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Seminars in Immunopathology

, Volume 40, Issue 6, pp 577–591 | Cite as

Macrophage-microbe interaction: lessons learned from the pathogen Mycobacterium tuberculosis

  • Somdeb BoseDasgupta
  • Jean Pieters
Review

Abstract

Macrophages, being the cornerstone of the immune system, have adapted the ancient nutrient acquisition mechanism of phagocytosis to engulf various infectious organisms thereby helping to orchestrate an appropriate host response. Phagocytosis refers to the process of internalization and degradation of particulate material, damaged and senescent cells and microorganisms by specialized cells, after which the vesicle containing the ingested particle, the phagosome, matures into acidic phagolysosomes upon fusion with hydrolytic enzyme-containing lysosomes. The destructive power of the macrophage is further exacerbated through the induction of macrophage activation upon a variety of inflammatory stimuli. Despite being the end-point for many phagocytosed microbes, the macrophage can also serve as an intracellular survival niche for a number of intracellular microorganisms. One microbe that is particularly successful at surviving within macrophages is the pathogen Mycobacterium tuberculosis, which can efficiently manipulate the macrophage at several levels, including modulation of the phagocytic pathway as well as interfering with a number of immune activation pathways that normally would lead to eradication of the internalized bacilli. M. tuberculosis excels at circumventing destruction within macrophages, thus establishing itself successfully for prolonged times within the macrophage. In this contribution, we describe a number of general features of macrophages in the context of their function to clear an infection, and highlight the strategies employed by M. tuberculosis to counter macrophage attack. Interestingly, research on the evasion tactics employed by M. tuberculosis within macrophages not only helps to design strategies to curb tuberculosis, but also allows a better understanding of host cell biology.

Keywords

Macrophages Pathogens Mycobacterium tuberculosis Inflammation 

Tissue-specific macrophages as professional phagocytes

Macrophages, being professional phagocytes, ingest and degrade dead cells, debris, and foreign material and orchestrate inflammatory processes [1, 2]. As such, different types of macrophages, residing in different tissues and organs, have evolved disparate functions. It is however important that under homeostatic conditions within tissues, macrophages maintain a non-inflammatory state to avoid damage. For example, in the lung, macrophages are being maintained in a non-inflammatory state through an interaction with alveolar epithelial cells via signaling through CD200 and transforming growth factor (TGF)-β [3]. Also, pulmonary surfactant appears to be important to maintain a non-inflammatory state, since mice lacking expression of the surfactant D protein show significant inflammation as judged by spontaneous expression of metalloproteinases and oxidant production [4]. Kupffer cells, the resident macrophages of the liver, are involved in surveillance and filtering of blood entering the hepatic sinusoids. These cells also regulate the efficient clearance of potentially harmful endogenous compounds, such as complement and fibronectin-coated particles, material released from dying cells, extracellular matrix components, as well as immune complexes [5]. Red pulp macrophages inside the spleen carry out iron recovery and express proteins involved in scavenging of senescent or damaged erythrocytes, hemoglobin uptake, heme breakdown, and iron export [6]. Splenic macrophages repair red blood cell (RBC) membranes by removing any unwanted damage. Furthermore, these macrophages not only clear senescent RBC’s but also keep these in a healthy state by being able to repair damaged RBC’s [7, 8]. Also, by providing iron for heme synthesis and by phagocytosing expelled nuclei during final erythroid differentiation, macrophages actively participate in erythroid development [9]. Besides these red pulp macrophages, marginal zone macrophages screen the arterial blood, while macrophages within the white pulp that structurally resembles lymph nodes, are involved in the initiation of immune response to blood borne antigens [10]. An important function of macrophages is to participate in homeostatic tissue remodeling and lineage development. Mononuclear phagocytes are involved in remodeling of the extracellular matrix (ECM), epithelial proliferation, development and organization of the vascular tree, and shaping of tissue organization [11]. Thus, macrophages, as professional phagocytes, play a plethora of roles in different tissues that are essential for proper functioning of the body.

Non-professional phagocytic cells; types and functions

Apart from professional phagocytes such as macrophages, dendritic cells, and polymorphic neutrophils (PMN’s), it has been observed that fibroblasts, epithelial cells, and several other cell types can engulf particles through phagocytosis. Owing to their limited expression of surface receptors involved in phagocytosis, they cannot elicit a phagocytic trigger as extensive as the professional phagocytes listed above when a particle is phagocytosed; hence, these cells are termed non-professional phagocytes [12]. Furthermore, these non-professional phagocytes have a limited range of particles and pathogens that can be internalized, for example through fibronectin, laminin receptors, or heparin sulfate moieties [13]. Contrary to uptake by professional phagocytes, uptake by non-professional phagocytes does not trigger the generation of reactive nitrogen and oxygen intermediates or secretion of cytokines to trigger immunological responses [14].

Pathogen-mediated subversion of macrophage attack

Phagocytosis involves engagement of the pathogen by the host cell, followed by the activation of a plethora of intracellular signaling cascades and cytoskeletal remodeling to engulf the cargo [15]. Those pathogens, for which macrophages are a favorable niche within the host, adopt several strategies to modulate phagocytic uptake and phagosome maturation for their benefit and survival. In order to mask pathogen-associated molecular patterns (PAMP’s) and thus prevent their recognition by macrophages, pathogens such as Neisseria meningitides, Haemophilus influenzae, Pseudomonas aeruginosa, Streptococcus spp., and Cryptococcus neoformans express a polysaccharide capsule [16, 17]. Other pathogens, such as Yersinia, inject effectors with tyrosine phosphatase activity, to counteract the activated tyrosine phosphorylation signals inside the host cell and thus evade internalization by phagocytes [18]. Salmonella typhimurium uses the so-called type IIII secretion system (T3SS) to inject a number of effectors into host cells. One of these, SopE/SopE2, is a guanine nucleotide exchange factor (GEF) that induces membrane ruffle formation and Salmonella internalization [19]. To counter this, Salmonella also releases a tyrosine phosphatase-containing effector, SptP, to reverse these cytoskeletal changes and return the host membrane to a steady-state condition [20, 21, 22]. Several pathogens, including pathogenic mycobacteria (see also below), are known to modulate host phosphoinositides during phagocytosis. Salmonella spp., Shigella spp., Vibrio spp., as well as M. tuberculosis all produce and inject phosphoinositide phosphatases into host cells during entry [23, 24, 25]. Salmonella, Burkholderia, and Chromobacterium secrete specific factors inside the host macrophage to prevent the maturation of the phagosome in which they reside [26, 27, 28]. Listeria, once inside the host, escapes from the phagosome and modulates actin nucleation and employs this for its movement inside the cell as well as its dissemination [29, 30]. Interestingly, pathogens can also avoid phagocytosis by becoming too large to ingest, as is the case for the hyphae of Candida albica and Aspergillus fumigates [15, 31, 32].

Mycobacterium tuberculosis: a pathogen capable of modulating many aspects of phagocytosis

Mycobacterium tuberculosis, the causative agent of tuberculosis, is probably the most successful pathogen on earth [33]. One reason for its success is its ability to survive within host macrophages, despite extensive immune attack by the innate and adaptive immune systems. However, in most infected individuals, M. tuberculosis is effectively controlled by the immune system and does not cause disease. Because the bacteria remain viable, the host often transfers into a state of persistent immune response towards mycobacterial antigens (referred to as ‘latent’ tuberculosis). Whenever the health state of the host deteriorates, for example because of malnutrition or co-infection, latent tuberculosis can transform into active tuberculosis, not only causing severe disease but also allowing the infected host to spread M. tuberculosis [34, 35].

Mycobacteria enter the body via aerosols and subsequently reach the alveoli. Upon crossing the alveolar epithelium, they enter the blood capillaries where the bacilli can be phagocytosed by alveolar macrophages as well as M cells, specialized epithelial cells that allow antigens to penetrate mucosal barrier [36, 37]. Interestingly, recent work showed that resident alveolar macrophages eradicate the phagocytosed mycobacteria, while the mycobacterial membrane component phenolic glycolipid induces the production of the chemokine CCL2 that results in the recruitment of circulating CCR2+ monocytes and induction of their fusion with these tissue resident macrophages [38]. Once inside the phagosome of permissive monocytes, mycobacteria employ a range of virulence factors that modulate expression of several host factors, allowing the bacilli to survive inside the cell and also result in an anti-inflammatory response that dampens downstream pro-inflammatory signaling cascades [14, 39, 40].

Besides avoiding lysosomal degradation, mycobacteria are adept at modulating arginine metabolism. On the one hand, the conversion of arginine to ornithine and urea via the arginase pathway can support the growth of M. tuberculosis, whereas on the other hand arginine is employed by the inducible nitric oxide synthase (iNOS2) to produce nitric oxide (NO) that is used as an anti-mycobacterial compound within macrophages. Thus, the competition between iNOS and arginase for arginine can contribute to the outcome of an infection, and, indeed, modulation of this pathway is an important strategy via which M. tuberculosis can manipulate both its growth and survival within macrophages as well as the macrophage response against the infection [41, 42, 43]; in parallel, mycobacteria also increase secretion of the anti-inflammatory cytokine interleukin-10 by macrophages [44], thereby maintaining the macrophages in a resting state and preventing the generation of bactericidal effectors such as reactive oxygen and nitrate induction [45, 46, 47]. In order to establish its niche within the macrophage and replicate inside these phagocytes, mycobacteria also prevent macrophage apoptosis [48]. Furthermore, after prolonged times within macrophages, mycobacteria can perforate the phagosomal membrane and escape to the cytosol [49]. Recently, it has also been shown that even in an event of phagosome-lysosome fusion, mycobacteria are able to withstand the low pH, survive and proliferate, among others through alteration of host cell trafficking pathways as well as induction of acid-tolerant proteins [50, 51]. Regardless of the site of survival of M. tuberculosis, their proliferation leads to their dissemination, which recruits more macrophages to the vicinity along with so-called foamy (lipid-laden) and epitheloid macrophages, monocytes, and multinucleated giant cells. These nascent granulomas at the site of infection are thereafter marked by fibroblasts that lay down a fibrous capsule around the macrophage-rich center along with lymphocytes hovering at the periphery to form a mature granuloma [52, 53, 54]. Such granulomas, in fact, are the host reaction in an attempt to contain the disease. From the pathogen’s perspective, the granuloma is a habitable niche where it can infect fresh macrophages, proliferate, and use the ruptured macrophages to generate a caseating center from where mycobacteria can be released to new infection sites, potentially also developing new granuloma’s [52]. Thus, mycobacterial pathogenesis inside these professional phagocytes is a tale of continuously changing paradigms, which we discuss in the paragraphs below.

Macrophage receptors and mycobacterial uptake

Being professional phagocytes, macrophages express a plethora of receptors at their surface, many of which are involved in phagocytosis of mycobacteria. Complement receptors represent the primary receptors for mycobacterial uptake owing to complement-mediated opsonization of the mycobacterial surface [55]. Also the mannose receptor, which recognizes lipoarabinomannan (LAM) on the mycobacterial surface, is important to achieve efficient phagocytosis of mycobacteria [56]. Owing to the airborne route of mycobacterial entry, the mycobacterial surface becomes coated with the lung surfactant protein A (Sp-A), which is then recognized by Sp-A receptors on the alveolar macrophage surface and initiates phagocytosis [57]. The presence of lipoteichoic acid on the mycobacterial cell wall can trigger mycobacterial binding to class A scavenger receptors and thereby result in phagocytic uptake by macrophages [58]. Inside the host, mycobacteria, while traversing the blood capillaries, are opsonized by circulating antibodies, which can in turn trigger phagocytic uptake through Fcγ receptors [59]. Interestingly, recent work identified different antibody profiles in patients from either latent or active tuberculosis [60, 61]. In particular, it was found that antibodies made by individuals with latent disease were superior when compared to those produced by people with active disease with respect to their ability to promote phagolysosome fusion and inducing macrophage killing of the internalized mycobacteria [61]. Also, several so-called Pattern Recognition Receptors (PRR’s) that, rather than recognizing a specific molecular ligand, can bind to pathogen-associated molecular patterns (PAMP’s) [62, 63, 64, 65], recognize mycobacteria, and induce its phagocytic uptake; in particular, the Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN, also known as CD209) as well as Toll-like receptor (TLR) 2, 4, 8, and 9 that recognize pathogen-associated molecular patterns (PAMP’s) are involved in mycobacterial uptake [66, 67]. For example, the surface lipoglycoprotein MPT83 expressed at the mycobacterial surface, one of the mycobacterial PAMP’s, is recognized by TLR2, while the surface lipoarabinomannan is also recognized by the surface molecule CD14 in conjunction with TLR 2 and 4, thereby resulting in uptake [68, 69]. Even extracellular DNA, for example occurring on the surface of the bacteria, can activate TLR-dependent signaling [70]. Another pathogen recognition receptor, dectin-1, is a versatile PRR that possesses an intracellular tyrosine-activated motif and an extracellular carbohydrate-binding domain through which it binds to β-glucan on mycobacterial membranes thereby mediating mycobacterial uptake [71]. Thus, the wide variety of receptors present at the macrophage surface allows mycobacteria to be readily internalized within these phagocytes; importantly, rather than representing an endpoint, as is the case for many bacteria entering macrophages, the entry of M. tuberculosis into the macrophage represents an important survival strategy.

The Trojan horse-phagosome maturation arrest

One of the primary mechanisms via which mycobacteria survive within macrophages is through efficient blockade of phagosome maturation wherein mycobacteria prevent the maturation and acidification of the phagosomes in which they reside, thereby preventing lysosomal delivery [72, 73, 74, 75, 76]. This survival strategy is steered through an intricate interplay of host factors and mycobacteria-released virulence factors. For example, phagosomal membrane-associated cholesterol is essential for the retention of macrophage protein coronin 1, (also known as TACO (for Tryptophan-Aspartate-containing Coat protein, or P57), which shields the mycobacterial phagosome from fusing with lysosomes [77, 78]. Coronin 1 is known to activate the Ca2+/calcineurin pathway, thereby preventing phagosome maturation through dephosphorylation of yet unknown host or mycobacterial factors [79, 80, 81, 82]. Interestingly, whereas all immune cells express coronin 1, the major function of coronin 1 (in the absence of an infection) is to regulate peripheral T cell numbers: in the absence of coronin 1, peripheral T cells rapidly disappear both in mice and men [80, 83, 84, 85, 86]. Macrophages lacking coronin 1 appear to be largely functional [79, 87], and while coronin 1 might be crucial for macrophage functionality under certain circumstances, such as during activation ([88] and see below), it could well be that mycobacterial retention within macrophages serves as natural adjuvants that enable rapid responses of the immune system. In this context, it is interesting to note that the liver-resident Kupffer cells seem to be the only leukocyte cell type that are devoid of coronin 1, thus perhaps ensuring an efficient mycobacterial clearance site [77, 80].

Phagosomal maturation requires phosphoinositide-3-kinase (PI3K)-mediated synthesis of phosphoinositide-3-phosphate (PI3P) on the phagosome surface [89, 90]. PI3P is a ligand for hepatocyte growth factor (HGF)-regulated tyrosine kinase substrate (Hrs), which is crucial for phagosome maturation [91]. Pathogenic mycobacteria, when internalized, can efficiently restrict the wave of PI3P on the phagosome membrane and thus prevent phagosome maturation [92]. PI3P is also linked to modulation of cytosolic Ca2+, and there is evidence for extensive crosstalk between Ca2+ and phosphoinositide signaling, although the exact mechanisms and consequences remain to be defined [93, 94, 95, 96]. Furthermore, it has been shown that the mycobacterial component trehalose dimycolate (also known as cord factor) is able to modulate phagosome-lysosome trafficking [97, 98].

An important virulence factor, with multiple functions, is the mycobacterial cell wall component mannosylated lipoarabinomannan (ManLAM). ManLAM is known to block the PI3P-dependent pathway involved in the transport of cargo between the trans-Golgi network and phagosomes that is a critical transport step required for phagolysosome biogenesis. ManLAM, by competing with PI3P, can prevent the PI3P-dependent rise of intracellular Ca2+ and as a result PI3K is not activated [99, 100]. In addition to this, M. tuberculosis secretes a phosphatase SapM that dephosphorylates any PI3P that might have accessed the phagosome membrane in order to halt phagosome maturation [101]. Pathogenic mycobacteria are also known to secrete another virulence factor, protein kinase G (PknG), one of which roles is to prevent phagosome maturation: upon infection of macrophages with PknG-deficient mycobacteria, the mutant bacilli are immediately delivered to lysosomes followed by their degradation thereby preventing survival of M. tuberculosis [50, 102, 103, 104]. How, exactly, PknG modulates the survival of M. tuberculosis within macrophages is unclear; PknG is secreted in a SecA2-dependent manner and released into the macrophage cytosol and may thus phosphorylate host substrates involved in the regulation of phagosome-lysosome fusion [102, 105, 106]. Furthermore, a number of mycobacterial substrates for PknG have been defined, such as the ribosomal protein L13 and the forkhead-associated (FHA) domain-containing protein GarA, phosphorylation of which may also provide survival advantages within the macrophage [107, 108, 109, 110, 111]. One possibility is that the dependence of mycobacterial survival on PknG is especially important during early phases of the infection, perhaps to prepare M. tuberculosis for subsequent lysosomal localization and/or release into the cytosol in an ESX-1-dependent manner. Mycobacteria have also been implicated in the regulation of the exchange of the small GTPases Rab5 with Rab7, an event that is crucial to phagosome maturation [99, 112]. Mycobacterium-secreted phosphatase PtpA is also known to dephosphorylate the Vesicular Protein Sorting 33B (VPS33B), that is involved in vesicular trafficking and membrane fusion events associated with phagosome maturation [113]. Thus, a close interplay of host factors along with mycobacterial components and secreted virulence factors can efficiently arrest phagosome maturation.

The complex interaction of pro- and anti-inflammatory cytokines with M. tuberculosis

In the context of an infection with M. tuberculosis, several cytokines have been implicated in controlling or promoting pathogenesis. Being both pro- as well as anti-inflammatory, cytokines are important for the fate of M. tuberculosis; moreover, mycobacteria can manipulate cytokine responses to their advantage.

An important class of cytokines involved in the modulation of the survival of M. tuberculosis is represented by the interferons. While type II interferon (IFNγ) is required for mycobacterial elimination, the class I interferons (IFNα,β) are believed to play predominantly a detrimental role for the host during mycobacterial infection. Indeed, mice and humans lacking type II interferon responses are highly susceptible for mycobacterial infections [114, 115, 116]. Interferon-γ acts predominantly as a phagocyte-activating molecule that is required for pathogen clearance, and, in fact, the induction of interferon-γ-producing T cells is widely considered as a requirement for a successful anti-TB vaccine design [117]. Interferon-γ binds to and activates interferon-γ receptors, which, through the linked Janus kinase/Signal transducer and activator of transcription (JAK/STAT) pathway, induces consecutive phosphorylation of the STAT transcription factors. Phosphorylated STAT1 enters the nucleus and modulates a plethora of interferon-γ response genes, including upregulation of LPS-stimulated RAW 264.7 macrophage protein 47/Immunity-related GTPase family M (LRG47/IGRM1) which is known to activate autophagy, as well as the inducible nitric oxide synthase which induces reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI) to result in effective mycobacterial killing [118, 119, 120]. Mycobacteria themselves also induce the expression of host Suppressor of Cytokine Signaling 1 (SOCS1) and Cytokine-induced SH2 domain-containing protein (CISH), proteins that then dampen the downstream signaling of IFNγ [121, 122].

Besides interferon-γ, also the type I interferons have been implicated in resistance against mycobacterial infections. Whereas mutations associated with type I IFN signaling are known to impair host resistance to mycobacterial infection, the overall impact of type I interferon signaling on the outcome of an infection by M. tuberculosis is less clear [123, 124]. In humans, type I interferons comprise several subtypes, namely IFN-α (that exists in multiple forms that are encoded by 14 different genes), IFN-β, IFN-ε, IFN-κ, and IFN-ω, all of which appear to signal via the common IFN-α receptor [125]. Type I interferons were initially identified as factors essential for the control of viral infections [126] these are also known to promote or impair M. tuberculosis control and influence disease pathology, depending on the acute or chronic state of the infection [114, 124]. The precise mechanisms involved in the induction of type I interferons upon an infection with M. tuberculosis remain to be clarified, while type I IFN induction was shown to occur through release of DNA or peptidoglycan in the host cell cytosol [127, 128, 129, 130]; other work suggests that rather than cytosolic access of mycobacterial products, mitochondrial stress and subsequent release of mitochondrial DNA in the cytosol results in type I interferon responses via the stimulator of interferon genes (STING) pathway [130, 131]. Incidentally, mycobacterial DNA also activates the AIM2-dependent NLRP3-inflammasome pathway and thereby counters STING-mediated type I interferon expression [132]. Also, type I interferon inhibits the production of the pro-inflammatory cytokines TNF-α, IL-12, as well as IL-1b, thus dampening pro-inflammatory responses [133]. It has also been observed that in the absence of interferon-γ signaling, type I interferon may facilitate the recruitment, differentiation, and/or survival of myeloid cells that control pathology, pointing also towards a protective role for type I interferon in mycobacterial pathogenesis [124, 134]. Thus, while it is clear that both type I and type II interferon responses are important modulators of mycobacterial pathogenicity, many aspects of the consequences of activating these pathways remain to be elucidated.

Interleukins are a group of cytokines that are predominantly secreted by CD4+-T cells but also by monocytes, macrophages, and endothelial cells, and play an important role in the immune system. There are 17 different families of interleukins with over 40 interleukin molecules characterized [135]. Of these, interleukin-6 (IL-6) is known to potentiate immunity towards M. tuberculosis by promoting interferon-γ secretion whereas its depletion increases bacterial load [136, 137]. IL-1 cytokines, which comprise of 11 members, signal through interleukin receptors that activate the cytosolic adaptors myeloid differentiation primary response gene 88 (Myd88) and interleukin-1 receptor-activated protein kinase (IRAK) 4, leading to the activation of many transcription factors resulting in an inflammatory response [138, 139]. IL-12 is produced by and influences multiple effector cells. IL-12p40 deficiency causes a predisposition to tuberculosis in both mice and men [140, 141]; conversely, delivery of IL-12 to M. tuberculosis-infected mice decreases bacterial burden [139, 142]. Another member of the IL-12 family of cytokines, IL-27, can function either as a pro-inflammatory or as an anti-inflammatory cytokine, depending on the surrounding and context. While IL-27R-deficient mice infected with M. tuberculosis show lower bacterial burden in the lungs, these mice were more susceptible to the pathological events that lead to death [143]. IL-4, IL-5, and IL-13 are the signature cytokines associated with an anti-inflammatory (also referred as TH2) response and are involved in the dampening of the pro-inflammatory response [144, 145]. Also, both IL-4 and IL-13 are independently capable of inhibiting autophagy as well as interferon-γ-induced autophagy-mediated killing of M. tuberculosis thereby allowing its survival within the host [146].

Another cytokine, transforming growth factor (TGF)-β, is induced in human blood monocytes by mycobacterial ManLAM [147]. TGF-β is able to induce IL-10 and to synergize with this cytokine to suppress interferon-γ production. Antigen-specific IL-10 production can be used to distinguish between latent TB and pulmonary active TB [148]. In macrophages, IL-10 can block phagosome maturation as well as inhibit antigen presentation through down regulation of MHC class II molecules [139, 149, 150]. Mycobacteria can thus, through TGF-β induction, efficiently upregulate IL-10 expression in order to induce a pathogen survival response and limit RNI and ROS generation.

Together, the research on the role for cytokines on the outcome of an infection with M. tuberculosis suggests that, as for many host defense mechanisms, cytokine-mediated macrophage activation mechanisms are both targeting M. tuberculosis and a target for its many virulence mechanisms.

Survival through degradation: the pup-proteasome system

Within the macrophage, M. tuberculosis is bound to encounter reactive nitrogen intermediates that are an important part of the macrophage antimicrobial arsenal. Given the exquisite ability of M. tuberculosis to survive within macrophages, Darwin et al. hypothesized that M. tuberculosis may possess a system that would counter nitric oxide stress. A screen designed to identify such genes revealed the importance of homologs of the eukaryotic proteasomal system in resistance towards reactive nitrogen intermediates [151, 152]. One of these proteasomal components, the chaperone Mpa (for proteasome-associated ATPase), was subsequently demonstrated to strongly interact with a 64 amino acid protein, termed prokaryotic ubiquitin-like protein, or pup, [153]. Pupylation is functionally, but not biochemically, similar to ubiquitylation, and is also involved in the regulation of protein degradation within mycobacteria [154, 155]. So how does pupylation protect M. tuberculosis from nitric oxide stress? An obvious mechanism would involve a protein whose accumulation would sensitize the bacteria to NO, and indeed, a suppressor screen of a nitric oxide sensitive strain that possessed a non-functional proteasomal system identified mutations in a gene with homology to plant enzyme (lonely guy, or log). Log is an enzyme involved in cytokinin synthesis, a family of plant hormones; in M. tuberculosis, cytokinins synergize with NO to kill the bacilli, and therefore the timely degradation of log by the pup-proteasome system, thereby avoiding the accumulation of cytokinins and their breakdown products, allows M. tuberculosis to resist NO stress [156]. The Pup-proteasome system, other than resistance to host RNI’s, has been implicated in metabolic pathways, protein turnover, and virulence [157, 158]. Important aspects of pupylation and proteasomal degradation in mycobacteria still remain elusive, such as substrate recognition by the Pup-ligase PafA or possible degradation-independent functions of Pup.

Macrophage activation status maintaining the balance

One of the consequences of macrophage activation is the modulation of intracellular trafficking and the promotion of phagolysosome formation followed by mycobacterial destruction [2]. For example, macrophage activation allows the replenishment of phosphoinositides at mycobacteria-containing vesicles and thereby promotes the exchange of Rab5 by Rab7, which is crucial to induce phagosome-lysosome formation as discussed above [112]. Furthermore, inflammatory stimuli mediated by interferon-γ or tumor necrosis factor-α result in the phosphorylation of the protein coronin 1, thereby delocalizing coronin 1 from the cell cortex to cytoplasmic punctae [88, 159]. Such delocalization not only effectively depletes coronin 1 from phagosomes, thereby restoring phagosome-lysosome fusion, but coronin 1 phosphorylation also reprograms the macrophage endocytic pathway from receptor-mediated phagocytosis to macropinocytosis for subsequent lysosomal delivery and destruction of mycobacteria [159].

Activation of macrophages by interferon-γ results in the expression of a large number of interferon-γ-induced genes [160], many of which are involved in the activation of a diverse set of host defense mechanisms, such as the phagocyte oxidase, generation of antimicrobial peptides, and induction of autophagy [161, 162]. Interestingly, mycobacteria can counteract such macrophage activation through different strategies; one of these relies on the presence of the associated lipid phthiocerol dimycocerosate (PDIM) on the mycobacterial surface, which allows mycobacteria to enter macrophages in a manner that prevents activation through toll-like receptors and in the absence of phagosome-lysosome fusion [163]. Notwithstanding these mycobacterial countermeasures, the importance of the interferon-γ-induced oxidative burst is also illustrated by the observation that deficiencies in the interferon-γ signaling pathway cause a predisposition to disease towards a variety of mycobacterial species, including the tuberculous M. bovis BCG and non-tuberculous, environmental bacteria [164, 165].

Macrophages residing within granulomas have been shown to have both pro- and anti-inflammatory phenotypes. The most peripherally localized macrophages have been generally shown to be less inflammatory and more similar to IL-4-stimulated (or so-called M2 macrophages, also sometimes referred to as “alternatively activated” or “repair” macrophages) with elevated expression of the scavenger receptor CD163 and arginase 1 and a generally anti-inflammatory profile [166, 167]. Alternative activation of macrophages thus supports intracellular persistence of M. tuberculosis. Apart from the peripherally located macrophages, the granuloma harbors centrally localized macrophages that are either foamy macrophages or naïve macrophages, both of which are key players in sustaining persistent bacteria and contributing to cavitation and release of infectious bacilli [52, 168].

Mycobacterial antigen presentation and lymphocyte activation

Macrophages present antigens in association with major histocompatibility complex (MHC) class I and class II molecules to stimulate CD8+ and CD4+ T cells, respectively, and this process is essential to contain M. tuberculosis infection. Macrophages process M. tuberculosis antigens through proteolysis to produce peptides that bind to major histocompatibility complex (MHC) class II molecules, which then translocate to the cell surface to mediate presentation of M. tuberculosis peptides to CD4+ T cells [150, 169, 170, 171]. Furthermore, antigen processing and presenting cells can express MHC class I-bound mycobacterial antigens either through the process of cross-presentation or from mycobacterial antigens that have gained access to the cytosol [172, 173].

T cell responses that have been activated by macrophages or dendritic cells presenting mycobacterial antigens are central to host resistance to M. tuberculosis through the induction of pro-inflammatory cytokines, whereas the responding CD4+ T cell population produces interferon-γ, IL-2, and tumor necrosis factor-α; the activated CD8+ T cells are predominantly interferon-γ producers. In addition to interferon-γ production, T cells can directly kill M. tuberculosis-infected target cells and provide help for other T cell subsets such as CD8+ T cells and γδ T cells [150, 174, 175]. Also, MHC-I-mediated presentation and initiation of a CD8+ T cell response has been linked to the presence of the antigen processing machinery on phagosomes, including MHC-I and the transporter associated with antigen processing, possibly through fusion of the phagosomes with endoplasmic reticulum membranes [173, 176, 177].

Residence of M. tuberculosis within macrophages can also lead to Toll-like receptor (TLR) 2-dependent inhibition of MHC class II transactivator expression, thereby preventing MHC class II expression and thus antigen presentation [150, 178]. Also, mycobacterial infection results in the expansion of so-called regulatory (Treg) cells that are T cells involved in immune suppression [179]. Further expansion of Tregs is achieved through mycobacteria-induced sonic hedgehog (SHH) [180].

Another important molecule involved in the presentation of mycobacterial antigens is CD1. CD1 proteins are similar in structure to MHC class I proteins, in that they consist of a membrane-anchored heavy chain associated with a β2 microglobulin. CD1 proteins reside in intracellular compartments, including mycobacterial phagosomes, where they can bind both self and foreign molecules that range from simple fatty acids or phospholipids, to more complex glycolipids, isoprenoids, mycolates, and lipopeptides prior to being delivered to the cell surface for presentation to CD1-restricted T cells expressing alpha/beta or gamma/delta T Cell Receptors (TCR) [181, 182, 183]. A third set of antigen presenting cells involved in T cell activation against mycobacterial antigens is represented by the non-classical, mucosal-associated non-variant T (MAIT) cells. These cells are a subset of αβ T lymphocytes characterized by a semi-invariant T cell receptor alpha (TCRα) chain, and can be activated through presentation of MHC-related protein 1 receptor (MR1) bound antigens, that can include bacteria-derived metabolites [184, 185, 186].

Cytosolic escape—role of the Esx proteins

As described above, an important survival strategy for M. tuberculosis relies on their capacity to inhibit phagosome-lysosome fusion within macrophages. Interestingly, evidence has emerged over the past years to suggest that mycobacteria may eventually escape from phagosomes by translocating to the cytosol. Cytosolic escape of M. tuberculosis is linked to the presence of the region of differentiation 1 (RD1) locus of mycobacteria that encodes for the Early Secretory Antigenic Target of 6 kD (ESAT6) secretion system (Esx1 or type VII secretion system) [49, 187, 188, 189, 190, 191, 192]. The components of this system are involved in the secretion of the virulence factors (ESAT6) and Culture Filtrate Protein of 10 kD (CFP10). ESAT6, an important substrate of the type VII secretion system, has been implicated in the rupture of phagosomal membrane [193, 194, 195]. Following phagosomal rupture and mycobacterial escape, the escaped mycobacteria become ubiquitinated, and subsequently become labeled with microtubule-associated protein 1A/1B-light chain (LC)3 that induces them to be delivered to the autophagic pathway from where the mycobacteria are delivered to the lysosome. Additionally, the presence of mycobacterial DNA in the cytosol acts as an autophagic trigger via the STING pathway [196]. A “pathogenesis pattern” is constituted by the combination of ESX-1 secretion and DNA exposure, which is recognized by host cells to mount innate responses against M. tuberculosis [197, 198].

Mycobacterial infection and induction of autophagy

Autophagy is an important cellular pathway for intracellular degradation of cytoplasmic constituents in specialized structures called autophagosomes, and cytosolically localized M. tuberculosis is no exception to being susceptible to autophagy [199]. One of the autophagy-inducing signals occurs through ligation of TLR7, which subsequently signals through Myd88, Beclin1, and ATG5. Although M. tuberculosis is not known to induce TLR7 signaling, exogenous stimulation through TLR7 nevertheless results in its elimination through autophagy [200]. Also TLR2 and TLR4 have been shown to induce autophagy via its effector IRGM1 (interferon-inducible immunity-related GTPase family member 1), through an interaction with ULK1 and Beclin-1 [200]. Furthermore, the mycobacterial lipoprotein LpqH stimulates TLR2/1/CD14 and upregulates the Vitamin D receptor and Vitamin D-1-hydroxylase, resulting in the induction of the antimicrobial peptide cathelicidin, which, besides directly killing intracellularly residing M. tuberculosis can also induce autophagy through upregulation of Beclin-1 [201, 202]. Phagosomal permeabilization, mediated by the ESX-1 secretion system of M. tuberculosis as described above, could allow the cytosolic sensing of extracellular bacterial DNA by cGAS/STING leading to ubiquitination of mycobacteria, and their subsequent delivery to autophagosomes [196, 197, 203]. Type 1 interferons are also known to increase autophagy [204]. However, mycobacteria can counter autophagosome-mediated elimination through a variety of mechanisms, including the release of virulence factors within the host cell through dedicated secretion systems [106, 205]. Thus, autophagy is an essential pathogen elimination strategy employed by macrophages in the context of a mycobacterial infection, against which mycobacteria have developed successful strategies to avoid such elimination.

Programmed cell death and mycobacterial pathogenesis

Apoptosis, or programmed cell death, can serve as a defense mechanism for infected cells, for example to prevent intracellular pathogens from using up host resources; also, apoptosis of infected cells would eliminate the pathogen’s replication niche and expose these to humoral immunity. Subsequent efferocytosis, the process by which dying cells are being removed through phagocytosis, thus provides a mean to neutralize virulence mechanisms of intracellular pathogens. However, in the case that apoptosis eliminates key host defense cells, apoptosis would facilitate the spreading and proliferation of the pathogen [206]. It has been shown that treatment of infected macrophages with ATP can induce apoptosis of the infected macrophages through activation the purinergic P2Z receptors and thus lead to mycobacterial elimination [207, 208, 209]. Programmed cell death also occurs as a response to mycobacterial infection and is triggered by the pro-inflammatory cytokine tumor necrosis factor-α [210]. Mycobacterial proteins such as SecA2 and NuoG are also involved in suppressing apoptosis, among others by reducing ROS levels within mycobacterium-containing phagosomes [211, 212, 213, 214]. Interestingly, a transcriptional repressor has been identified that is responsible for escape from the phagosome and host cell necrosis induction [215]. Also, M. tuberculosis was found to promote necrosis through mitochondrial membrane disruption as well as blocking plasma membrane repair [216, 217]. Furthermore, the Sec2A-dependent export pathway enables secretion of mycobacterial superoxide dismutase which reduces intracellular ROS [106], while the product of the nuoG gene, a subunit of a type I NADH dehydrogenase, neutralizes ROS generated by the host NADPH oxidase heavy chain subunit (iNOS2), thereby inhibiting tumor necrosis factor-α-stimulated apoptosis [218]. Thus, multiple cell death programs may be active during an infection with M. tuberculosis, affecting the overall outcome [206].

DosR regulon: mycobacterial latency and reactivation switch

During latency, M. tuberculosis exists in a dormant or a non-replicating persistent state and survives within the hostile environment within granulomas where it is believed to withstand hypoxia, low pH, and high nitric oxide intermediates [219]. In this state, the mycobacteria downsize their metabolic activity resulting in a decrease in RNA and protein synthesis through upregulation of a regulon of a set of 48 genes known as the Dormancy Survival Regulator (DosR) regulon [220]. Two sensor kinases, DosS and DosT (members of the regulon), activate DosR, a transcription factor that further controls the 48 genes of the regulon. DosR itself can be activated following nitric oxide exposure through the activity of the transcriptional regulator WhiB6 [221]. DosS/DosR is a two-component regulatory system in which DosS, a heme-containing sensor, under hypoxic and stressed conditions undergoes autophosphorylation and subsequently transfers the phosphate to DosR. DosT is a gas sensor, that is activated in the ferrous state by the absence of an oxygen ligand or by the binding of nitric oxide or carbon monoxide [222]. Under limited oxygen conditions, mycobacteria express another Dos response protein, α-crystallin homolog protein (Acr), which is a chaperonin that by itself can upregulate approximately 50 further genes [223]. Interestingly, mycobacterial infection itself causes DosR regulon upregulation through activation of host heme oxygenase 1, which by virtue of generating carbon monoxide activates the DosR regulon [224]. Importantly, inhibition of the DosS-DosT/DosR sensor system hinders the entrance of infected mycobacteria into a latent state and results in reversion from the latent to the active state of infection [222]. The DosR regulon thus orchestrates metabolic mechanisms essential for mycobacteria to survive in the absence of respiration and to successfully and rapidly transition between respiring and non-respiring conditions without loss of viability.

Mycobacterial acid tolerance and proliferation within lysosomes

Whereas the ability of M. tuberculosis to arrest phagosome-lysosome fusion is key to the successful establishment of an intracellular mycobacterial infection, recent work suggests that a certain fraction of phagosome-restricted mycobacteria adapt themselves to resist the environment of the lysosomes. For example, mycobacteria lacking the virulence factor protein kinase G (PknG), and therefore fail to prevent phagosome-lysosome fusion within macrophages, have been found to survive lysosomal delivery in vivo, thus adapting to infection-specific host responses [50]. Interestingly, M. tuberculosis produces an acid-resistant protease, MarP, that allows the bacteria to maintain their pH at near neutrality in the acidic environment of phagosomes within activated macrophages, and phagolysosomal transfer of an acid-tolerant mycobacterial population has been observed to coincide with overexpression of MarP [51, 225]. During acid stress, MarP cleaves the peptidoglycan hydrolase, RipA (Rpf interaction protein), a process required for RipA’s activation. Thus, sustained peptidoglycan hydrolysis, a process required for cell elongation, separation of progeny cells, and cell wall homeostasis in growing cells, is essential for mycobacterial survival under acidic conditions [226]. It needs to be determined whether RipA activation is required for mycobacterial replication in acidic conditions or whether it regulates peptidoglycan hydrolysis. It also remains currently unknown which host factors are involved in the acid tolerance of mycobacteria inside the phagolysosomes.

Concluding remarks

The interaction of M. tuberculosis with their host macrophages is a tale of enormous complexity. While macrophages have evolved as being the prime cells involved in bacterial killing, M. tuberculosis is capable to manipulate the macrophage at virtually every level in order to ensure its own survival. As a result, M. tuberculosis continues to be one of the world’s leading pathogens, and, together with the increasing problem of acquisition of antibiotic resistance, highlights the necessity of a detailed understanding of the mechanisms of pathogenicity. Such knowledge, on the one hand, may be instrumental in the design of compounds and strategies to combat the pathogenicity of M. tuberculosis, while on the other hand, research into the interactions of this pathogen with host macrophages may continue to uncover hitherto unknown aspects of macrophage biology.

Notes

Acknowledgements

We thank Rajesh Jayachandran and Liem Nguyen for the critical reading of the manuscript.

Funding information

Work in our laboratories is funded by the Swiss National Science Foundation, the Gebert Ruff Foundation, the Optimus Foundation, the Canton of Basel (to JP), the European Molecular Biology Organization (EMBO, through a Long Term Fellowship awarded to SBDG), and DST-SERB (YSS/2015/000471) and DBT (BT/RLF/Re-entry/33/2014) to SBDG.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of BiotechnologyIndian Institute of Technology KharagpurKharagpurIndia
  2. 2.Department of Biochemistry, BiozentrumUniversity of BaselBaselSwitzerland

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