MINI REVIEW

published: 27 August 2019

doi: 10.3389/fped.2019.00350

Immune Response to Mycobacterium

tuberculosis: A Narrative Review
Maurizio de Martino, Lorenzo Lodi, Luisa Galli and Elena Chiappini*

Department of Health Sciences, University of Florence, Florence, Italy

The encounter between Mycobacterium tuberculosis (Mtb) and the host leads to
a complex and multifaceted immune response possibly resulting in latent infection,
tubercular disease or to the complete clearance of the pathogen. Macrophages and
CD4+ T lymphocytes, together with granuloma formation, are traditionally considered
the pillars of immune defense against Mtb and their role stands out clearly. However,
there is no component of the immune system that does not take part in the response to
this pathogen. On the other side, Mtb displays a complex artillery of immune-escaping
mechanisms capable of responding in an equally varied manner. In addition, the role of
each cellular line has become discussed and uncertain further than ever before. Each
defense mechanism is based on a subtle balance that, if altered, can lean to one side
to favor Mtb proliferation, resulting in disease progression and on the other to the host
tissue damage by the immune system itself. Through a brief and complete overview of
the role of each cell type involved in the Mtb response, we aimed to highlight the main
Edited by:
literature reviews and the most relevant studies in order to facilitate the approach to such
Gian Luigi Marseglia,
Policlinico San Matteo Fondazione a complex and changeable topic. In conclusion, this narrative mini-review summarizes
(IRCCS), Italy the various immunologic mechanisms which modulate the individual ability to fight Mtb
Reviewed by: infection taking in account the major host and pathogen determinants in the susceptibility
Silvia Garazzino,
University Hospital of the City of
to tuberculosis.
Health and Science of Turin, Italy Keywords: Mycobacterium tuberculosis, tuberculosis, children, immune response, immunity, macrophage,
Sara Manti, adaptive immunity, granuloma
University of Catania, Italy

*Correspondence:
Elena Chiappini INTRODUCTION
elena.chiappini@unifi.it
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) infection, was among the top
Specialty section: 10 causes of death worldwide in 2017 with about 1.5 million registered deceases (1). Mtb was
This article was submitted to responsible for approximately 10.0 million incident cases of TB disease with 10% of these occurring
Pediatric Immunology, among children (1). One to five bacilli may suffice to transmit the infection by air (2). When
a section of the journal
inhaled, Mtb encounters a first line of defense consisting of airway epithelial cells (AECs) and
Frontiers in Pediatrics
“professional” phagocytes (neutrophils, monocytes and dendritic cells) (3, 4). If this first line
Received: 07 April 2019 succeeds in eliminating the Mtb rapidly, the infection aborts (5). Otherwise, phagocytes are infected
Accepted: 06 August 2019
and the Mtb reproduces inside the cells, initially causing few, if any, clinical manifestations (5).
Published: 27 August 2019
The establishment of the infection, the development of active TB (ATB) rather than latent TB
Citation:
infection (LTBI) and the eventual evolution of LTBI to ATB depends on the complex relation
de Martino M, Lodi L, Galli L and
Chiappini E (2019) Immune Response
between bacterial and host factors.
to Mycobacterium tuberculosis: A The aim of this narrative minireview is to give a hint of the complexity of the above-
Narrative Review. mentioned determinants and to briefly summarize the major defense mechanisms of innate and
Front. Pediatr. 7:350. adaptive immunity against Mtb outlining the role of the different cell populations and their
doi: 10.3389/fped.2019.00350 complex interplay.

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de Martino et al. Immune Response to Tuberculosis

METHODS 21 different genetic disorders related to interferon (IFN)-γ

immunity and responsible for MSMD have been identified (12).
In order to perform a narrative review of the available literature, Furthermore, transcriptomic studies have described a TB
we searched the PubMed database from April 2014 through April signature of neutrophil-driven IFN-inducible genes in ATB,
2019, using the following key words: “immune,” “immunity,” including IFN-γ but also type I IFNs, reflecting disease
“tuberculosis,” “Mycobacterium tuberculosis.” Subsequently, for extension and response to treatment and highlighting the
each topic, specific key words (“susceptibility,” “resistance,” previously under-appreciated role of IFNαβ signaling in TB
“virulence,” “airway epithelial cell,” “macrophage,” “neutrophil,” pathogenesis (4, 13, 14).
“dendritic cell,” “natural killer,” “mast cell,” “complement,” Beyond host factors, bacterial virulence constitutes the other
“CD4,” “CD8,” “humoral,” “antibody,” and “granuloma”) were major player when evaluating the risk of TB infection. Virulence
associated with the word “tuberculosis” in order to access is not merely limited to bacterial strain or burden in respiratory
proper specific literature. The search and the selection process secretion but takes into account the differential Mtb gene
were not systematic. Articles were limited to English language expression in the different phases of infection. Mtb lacks
and full text availability, and they were excluded if they were classical virulence factors such as toxins and its immune-
redundant or not pertinent. References of all relevant articles escaping ability depends on the modulation of lipid metabolism,
were also evaluated, and studies published previously than metal-transporter proteins, protease, proteins inhibiting the
2014 were cited if considered relevant. Results were critically antimicrobial effectors of macrophages (M8s) and many
summarized in the following paragraphs: (1) “host and bacterial others (15).
determinants in human tuberculosis,” (2) “innate immune The study of immune response in resilient and susceptible
response against Mycobacterium tuberculosis,” and (3) “adaptive individuals, together with bacterial factors, has offered
immune response against Mycobacterium tuberculosis.” fundamental information for the understanding of TB
immunology suggesting potential improvements in diagnostic
and therapeutic approaches (Table 1).

HOST AND BACTERIAL DETERMINANTS INNATE IMMUNE RESPONSE AGAINST

IN HUMAN TUBERCULOSIS Mycobacterium tuberculosis
Several epidemiological models of family members who have The significance of innate immunity in the defense against Mtb
long shared the bedroom with subjects with ATB, sailors who stands out clearly as we consider the MSMD where a disruption
lived in confined spaces with subjects with open TB and extensive of the innate axis leads to dramatic, life-threatening clinical
case studies of South African miners and Norwegian or American presentation of TB (12).
students, have clearly demonstrated that 5 to 20% of those M8, neutrophils, dendritic cells (DCs), natural killer cells
who meet subjects with ATB do not become infected (resilient (NK), mast cells and complement are the major players of innate
individuals or resisters), or become infected only transiently immunity. On the other hand, AECs also contribute to the
and then get rid of the infection (early sterilization or early defense attempt against Mtb and could be considered as innate
clearance) (6). An individual can be defined resilient if after close immunity components (Table 1).
and prolonged contact with the index case shows simultaneous
negativity of the skin reactivity test and of the IFN-γ release assay Airway Epithelial Cells
(IGRA) which persists for at least 1 year. Studies carried out on AECs are the first cells to come in contact with Mtb. Beyond
siblings have shown that Mtb resilience is more frequent between their major role as physical barriers, they display several
two siblings than between two unrelated subjects, suggesting immunological functions albeit being traditionally considered as
the role of genetics in the development of Mtb resilience (7). “non-professional” immune cells. Through pattern recognition
Genome wide linkage analysis detected several loci like 2q21- receptors (PRRs), AECs can perceive the presence of Mtb and
2q24, 5p13-5q22, and the TST1 on 11p14 associated with the consequently modulate the composition of the airways surface
resilient phenotype (8, 9). liquid improving its antimicrobial capacity (16). Moreover,
On the other side, the study of TB susceptibility, has shed PRRs activation leads to the production of inflammatory
light onto various components of immunity to mycobacteria cytokines and to the activation of mucosal-associated invariant
in humans. Different genetic polymorphisms which modulate T cells stimulating IFN-γ and tumor necrosis factor (TNF)-α
the host immune response in favor of TB infection and production (17).
disease progression have been identified in human leukocyte
antigens (HLA), toll like receptors (TLR), vitamin D receptors Macrophages
(VDR), cytokines with their receptors and many other M8s are the first line of defense, but only if the ratio of
functional immune components (10, 11). Moreover, mendelian forces lies clearly to their advantage and the intervention is
susceptibilities to mycobacterial disease (MSMD) have been immediate they can cancel the infection (5, 18). Otherwise, they
identified as clinical conditions with selective susceptibility favor its development because they become first a niche for
to poorly virulent mycobacteria in the absence of patent the slow replication of the Mtb and then the sanctuary for the
immunodeficiency (12). Since 1996, 11 genes which underlie persistence of the infection inside the phagosome during the

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de Martino et al. Immune Response to Tuberculosis

TABLE 1 | Key literature of the present review. latent infection phase. Mtb expresses an extremely wide variety of
virulence factors that counteract M8s efforts in suppressing the
Paragraph Topic Major references
pathogen. Among Mtb strategies we can include the inhibition
Host and bacterial Host Genetic - Harishankar et al. (10) of intracellular trafficking, the inhibition of autophagy, the
determinants in human polymorphism - Casanova and Abel (7) acquisition of cytosol access, the induction of host cell death and
tuberculosis - Cobat et al. (8) the neutralization of toxic components as reactive oxygen species
- Stein et al. (9)
and toxic metals (19).
- van Tong et al. (11)
MSMD - Rosain et al. (12)
Whilst IFN-γ is a key element in the containment of Mtb
Transcriptomic - Berry et al. (13) within the M8, it is now widely recognized that performing
studies - Blankley et al. (14) this function requires the presence of vitamin D (63). Thanks to
Bacterial - Forrellad et al. (15) vitamin D, the macrophage increases phagosome maturation and
Virulence factors the production of antimicrobial peptides through the maximal
Innate immune response AECs - Li et al. (16)
regulation of the hCAP-18 gene encoding for cathelicidin
against Mycobacterium - Harriff et al. (17)
tuberculosis
antimicrobial peptide which activates, in turn, the transcription
Macrophages - Queval et al. (18) of autophagy-related genes (20). The 6 kDa early secretory
- Lerner et al. (19) antigenic target (ESAT-6) protein family secretion (ESX) system
- Yuk et al. (20) is a sophisticated secretion system that Mtb uses to export
- Gröschel et al. (21)
proteins with immune-escaping activity. So that while the
- Bustamante et al. (22)
- Sia et al. (23)
IFN-γ axis is struggling against the ESX-system to enhance
- Sun et al. (24) phagolysosmal activity, vitamin D deficiency abets the Mtb
- Neyrolles et al. (25) replication (21).
- Botella et al. (26) Nitric oxide (NO) within macrophages plays a less important
Neutrophils - Kroon et al. (27)
role in humans than that one observed in animal models (19).
- Lowe et al. (28)
- Tan et al. (29)
Although, in humans too, reactive oxygen species (ROS) play
- Zhang et al. (30) a well-documented role in the immune response to Mtb as
Dendritic cells - Mihret (31) highlighted by the discovery of TB susceptibility in patients
- Khan et al. (32) displaying mutations in a catalytic subunit of NADPH-oxidase
- Wu et al. (33) 2 involved in ROS production on phagolysosomal membrane
- Balboa et al. (34)
- Georgieva et al. (35)
(22, 23). Moreover, it is demonstrated that Mtb affects NADPH-
- Velasquez et al. (36) oxidase activity through nucleoside diphosphate kinase (Npk)
- Ehlers (37) interaction with small GTPases involved in NADPH-oxidase
NK cells - Esin and Batoni (38) assembly and functioning (24).
- Arora et al. (39) The fight unfolds inside the phagosome of the M8 between
- Zhang et al. (40)
the cell and the Mtb with metals as a battlefield of sorts (25). The
Mast Cells - Garcia-Rodriguez et al. (41)
- Carlos et al. (42)
M8 delivers an overload of copper and zinc, which are toxic to
Complement - Lubbers et al. (43)
Mtb at high concentrations. Mtb deploys a series of protection
- Cai et al. (44) mechanisms that include controlling the capture of such metals,
Adaptive immune response CD4+ T - Cooper (45) oxidation, and an increase in efflux (25). The up-regulation of
against Mycobacterium lymphocytes - Sia et al. (46) ctpC gene encoding for the P-type ATPase which regulates the
tuberculosis - Domingo-Gonzalez et al. (47) intra-bacterial levels of Zinc is a clear example of how Mtb
- Parkash et al. (48)
- Sallin et al. (49)
manages to prevent heavy metal poisoning (26). As a counter-
CD8+ T - Lin and Flynn (50)
move, the M8 then attempts to block the arrival of nutrients to
lymphocytes - Canaday et al. (51) the Mtb such as iron and manganese (25).
- Oddo et al. (52)
Humoral - Kozakiewicz et al. (53) Neutrophils
immunity - Jacobs et al. (54) Neutrophil granulocytes are the most widely present cell
- Glatman-Freedman
and Casadevall (55)
population within BAL and sputum in patients with active TB
- Lu et al. (56) (27). There is evidence of their role as defense mechanisms
Granuloma - Ramakrishnan (57) against Mtb. In particular, there is a clear inverse correlation
- Russell (58) between the number of neutrophilic granulocytes in the
- Reece and Kaufmann (59) peripheral blood and the hazard of developing TB after
- Refai et al. (60)
contact with an infectious subject. Antimicrobial peptides and
- Martinot (61)
- Russell et al. (62) apoptotic neutrophils are phagocytized by M8 and carry out
an effective activity against Mtb inside these cells (28). This is
The major references are grouped basing on the different topics addressed in each
possible thanks to the fusion, within the M8, of neutrophil
paragraph. The most relevant and comprehensive review or study for each topic is
highlighted in bold. MSMD, Mendelian Susceptibility to Mycobacterial Disease; AEC, granules with phagosomes containing Mtb (29). Furthermore,
Airway Epithelial Cell; NK, Natural Killer cells. ETosis, extracellular traps (ET) formation, is a type of cell

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de Martino et al. Immune Response to Tuberculosis

death that differently from apoptosis is characterized by DNA the percentage representation of NK cell is augmented in the
release, consequent M8 activation and the formation of a peripheral blood of patients with ATB (65). There is a direct
DNA scaffold that incorporates pathogens and exposes them relationship between NK cell representation, clinical condition
to antimicrobial molecules (64). The formation of neutrophils and response to therapy (38, 65). Nonetheless, it has not yet been
ETs, thus constitutes an improved killing strategy and a synergic ascertained exactly what the cause and the consequence is (38).
alliance between phagocytes. Several components of the Mbt wall are recognized and bound
Moreover, as with many immune mechanisms, neutrophils by the NKp44 receptor of NK cells (39). In addition, Mtb-
do not only play a positive role, but can eventually constitute infected NKs lyse and stimulate M8s to produce IFN-γ and IL-
a negative element, causing tissue damage through production 22, which increase phagolysosomal fusion thus inhibiting Mtb
and subsequent release of their antimicrobial products (27). To replication and stimulate the production of additional IFN-γ by
this phenomenon, it must be added the potentially negative CD8+ lymphocytes. This effect is mediated by the IL-15 and IL-
interaction with lymphocytes. Neutrophils express on their cell 18 production by an infected M8. As a further infection control
membrane the ligand 1 of cell death (programmed death ligand mechanism DCs favor the development of T lymphocytes with
1 or PD-L1), which interacts with the lymphocyte receptor γδ receptor through TNF-α and IL-12 production (40).
for programmed death (programmed death receptor or PD-1),
and determines, in the course of chronic infections, the loss of
function and finally the death of lymphocytes (30).
Mast Cells
The role of mast cells in Mtb infection is not well-known
Neutrophils with expressed PD-L1 are present in high
in humans (41). In mice, mast cells capture Mtb via CD48
proportion in patients with ATB.
and internalize it. This process ensues the development of a
cytokine cascade, some of them with protective roles, including
Dendritic Cells IL-12, IL-13, IL-6, CXLL2, CCL7, CCL2, TNF-α, and consequent
DCs are functionally located in the middle between innate
neutrophils recall in the site of infection (41). Histamine’s
and adaptive immunity. These cells play a fundamental role in
role is ambivalent in terms of Mtb clearance as on one hand
the immune defense system due to antigen presentation, co-
it augments lung neutrophilia but on the other it seems
stimulating activity and the large cytokine production capacity
to impair the efficient production of a T helper 1 (Th1)
with activity on the lymphocytes cluster of differentiation (CD) 4
response (42). The presence of mast cell ETs containing Mtb
(32). DCs role in TB immunity is controversial. Present evidence
in humans has not been proved. However, mast cells enclose
is not sufficient to establish whether these cells strengthen
a large number of mediators known to take part in the
cellular immunity or if their manipulation by the Mtb can be
process (41).
used as a tool to diminish specific T-cell response (31). DCs
soon become a niche for the Mtb. CD209, also called DC-
specific intercellular adhesion molecule 3-grabbing non-integrin Complement Proteins
receptor (DC-SIGN), represents the gateway of Mtb into the The role of the complement cascade on the progression of the
DC (31). CD209 is, under normal conditions, a receptor for infection and Mtb disease is almost unknown (44). It is likely
CD54, the intercellular adhesion molecule 1 (ICAM1) present that the C5 and C7 components play a defensive role. However, it
on endothelial cells where it favors DCs migration. CD209 is has been observed that a high expression of C1q correlates with
coupled with the lipoarabinomannan mannose (ManLAM) of a worse clinical condition, so as to be a marker between latent
the Mtb that penetrates into the cell. This penetration leads to TB and active TB but still with unclear significance in terms of
a disruption of DCs activity by prompting the production of pathogenesis (43, 44).
interleukin (IL)-10 and reducing the production of IL-12, thus
causing a suppression of T lymphocytes activity (33, 34). The
manipulation of the maturation of the DCs probably represents ADAPTIVE IMMUNE RESPONSE AGAINST
one of the winning strategies of Mbt that, by restraining the Mycobacterium tuberculosis
activity of DCs and, consequently, of T lymphocytes, allows
the Mtb, whose speed of growth is relatively slow, to efficiently The immune response of T lymphocytes begins at the moment
establish a bridgehead in the airways (35). Based on the above that Mtb spreads inside the lymph nodes but its arousal lays
mentioned mechanism DC-SIGN has recently been proposed in the early activation of the innate immune system. Inside the
as a potential target for a vaccine purpose eventually able to lymph nodes, T lymphocytes undergo a process of activation
enhance immunity against Mtb (36). On the other side, DC- and expansion of the specific populations for the Mtb antigens.
SIGN may prevent tissue pathology by maintaining a balanced However, at this point, the largest part is done and the
inflammatory state and thus promoting host protection (37). infection is now established. Cellular immune response can be
evidenced 2–6 weeks after Mtb infection by the development
Natural Killer Cells of a delayed hypersensitivity response to intradermal injected
It is certain that NK cells enter the immunological circuit tuberculin (DHT) or purified protein derivative. It is important
of Mtb infection both in their CD56 diminished phenotype to underline that protective response to TB does not relate
(preferential cytotoxic activity) and in CD56 bright phenotype with DHT positivity and disease can occur in those who mount
(preferential cytokines secreting activity) (38). In several studies adequate DHT response (66) (Table 1).

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de Martino et al. Immune Response to Tuberculosis

Lymphocytes T CD4+ molecules of the major histocompatibility complex (MHC), and

The in vivo human model of HIV-infected CD4+ -depleted produce IL-2, IFN-γ and TNF-α, which have a well-known role
patients is the most striking evidence of the pivotal role of in controlling Mtb. Furthermore, T lymphocytes CD8+ exert a
these cells in TB immunity. The process of maturation of the cytolytic action against Mtb by means of perforin and granulysin,
phagosome of M8 is facilitated and increased by IFN-γ, the albeit not by Fas (CD95) -Fas ligand (50, 51) interaction. This
production of which is mostly dependent on the T lymphocytes direct cell-to-cell contact determines the apoptosis of the Mtb-
CD4+ with a minor support of lymphocytes CD8+ and T infected cell (especially M8) depriving Mtb from its natural
lymphocytes with γδ receptor (45). Animal models of knockout growth environment and at the same time reducing its viability
mice for IFN-γ clearly show that these animals suffer a very by unknown mechanism (52). On the other hand, lymphocytes
severe course of Mtb infection exactly as it happens in humans CD8+ produce IL-10 and TGF-β which instead favor the
with MSMD. It is well known that patients with mutations in development of the Mtb infection.
genes encoding IFN-γ or its receptors undergo disseminated
infection by BCG or other non-tuberculous components of the Humoral Adaptive Immunity
mycobacteria genus (12). IFN-γ production is modest in patients The role of humoral adaptive immunity in TB is extremely
with active TB, but recovers with antitubercular treatment uncertain (53, 54). Complement-mediated opsonization does not
without reaching levels similar to those of uninfected subjects. alter Mtb survival. High levels of antibody titers correlate with
The optimal production of IFN-γ, as well as that of IL-17 (67), more serious conditions of infection and disease, and passive
is linked to an equally optimal cooperation between DCs and immunization with antibodies does not confer protection (55).
T lymphocytes CD4+ . In its defensive strategy, Mtb markedly Patients with a defective antibody-production mechanism and/or
interferes in the CD40-CD40 ligand binding, that is essential for B lymphocyte defect are not particularly at risk of TB infection.
the cooperation between both cell lines (46). The importance of The role of the crystallizable fragment or Fc in the constant
IFN-γ production by CD4+ cells is particularly relevant at the portion of the immunoglobulin, which binds and activates
early stages of Mtb infection as it is demonstrated that adequate various cell lines present in the granuloma (NK cells, monocytes,
IFN-γ levels can be obtained with 3 weeks of delay even in CD4- neutrophils) the low-affinity FcγRIIIb receptor and the high
disrupted mice thanks to the compensation offered by other cell affinity FcγRIIa receptor have shown different functional profiles
types like CD8+ (68). and glycosylation patterns in subjects with ATB rather than
Moreover, IFN-γ cannot control infection alone and it LTBI (54, 56).
requires the association of other molecules such as IL-6, IL-1 and The loss of FcγRIIIb activity and the increase of FcγRIIa-
the TNF-α. The chemokines CCL5, CCL9, CXCL10, and CCL2 mediated inhibitory function (which correlates with a high IL10
attract immunity cells at the site of infection and their production production) are associated with a worse clinical profile and can
is stimulated by TNF-α and boosts the production of NO by distinguish ATB from LTBI and suggests a role of antibodies
M8 (47). in the augmented phagolysosomal maturation and Mtb killing
Several studies, both in adult and pediatric patients, have observed in LTBI patients (56).
demonstrated CD4+ percentage and absolute value reduction in
the peripheral blood of patients with ATB suggesting both an The Ancestral Defense: Granuloma
augmented pooling in the site of infection but also eventually Following the development of adaptive immunity, a complex
a primary role of TB in immune modifications related with the and well-coordinated mechanism is established between both
severity of infection (65). immunity mechanisms, i.e., innate and adaptive, which seal the
A portion of T lymphocytes are Foxp3+ and perform a control Mtb inside granulomas (5, 58, 59). This mechanism develops
function over the activity of other T lymphocytes in fact, they in at least 90% of the infected subjects and leads to LTBI.
are defined as T regulators (Treg). It is only on a hypothetical During latent TB, which would be better described as non-
level that we can imagine any positive role of this cell line on replicating-persistence phase (in fact, Mtb works perfectly albeit
the disease progression limiting tissue damage by other immune in a different way than during active TB), the subject is generally
cells; however, it has been ascertained that, by restraining the positive for the tuberculin skin test and for the IGRA (69).
response of the T lymphocytes, the Tregs favor the infection Latent TB becomes active when, for the most various reasons,
development and persistence (48). Similarly, T lymphocytes a condition of immunodepression develops. At this stage, the
CD4+ may deal more damage, or at least become irrelevant, subject may become capable of transmitting the infection because
rather than hinder the progress of the infection (49). the granuloma opens in the bronchial lumen and Mtb are
expelled when coughing. At the beginning of the infection, Mtb
Lymphocytes T CD8+ demands an environment with inflammatory traits to develop
For a long time, it was considered that, unlike T lymphocytes the granuloma; subsequently, however, its survival is linked to
CD4+ , T lymphocytes CD8+ had no role in controlling an environment lacking or with low inflammation. This switch
the infection and Mtb disease. This concept stemmed from is caused by ESAT-6 (60), a well-known Mtb virulence factor
the modest availability of human models with T lymphocyte involved in the ESX secretion system, to which it gives its
CD8+ defect, unlike the large human model of HIV infection. name. ESAT-6 causes the transformation of M8 from phenotype
An activity against Mtb is conceivable considering that T M1, which produces IL-6, IL-12 and TNF-α, into M8 with
lymphocytes CD8+ recognize Mtb antigens through class I phenotype M2, which is capable of stimulating production of

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de Martino et al. Immune Response to Tuberculosis

IL-10 (60, 61, 70). As currently known, IL-6 and TNF-α favor NADPH-oxidase activity (31). With various mechanisms, some
inflammation, whilst IL-10 curbs it. Accordingly, the formation of which also operate at the level of macrophage DNA, the Mbt
of the granuloma is triggered by the M8 and then develops prevents the activation of pathogen destruction systems, which
with multi-nucleated giant cells and M8 with abundant presence are implemented through autophagy. The Mtb DNA manages to
of intracytoplasmic lipids, which lend these cells their frothy prevent the activation of the AIM2 inflammasome thus hindering
appearance. Around these cells, there is a ring of T lymphocytes the synthesis of IL-1β and IL-18 (31). Under normal conditions,
although B lymphocytes, neutrophils and dendritic cells (CD) IFN-γ stimulates the expression of MHC class II molecules
also participate in the formation of granuloma (4). on the M8. But Mtb, thanks to the prolonged activation of
Inside the granuloma, cholesterol—and not glucose or TLR2, succeeds in suppressing this mechanism. Even in cells that
glycerol—is the only carbon source. This leads to a lack of carbon already express class II MHC molecules, Mtb manages to block
and nutrients, hypoxia and a high concentration of nitric oxide the presentation of antigens by the action on ESCRT (endosomal
(NO). The significance of cholesterol in the survival of Mtb inside sorting complexes required for transport) of its EsxG·EsxH
the granuloma is evidenced by the negative role that statins play protein (31). The “great manipulator” also interferes with the
against Mtb (61, 70). functions of DCs, neutrophils and all other components of the
The debate remains open on whether the granuloma is purely immune system.
protective for the host or if it promotes disease progression In conclusion, having to deal with a micro-organism of great
and tissue damage (4). This uncertainty depends on the evasive abilities, immune mechanisms have only one way to go:
extreme heterogeneity detected in granuloma morphology at the to focus on a very rapid response at the onset of the infection.
different stages of disease, on the role of inflammation, hypoxia Paraphrasing a famous aphorism by General Erwin Rommel
and differential Mtb gene expression and lipid metabolism about amphibious battles that is well-suited to TB, victory
manipulation inside the granulomas of ATB and LTBI patients or defeat against Mtb is decided in the first moments
(62). The most likely answer is that an homeostatic interaction of the infection (5). Exactly as it happened on the first
establishes and the granuloma becomes a well-suited shelter for day of the amphibious assault, the day that General Erwin
both Mtb long-term survival and host protection (57). Rommel defined as “the longest day.” When it comes to
implementing new prevention and therapeutic approaches, a
clear understanding of the interplay between the immune system
DISCUSSION
and Mtb at a molecular level is the only way to unravel this
Mycobacterium tuberculosis: The Great millenary skein.
Manipulator
The different cell lines of innate and adaptive immunity come AUTHOR CONTRIBUTIONS
into play at different times in the battle against Mtb in a clash
in which the genetic susceptibility of the host and the virulence MdM wrote the main body of this minireview. LL, LG, and EC
of the pathogen play decisive roles for the final outcome. The contributed with literature search and revisions.
success of Mtb over thousands of years against man arises
from its extraordinary ability to subvert the mechanisms that FUNDING
should eliminate it in the M8 from the infection onset. At the
onset of the infection, Mtb manages to perforate the phagosome This work received no fundings. The payment of fees for open
in the M8 through the ESX system and, therefore, to block access publication will be supported by the Dipartimento di
its maturation via Npk, which inhibits lysosomal traffic and Medicina Sperimentale e Clinica of the University of Florence.

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62. Russell DG, Cardona P-J, Kim M-J, Allain S, Altare F. Foamy macrophages article distributed under the terms of the Creative Commons Attribution License (CC
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63. Gou X, Pan L, Tang F, Gao H, Xiao D. The association between publication in this journal is cited, in accordance with accepted academic practice.
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(2018) 97:e12179. doi: 10.1097/MD.0000000000012179 terms.

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