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Phagocytosis of Mycobacterium tuberculosis: A Narrative of the Uptaking and Survival

Written By

Gabriela Echeverría-Valencia

Submitted: 08 January 2023 Reviewed: 18 January 2023 Published: 15 February 2023

DOI: 10.5772/intechopen.110067

Phagocytosis IntechOpen
Phagocytosis Main Key of Immune System Edited by Seyyed Shamsadin Athari

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Phagocytosis - Main Key of Immune System

Edited by Seyyed Shamsadin Athari and Entezar Mehrabi Nasab

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Abstract

Mycobacterium tuberculosis is the causal agent of human tuberculosis. The initial events of the establishment of the infection include the phagocytosis by several innate immune response cells. This chapter will discuss the immune cells involved, the phagocytic pattern recognition receptors (PPRs) that recognize and mediate bacteria phagocytosis (such as C-type lectin receptors, Toll-like receptors, complement receptors, and scavenger receptors), and the outcome of this initial interaction. Additionally, the bacterial strategies to evade the immune response—which includes the inhibition of the phagosome maturation and arresting of phagosome acidification, the mechanisms to survive to the reactive nitrogen species and reactive oxygen species, and finally, the resistance to the apoptosis and autophagy—will be reviewed. Finally, the host-pathogen interaction of M. tuberculosis with the phagocytic human cells during the primary events of the tuberculosis infection will also be reviewed.

Keywords

  • phagocytosis
  • tuberculosis
  • macrophages
  • receptors
  • phagosome

1. Introduction

Mycobacterium tuberculosis (MTB) is a human pathogen, which belongs to a group of nine species phylogenetically related, called M. tuberculosis complex [1]. MTB is the causative agent of tuberculosis: An infectious disease that causes mainly a pulmonary infection although, renal, meningeal, genital tuberculosis, and other anatomical sites have been affected. Is a human pathogen and both (human hosts and MTB) have co-evolved together for an extended period of time of approximately 70,000 years [2].

Before the COVID-19 pandemic, tuberculosis (TB) was the first cause of death from a single infectious agent. It is estimated that 25% of the global population is infected with the bacteria, but only 10% of them will develop the disease during their lifetime. TB continues to be a public health problem due to the increased number of co-infections in HIV patients and the augmented antimicrobial resistance by MTB [3].

The mycobacterial infection in humans originates by the inhalation of aerosols containing the bacteria on flügge droplets, which is dispersed by the sneeze or cough of infected individuals. Once in the alveolus, the microorganism interacts with the innate immune response cells; the receptors at the macrophage identify the bacteria through pathogen-associated molecular patterns called PAMPs, and the said PAMPs are composed of lipids, carbohydrates, and protein characteristic of the mycobacteria and other pathogens [4]. During this initial immune response against tuberculosis, various cell types interact with the bacteria, such as dendritic cells, NK cells, neutrophils, and macrophages [5, 6, 7].

The phagocyted MTB can survive inside the macrophages through specific strategies. Namely, evasion of the immune response by phagosome, arresting inhibition of phagosome acidification [8], resistance to nitrogen species and reactive oxygen species [9], and also apoptosis and autophagy evasion [10]. The previously mentioned survival mechanisms are live-defining determinants on which mycobacterial efficiency to invade, establish, and survive inside macrophages depends. The phagocytosis constitutes a fundamental event during host-pathogen interaction in TB because this initial interplay determines the outcome of the disease.

As described before, MTB evades the immune response inside the macrophages, it uses the cell as a niche to survive latently, and it even multiplies efficiently within the phagocytic cell during reduced immune containment. The host search for containment and isolation produces cytokines and chemokines, which induce the migration of cells, and thus, granuloma formation. At the beginning of granuloma formation, the immune cells that constitute the granuloma are monocytes, neutrophils, and macrophages; subsequently after, the development of the acquired immune response induces the migration of lymphocytes. At times, the presence of extracellular matrix components and fibroblasts has been found around the mycobacterial granuloma [11, 12].

In the next sections, the initial process of human tuberculosis infection by MTB will be reviewed, focusing on:

  1. The interaction with a variety of cells can phagocyte and exert the innate immune response against the bacteria.

  2. The earliest events of the immune response: recognition and phagocytosis.

  3. MTB’s strategies to evade the immune response successfully, and the importance of said strategies for its survival, latency, and persistence.

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2. The innate immune response against tuberculosis and the host-pathogen interaction with mycobacteria

The main entrance gate of MTB to the human body is the lung. There, air particles can be cleared by sneezing and coughing. Also, the presence of cilia and mucus contributes to the removal of particles allocated in deeper locations. In addition to that, the epithelia at the lung provide biochemical mechanisms to battle pathogens; among them the hydrolytic enzyme Lysozyme, and peptides (such as cathelicidins and defensins) contribute to the innate immune response through pathogen membrane destruction [13]. Microorganisms that cannot be cleared by these means will be phagocyted by alveolar macrophages (AM). During MTB infection, macrophages become a cellular niche of survival and bacterial multiplication. However, AM are not the only innate immune cells that interplay with MTB, neutrophils, dendritic cells, NK cells (natural killer) also interact with the pathogen.

Mycobacterial recognition by macrophages begins with the cell expression of a variety of phagocytic pattern recognition receptors (PPRs) that identify MTB through PAMPs. Cellular receptors of the C-type lectin receptors (CLRs) recognize microorganisms through carbohydrate patterns; among these receptors are mannose receptor (MR), Mincle, dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN), and Dectin-1. Also, complement receptors (CR) and immunoglobulin receptors assist in the recognition of opsonized mycobacteria. Likewise, receptors that contribute to mycobacterial interaction are Toll-like receptors (TLRs), Scavenger receptors (SRs), NOD-like receptors (NLRs), and CD14 [14, 15]. These PPRs (which intervened and were stimulated during the interaction with MTB) determine the outcome of the acquired immune response, survival, autophagy, and apoptosis [16].

2.1 Dendritic cells

Dendritic cells originate from bone marrow progenitor cells and migrate as immature cells to different anatomical locations in order to detect pathogens. Part of their function as presenting cells is being an important link between the innate and acquired immune response. After recognition and phagocytosis of antigens (Ag) or pathogens, they increase the expression of MHC I and II [17]. Then, dendritic cells migrate through lymphatic circulation to lymph nodes after antigen processing [18]. At this location, dendritic cells induce T-cell activation through antigen presentation to lymphocytes [19]; however, MTB limits the response of dendritic cells as part of the immune response evasion [20], and moreover, the increased number of MTB found inside the dendritic cells suggests the replication of it (event associated with an increased expression of IL-10) [21]. Additionally, dendritic cells infected with MTB induce the expression of cytokines such as IFN alpha and beta, which contribute to the cell migration of NK cells and T cells, and might promote granuloma formation [22].

2.2 Neutrophils

If neutrophils are present in the lungs before infection, they reduce the bacterial number; however, if they are absent immediately after infection, the bacterial count increases [23, 24]. During MTB infection, neutrophils are recruited to the site of infection due to the cytokine and chemokine expression [25]. Neutrophils exert the innate immune response against MTB through diverse mechanisms, such as bacterial phagocytosis, production of hypochlorous acid, expression of enzymes that destroy bacteria and human cells indiscriminately, and the release of the neutrophil extracellular traps (NETs) [26].

2.3 NK cells

NK cells are lymphocytes that contribute directly to the innate immunity. As part of their capabilities, they produce cytokines to assist the acquired and innate immune response. NK cells destroy infected cells through chemical weapons such as perforin, granzyme, defensin, and NO (nitric oxide). It has been observed that during MTB infection in T cells-deficient mice, NK cells contribute to the resistance against the bacteria. In that regard, in T cell-deficient individuals, the expression of IFN gamma enhances the mycobacterial control [27].

2.4 Macrophages

Macrophages are hematopoietic-derived cells from bone marrow, which are distributed almost throughout the human body. They eliminate foreign particles and microorganisms, remove cell debris, and contribute to homeostasis. When MTB is present in the lungs, alveolar macrophages constitute the central place of survival, growth, and control of it. Furthermore, macrophages comprise the tie with the acquired immune response (which is the responsibility of the outcome of the pathology).

During infection, AM regulate precisely the inflammatory and anti-inflammatory response in order to reduce tissue damage [28].

The mycobacterial recognition through PAMPs, identified by PPRs in the macrophage, induces immune response and phagocytosis. MTB recognition is mediated by TLR, NLRs, and CTLs [29, 30]. On the other hand, phagocytosis is dependent on the interaction of bacteria with macrophage receptors such as MR and DC-SIGN [31]. Additionally, the macrophage activation has been related to the intervention of the NOD2, MR, Mincle, DC-SIGN, Dectin, and TLR 2, 4, and 9 receptors [32].

Mycobacteria phagocytosis is dependent on the movement of cytoskeleton proteins; after the bacteria is located in the phagosome, ATPases are engaged in order to acidify it. Then, the phagosome merges with the lysosome and the content is poured. However, these microbicidal mechanisms (and some others that will be discussed later) are manipulated by MTB in order to survive and replicate inside the macrophage.

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3. Innate immune receptors involved in phagocytosis

The interaction of cells of the innate immune response with MTB is based on the contact of PPRs with it and the recognition of PAMPs. The outcome of this encounter will define the response and development of the infection. Among the innate immune PPRs involved in the MTB phagocytosis are: MR, DC-SIGN, Dectin, Mincle TLR, SR, and CR.

3.1 Mannose receptor

MR (CD206) belongs to the C-type lectin receptors that recognize polysaccharides such as mannose, fucose, and N-acetylglucosamine. MR can be found in monocyte-derived macrophages (MDMs), and AM and dendritic cells, but it is absent in monocytes [33, 34].

MR is a transmembrane protein constituted by protein domains that recognize carbohydrates, and a cytoplasmatic region enriched with tyrosine and related to phagocytosis [35]. MR binds lipoarabinomannan (LAM), phosphatidylinositol manosides (PIM), mannoproteins, mannans, and arabinomannans from mycobacteria [36, 37]. Cytokine production in response to MTB recognition through MR, in immature monocyte-derived dendritic cells, induces the expression of an anti-inflammatory profile [38]; furthermore, it inhibits the production of ROS and reduces the expression of IL-12 [39, 40]. In addition, the recognition ofmannosylated LAM by MR prevents phagosome-lysosome fusion and prevents phagosome maturation [36].

3.2 DC-SIGN

Also known as CD209, it is a C-type lectin receptor that can be found in some populations of macrophages and dendritic cells, whereas in AM it is induced after infection with MTB [41, 42]. CD209 is an important link between the innate and acquired immune response, and after the encounter with MTB, it mediates the mycobacterial entry. DC-SIGN identifies glycoproteins, lipomannan (LM), arabinomannan, PIM, and ManLAM from MTB, and discriminates from species with arabinofuranosyl-terminated LAM (AraLAM) such as Mycobacterium smegmatis [43]. MTB ManLAM recognized by DC-SIGN induces the expression of the anti-inflammatory cytokine IL-10, where it also counteracts the TLR-4 response [44]. Moreover, the interaction of DC-SIGN with MTB reduces the expression of IL-12, which has caused a decrease in the activity of T cells [45].

3.3 Dectin-1

Dectin is a group of C-type lectin PPR involved in cellular activation, found in neutrophils, dendritic cells, monocytes, and some clusters of T cells [46]. Dectin-1 recognizes beta-glucans and mannosylated lipids and discriminates between mycobacteria species and its strains, such as MTB Ra, Mycobacteruim bovis BCG (BCG), Mycobacterium phlei, and Mycobacterium abscessus [47, 48, 49, 50]. MTB triggers the production of IL-17A through the response produced by its interaction with Dectin-1 and TLR4 dependent on IL-1 signaling [51]. Also, it has been found that murine macrophages derived from bone marrow, which contain Dectin-1, showed an increased expression of IL-6, TNF alpha, and G-CSF, when infected with virulent mycobacteria such as BCG, M. smegmatis, M. phlei, or Mycobacterium avium [49]. Dectin-1 contribution seems to be important during MTB infection in splenic dendritic cells; it is involved with the production of IL-12p40 an important subunit to granuloma development [52].

3.4 Mincle

Macrophage-inducible C-type lectin (Mincle) is a C-type lectin receptor found in leucocytes and macrophages after stimulation [53]. Mincle intervention during MTB infection showed to be fundamental to the recognition of TDM, with an increased production of inflammatory cytokines by macrophages, which contribute to granuloma development [54, 55]. In AM from Mincle deficient mice, the exposure to BCG revealed a reduction in the proinflammatory cytokines, a decreased number of leucocytes in lung tissue, and an increased bacterial count inside and outside the lungs [56]. However, during MTB infection in Mincle-deficient mice, the animals developed a protective immune response TH1, TH17, and a granulomatous response [57].

3.5 TLR

TLRs are a family of 10 human PPRs involved in recognition and phagocytosis of intra- and extracellular pathogens. TLRs are composed of a transmembrane domain of leucine-rich repeats that identify the PAMPs; in their structure can also be identified the intramembrane domain that allows the assembly of signaling-related components [58].

TLRs are found in a variety of human cells, such as dendritic cells and AM. These PPRs can be intracellular (such as TLR-3, TLR-7, TLR-8, and TLR-9) or extracellular (such as TLR-1, TLR-2, TLR-4, TLR-5, and TLR-6). TLR-10 can be found in plasmacytoid dendritic cells and B cells. TLR 10 can be found in plasmacytoid dendritic cells and B cells [59]. During MTB infection, TLR triggers the antibacterial response dependent on vitamin D addition [60]. Multiple mycobacterial Ag can be recognized by TLR receptors. The mycobacterial lipoprotein 19 kDa, phosphor-myo-inositol-capped LAM, lipomannans and PIM, are recognized through TLR-2 [61, 62]. The CpG motives of MTB are recognized by TLR-9 [63]. TLR-4 recognizes the MTB heat shock protein 65 (Hsp-65).

The intracellular signaling of MTB recognition by TLR is dependent on the production of the myeloid differentiation factor 88 (MyD88). However, TLR 2, 4, and 9 deficient mice controlled the inflammation during MTB infection and developed a T cell response [64].

3.6 SR

Scavenger receptors are a group of transmembrane glycoproteins found on the surface of dendritic cells, some endothelial cells, macrophages, and monocytes. SR are classified in SR sub-group A and SR sub-group B. The A group comprehends MARCO (a macrophage receptor), SR-A1, and SR-A2, whereas the B group includes SR-B1 and CD36 [65]. The absence of SR-A in infected mice with MTB H37Rv prolonged the life of this animal above the average lifespan of a wild type [66]. MARCO recognizes TDM and this receptor, accompanied by CD14 and TLR-2, mediates cytokine production [67]. However, MARCO-deficient mice had no difference in acute and chronic infection with MTB in comparison with the wild type [68]. In contrast, a MARCO polymorphism is associated with an augmented susceptibility to the infection with MTB in Gambian population [69]. Cd36−/− macrophages had an increased capacity to destroy Mycobacterium marinum and MTB, whereas CD36-deficient mice had a reduced susceptibility to the BCG infection [70].

3.7 CR

Complement receptors are a group of extracellular receptors that mediate the phagocytosis of non-opsonized, and opsonized bacteria, covered with fragments of proteins of the complement cascade. There are three types of CRs: CR1, CR3, and CR4 located in macrophages, neutrophils, monocytes, NK cells, and lymphocytes. CRs recognize glycopeptolipids from non-opsonized MTB and PIMs [71, 72]. Also, CR3 from monocytes recognize phagocyte microbeads coated with the 85C antigen from BCG and MTB [73]. MTB can be recognized by CR1, CR3, and CR4; however, 80% of the phagocytosis mediated by complement is dependent on the recognition by CR3 [74].

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4. Evasion of the immune response in macrophages

Macrophages developed a variety of strategies to destroy bacteria: production of ROS and nitrogen intermediates, iron restriction, use of heavy metals, production of antimicrobial peptides, phagosome acidification, and fusion of the phagosome with the lysosome.

MTB evades and endures the strategies to eliminate bacteria and survive inside the macrophages; this attribute allows them to multiply and increase the population in order to establish the infection or trigger latency. The basic mycobacterial mechanisms to evade the immune response and survive inside the macrophages will be briefly described below.

4.1 Phagosome maturation arresting and inhibition of the phagosome acidification

The phagosome is described as a membrane structure vacuole containing the microorganism; this structure is formed immediately after the phagocytosis. The phagosome maturation is dependent on the actin-mediated movement and is supported by the reactions and delivery of the late and lysosomal constituents [75].

Throughout the establishment of the pathogenic mycobacterial infection, and soon after the bacterial recognition by PPRs, the arresting of the phagosome maturation constitutes a strategy that MTB employs to evade the immune response; specifically, the phagosomal molecule migration pathway is modified in order to avoid the microbicidal activity. During the phagosome maturation, Rab GTPases proteins are recruited to the phagosome membrane; they regulate the membrane fusion and the sorting of lipids and proteins to the organelles. The presence of these molecules is a marker of the phagosome/endosome maturation status. Also, Rab molecules allow identification of the maturity of the structure, specifically Rab5 (which is present on early endosomes) and Rab7 (present on late endosomes) [76, 77, 78, 79].

The recruiting of Rab effectors, the endosomal tethering molecule (EEA1), and the phosphatidylinositol 3 kinase hVPS34 to mycobacteria-infected phagosomes are inhibited by mycobacterial PIM and LAM, leading to an arresting of the phagolysosome development [80, 81, 82]. Also, MTB ManLAM inhibits the augmentation of Ca2+ in the cytosol, avoiding the phosphatidylinositol 3-phosphate fusion with calmodulin at the phagosomal membrane, driving the inhibition of the recruitment of GTPases to the phagosome [81].

The mycobacterial antigens—early secretory antigen target 6 (ESAT-6), culture filtrate protein 10 (CFP10), the eukaryotic-like serine/threonine protein kinase G (PknG), and the SecA1 and SecA2—arrest the phagosome maturation and contribute to the mycobacterial survival inside the macrophages [83, 84, 85]. M. avium keeps the phagosomal pH between 6.2 and 6.5, due to the exclusion of the proton ATPase in phagosomal acidification [86]. MTB protein tyrosine phosphatase (PtpA) contributes to the survival of the bacteria inside the phagosome, as a consequence of the inhibition of the complex V-ATPase + H with the phagosomal membrane [8].

MTB permits the V-ATPase catalytic subunit A proteasome degradation because of ubiquitination signaling, while also regulating the reduction of the phagosome pH [87]. Glycolipid TDM recognition by the receptor Mincle induces the blockage of signaling involved in the phagosomal formation [88].

4.2 Resistance to reactive nitrogen species and reactive oxygen species

Reactive nitrogen species (RNS) and ROS are short-lived chemical compounds that mediate and contribute to the innate immune response through microbicidal mechanisms [89]. The ROS generation is dependent on the phagosomal acidification. Among the effects of the oxidative stress due to the ROS activity, can be described the oxidation of lipids, proteins and DNA damage. During the MTB infection, the sigma factor and the stress response factor SigH, produced during ROS and RNS action, contribute to the infection [90, 91, 92]. The mycobacterial mycothiol has an antioxidant activity and keeps the cell reduced. The MTB mutation of the gene that encodes for the mycothiol synthase, mshD, had an increased susceptibility to H202 [93, 94]. MTB Cu, Zn superoxide dismutase SodC contributes to the resistance to the oxidative burst produced by the ROS of macrophages; also, the MTB sodC mutant was sensitive to the superoxide and was susceptible to IFN-gamma too [95]. Similarly, the alkyl hydroperoxide reductase (AphC) contributes to the resistance to ROS of the innate immune response [96].

MTB exposed to NO had a bacteriostatic effect and induced the expression of genes related to dormancy [9]. The expression of inducible nitric oxide synthase (iNOS) confers alveolar macrophages with the ability to kill MTB, and the latency of MTB in macrophages from healthy subjects was dependent on the production of the NO [97]. MTB controls the production of ROS by the increased expression of host histamine receptor H1 (HRH1), by regulating the GRK2-p38MAPK signaling pathway [98].

4.3 Apoptosis and autophagy evasion

Cell apoptosis is a hosting strategy to destroy the intracellular niche of the bacteria. The evasion of apoptosis is related to the mycobacterial virulence. The avirulent strains like Mycobacterium kansasii, M. tuberculosis H37Ra, and BCG induced more human alveolar macrophages apoptosis, whereas Mycobacterium bovis, M. tuberculosis H37Rv, and the MTB clinical isolated, named as BMC 96.1, did not [99]. Virulent MTB stimulates the cell necrosis of macrophages by the mitochondrial inner membrane rupture, favoring the release of the microorganism [100].

The autophagy leads to the destruction of damaged cell parts resulting in the cell survival. In MTB infection, the autophagy development conducts a defense mechanism against it. In macrophages infected with MTB or BCG, the autophagy induces the phagolysosomal formation and mycobacterial death [101]. Finally, the foamy phenotype in macrophages protects the cell and reduces autophagy of MTB-infected macrophages [102].

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5. Conclusions

The phagocytosis of MTB is the clue event during the development of tuberculosis. The knowledge of human cells involved and the receptors that recognize the strains and species are vital for the understanding of the disease. In addition to that, the information of the variety of mycobacterial strategies to resist cellular control constitutes a contribution to the same aim. Investigative efforts to comprehend the mechanisms involved in MTB survival are important because they contribute to the development of vaccines, therapeutic strategies, and new, more efficient, drugs.

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Written By

Gabriela Echeverría-Valencia

Submitted: 08 January 2023 Reviewed: 18 January 2023 Published: 15 February 2023

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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