challenges to individualize treatment MTB entry in the airways innate immune responses
Mediterr J Hematol Infect Dis 2014; 6: Open Journal System
predominate. Early granulomas are composed of been shown to involve induction of host matrix-
inflammatory macrophages, neutrophils and DCs that metalloprotase-9 (MMP-9) production by macrophages
progressively accumulate upon recruitment. All the and epithelial cells upon interaction with RD-1 locus-
cells of the early granulomas engulf the mycobacteria encoded, secreted ESAT-6.25,35 In line with this view,
and become infected. Pathogenic mycobacteria such as MMP-9 knockout mice have decreased granuloma
M.tubercuolosis and M.marinum in the zebrafish model formation and improved control of infection and has
have evolved multiple mechanisms to manipulate this been found to be enriched in tissues and pleural fluid in
cellular niche to their own advantage. Trafficking and human pulmonary TB.36
maturation of phagosomes in which pathogenic Death matters: Apoptosis vs. Necrosis. During early
mycobacteria reside is manipulated to prevent phases, mycobacterial load is rapidly rising through
lysosomal killing and degradation.20 Surprisingly, in granuloma formation with influx and infection of
spite of overwhelming infection, macrophages and DCs neutrophils and macrophages and cell death. While
in the early granuloma are inefficient in presenting M. necrosis, with cell lysis, propagates locally viable
tuberculosis antigens in the early granuloma to CD4+ mycobacteria and increases pathogen load,
T-cells.21 Efficient MTB Antigen (Ag)-presentation programmed cell-death or apoptosis maintains intact
only takes place later in the lymphnode.22 cellular membranes favoring cellular
Mycobacteria, as exemplified by the zebrafish- compartmentalization and mycobacterial
M.marinum model, exploit granuloma formation for containment.37,38 The type of cell death that is induced
their proliferation and dissemination in the infected depends on the regulation of the lipid mediator
host. Dynamic imaging studies reveal that macrophage eicosanoids prostaglandin E2 (PGE2, proapoptotic) and
move rapidly within granulomas, at speeds comparable lipoxin A4 (LXA4, pronecrotic).39 Differences in
to lymphocytes in a chemokine gradient.23 Movement eicosanoid pathway activity and regulation may
is dictated by the RD1 virulence locus that is contribute to inter individual differences in cross-
responsible for M. tuberculosis ESX-1 secretion system presentation of M. tuberculosis by Dendritic Cells
(which is lost in attenuated Bacillus Calmette- (DC), thus affecting also adaptive immune differences
Guerin),24,25 and ceases when macrophages contact and the clinical evolution from infection to primary
dying infected cells, thereby increasing the number of disease or to true latency.40 Neutrophils support M.
infected cells. Also the necrotic core of granuloma, tuberculosis replication and spread16,41 and may have
which was regarded as being not involved in immune dual roles in the early defense against the pathogen.
interactions, is crossed by infected and non-infected Activation of antigen-specific CD4+ T cells is
macrophages.21,26 Finally, tertiary lymphoid structures facilitated by neutrophils,42 however inhibition of
are found in granulomas in the lungs of mice.27 Here, neutrophil apoptosis by MTB determines their delayed
macrophage and T-cell movement resemble those of T activation.43
and B cell trafficking in secondary lymphoid Therefore early - and sometimes late - granuloma
organs,21,28 and chemokines are produced (CCL19, formation does not “wall off” mycobacteria. The view
CCL21), which are characteristic chemoattractants for of a mechanical containment in granulomas following
CCR7-bearing lymphocytes homing to lymphoid TNF induction is being replaced with a new
structures.29 Thus, despite macrophage, T-cell and DC perspective indicating that granuloma formation is
entry into the granuloma in the early phase, these cells induced by pathogenic mycobacteria through
do not leave, and at the same time cannnot proceed to mechanism(s) including ESAT-6-induced25 MMP-9
antigen presentation neither locally nor in lymphnodes. production.35 Thus early granulomas favor increased
TNF- vs. MMP-9 in granuloma formation. During macrophage accumulation, mycobacterial replication,
early granuloma formation, TNF has been historically and systemic MTB spread. Even adoptive transfer of
considered instrumental to granuloma formation and to Ag-specific CD4+ T cells shows that in this phase of
increase the ability of macrophage control of the infection Mycobacteria are secluded in a protected
intracellular mycobacteria.30 This view is however niche within the granuloma44 and that intervention
challenged by the observation that in non-human should target innate immune events (including anti-
primates TNFblockade results in disseminated MMP-945 or pro-apoptotic treatments), that
disease with normal granuloma structure,31 and by predominate during the early phase but that persist also
similar findings in patients treated with anti-TNF in later equilibrium phases of the infection.
treatment.32,33 Indeed in the zebrafish model, Overall, therefore, the early stages of
TNFincreases pathogenic M.marinum death and its antimycobacterial immune responses are dominated by
absence is associated with accelerated and increases innate immune responses that have little immediate
granuloma formation.34 Rather than TNF, the antimycobacterial effect and rather favor its spread and
mechanism(s) underlying granuloma formation have replication. The subsequent adaptive phase however
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