Mtb encounters a vastly changed environment, soon after it gets internalized by macrophages. The compartment it resides in, the phagosome, is acidified and devoid of important metal ions. It is flooded with reactive oxygen and nitrogen species. And steps will be soon taken by the macrophage to "mature" the phagosome with all kinds of lysosomal digestive enzymes. However, unlike most other bacteria species Mtb. has evolved solutions to each of these threats and, after making sure these are installed, it soon will enter a dormant state (de Chastellier, 2009; Flannagan et al, 2009). A combination of the host defense and the response of the infecting bacillus (active and passive) ensure suppression of bacterial metabolic activity and replication, resulting in a non-replicating state (Russell 2011, Russell et al. 2010).
Dayaram YK, Talaue MT, Connell ND, Venketaraman V.; ''Characterization of a glutathione metabolic mutant of Mycobacterium tuberculosis and its resistance to glutathione and nitrosoglutathione.''; PubMedEurope PMCScholia
Yang Y, Bazhin AV, Werner J, Karakhanova S.; ''Reactive oxygen species in the immune system.''; PubMedEurope PMCScholia
Nagy JM, Cass AE, Brown KA.; ''Purification and characterization of recombinant catalase-peroxidase, which confers isoniazid sensitivity in Mycobacterium tuberculosis.''; PubMedEurope PMCScholia
Madigan CA, Cheng TY, Layre E, Young DC, McConnell MJ, Debono CA, Murry JP, Wei JR, Barry CE, Rodriguez GM, Matsunaga I, Rubin EJ, Moody DB.; ''Lipidomic discovery of deoxysiderophores reveals a revised mycobactin biosynthesis pathway in Mycobacterium tuberculosis.''; PubMedEurope PMCScholia
Ouellet H, Ouellet Y, Richard C, Labarre M, Wittenberg B, Wittenberg J, Guertin M.; ''Truncated hemoglobin HbN protects Mycobacterium bovis from nitric oxide.''; PubMedEurope PMCScholia
Harrison PM, Arosio P.; ''The ferritins: molecular properties, iron storage function and cellular regulation.''; PubMedEurope PMCScholia
Dasgupta A, Sureka K, Mitra D, Saha B, Sanyal S, Das AK, Chakrabarti P, Jackson M, Gicquel B, Kundu M, Basu J.; ''An oligopeptide transporter of Mycobacterium tuberculosis regulates cytokine release and apoptosis of infected macrophages.''; PubMedEurope PMCScholia
Reddy PV, Puri RV, Khera A, Tyagi AK.; ''Iron storage proteins are essential for the survival and pathogenesis of Mycobacterium tuberculosis in THP-1 macrophages and the guinea pig model of infection.''; PubMedEurope PMCScholia
Vogt RN, Steenkamp DJ, Zheng R, Blanchard JS.; ''The metabolism of nitrosothiols in the Mycobacteria: identification and characterization of S-nitrosomycothiol reductase.''; PubMedEurope PMCScholia
Zhang Y, Lathigra R, Garbe T, Catty D, Young D.; ''Genetic analysis of superoxide dismutase, the 23 kilodalton antigen of Mycobacterium tuberculosis.''; PubMedEurope PMCScholia
Lee WL, Gold B, Darby C, Brot N, Jiang X, de Carvalho LP, Wellner D, St John G, Jacobs WR, Nathan C.; ''Mycobacterium tuberculosis expresses methionine sulphoxide reductases A and B that protect from killing by nitrite and hypochlorite.''; PubMedEurope PMCScholia
St John G, Brot N, Ruan J, Erdjument-Bromage H, Tempst P, Weissbach H, Nathan C.; ''Peptide methionine sulfoxide reductase from Escherichia coli and Mycobacterium tuberculosis protects bacteria against oxidative damage from reactive nitrogen intermediates.''; PubMedEurope PMCScholia
de Chastellier C.; ''The many niches and strategies used by pathogenic mycobacteria for survival within host macrophages.''; PubMedEurope PMCScholia
Wu CH, Tsai-Wu JJ, Huang YT, Lin CY, Lioua GG, Lee FJ.; ''Identification and subcellular localization of a novel Cu,Zn superoxide dismutase of Mycobacterium tuberculosis.''; PubMedEurope PMCScholia
Flannagan RS, Cosío G, Grinstein S.; ''Antimicrobial mechanisms of phagocytes and bacterial evasion strategies.''; PubMedEurope PMCScholia
Purwantini E, Mukhopadhyay B.; ''Conversion of NO2 to NO by reduced coenzyme F420 protects mycobacteria from nitrosative damage.''; PubMedEurope PMCScholia
Hugo M, Turell L, Manta B, Botti H, Monteiro G, Netto LE, Alvarez B, Radi R, Trujillo M.; ''Thiol and sulfenic acid oxidation of AhpE, the one-cysteine peroxiredoxin from Mycobacterium tuberculosis: kinetics, acidity constants, and conformational dynamics.''; PubMedEurope PMCScholia
Venugopal A, Bryk R, Shi S, Rhee K, Rath P, Schnappinger D, Ehrt S, Nathan C.; ''Virulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multienzyme complexes.''; PubMedEurope PMCScholia
Ryndak MB, Wang S, Smith I, Rodriguez GM.; ''The Mycobacterium tuberculosis high-affinity iron importer, IrtA, contains an FAD-binding domain.''; PubMedEurope PMCScholia
Bryk R, Lima CD, Erdjument-Bromage H, Tempst P, Nathan C.; ''Metabolic enzymes of mycobacteria linked to antioxidant defense by a thioredoxin-like protein.''; PubMedEurope PMCScholia
Farhana A, Kumar S, Rathore SS, Ghosh PC, Ehtesham NZ, Tyagi AK, Hasnain SE.; ''Mechanistic insights into a novel exporter-importer system of Mycobacterium tuberculosis unravel its role in trafficking of iron.''; PubMedEurope PMCScholia
Guimarães BG, Souchon H, Honoré N, Saint-Joanis B, Brosch R, Shepard W, Cole ST, Alzari PM.; ''Structure and mechanism of the alkyl hydroperoxidase AhpC, a key element of the Mycobacterium tuberculosis defense system against oxidative stress.''; PubMedEurope PMCScholia
Khare G, Gupta V, Nangpal P, Gupta RK, Sauter NK, Tyagi AK.; ''Ferritin structure from Mycobacterium tuberculosis: comparative study with homologues identifies extended C-terminus involved in ferroxidase activity.''; PubMedEurope PMCScholia
Braunstein M, Espinosa BJ, Chan J, Belisle JT, Jacobs WR.; ''SecA2 functions in the secretion of superoxide dismutase A and in the virulence of Mycobacterium tuberculosis.''; PubMedEurope PMCScholia
Miller CC, Rawat M, Johnson T, Av-Gay Y.; ''Innate protection of Mycobacterium smegmatis against the antimicrobial activity of nitric oxide is provided by mycothiol.''; PubMedEurope PMCScholia
Chauhan R, Mande SC.; ''Characterization of the Mycobacterium tuberculosis H37Rv alkyl hydroperoxidase AhpC points to the importance of ionic interactions in oligomerization and activity.''; PubMedEurope PMCScholia
Jaeger T, Budde H, Flohé L, Menge U, Singh M, Trujillo M, Radi R.; ''Multiple thioredoxin-mediated routes to detoxify hydroperoxides in Mycobacterium tuberculosis.''; PubMedEurope PMCScholia
Bashiri G, Squire CJ, Moreland NJ, Baker EN.; ''Crystal structures of F420-dependent glucose-6-phosphate dehydrogenase FGD1 involved in the activation of the anti-tuberculosis drug candidate PA-824 reveal the basis of coenzyme and substrate binding.''; PubMedEurope PMCScholia
Rho BS, Hung LW, Holton JM, Vigil D, Kim SI, Park MS, Terwilliger TC, Pédelacq JD.; ''Functional and structural characterization of a thiol peroxidase from Mycobacterium tuberculosis.''; PubMedEurope PMCScholia
Pathania R, Navani NK, Gardner AM, Gardner PR, Dikshit KL.; ''Nitric oxide scavenging and detoxification by the Mycobacterium tuberculosis haemoglobin, HbN in Escherichia coli.''; PubMedEurope PMCScholia
The first line of defense against infectious agents involves an active recruitment of phagocytes to the site of infection. Recruited cells include polymorhonuclear (PMN) leukocytes (i.e., neutrophils) and monocytes/macrophages, which function together as innate immunity sentinels (Underhill DM & Ozinsky A 2002; Stuart LM & Ezekowitz RA 2005; Flannagan RS et al. 2012). Dendritic cells are also present, serving as important players in antigen presentation for ensuing adaptive responses (Savina A & Amigorena S 2007). These cell types are able to bind and engulf invading microbes into a membrane-enclosed vacuole - the phagosome, in a process termed phagocytosis. Phagocytosis can be defined as the receptor-mediated engulfment of particles greater than 0.5 micron in diameter. It is initiated by the cross-linking of host cell membrane receptors following engagement with their cognate ligands on the target surface (Underhill DM & Ozinsky A 2002; Stuart LM & Ezekowitz RA 2005; Flannagan RS et al. 2012). When engulfed by phagocytes, microorganisms are exposed to a number of host defense microbicidal events within the resulting phagosome. These include the production of reactive oxygen and nitrogen species (ROS and RNS, RONS) by specialized enzymes (Fang FC et al. 2004; Kohchi C et al. 2009; Gostner JM et al. 2013; Vatansever F et al. 2013). NADPH oxidase (NOX) complex consume oxygen to produce superoxide radical anion (O2.-) and hydrogen peroxide (H2O2) (Robinson et al. 2004). Induced NO synthase (iNOS) is involved in the production of NO, which is the primary source of all RNS in biological systems (Evans TG et al. 1996). The phagocyte NADPH oxidase and iNOS are expressed in both PMN and mononuclear phagocytes and both cell types have the capacity for phagosomal burst activity. However, the magnitude of ROS generation in neutrophils far exceeds that observed in macrophages (VanderVen BC et al. 2009). Macrophages are thought to produce considerably more RNS than neutrophils (Fang FC et al. 2004; Nathan & Shiloh 2000).
The presence of RONS characterized by a relatively low reactivity, such as H2O2, O2˙− or NO, has no deleterious effect on biological environment (Attia SM 2010; Weidinger A & and Kozlov AV 2015). Their activity is controlled by endogenous antioxidants (both enzymatic and non-enzymatic) that are induced by oxidative stress. However the relatively low reactive species can initiate a cascade of reactions to generate more damaging “secondary� species such as hydroxyl radical (•OH), singlet oxygen or peroxinitrite (Robinson JM 2008; Fang FC et al. 2004). These "secondary" RONS are extremely toxic causing irreversible damage to all classes of biomolecules (Weidinger A & and Kozlov AV 2015; Fang FC et al. 2004; Kohchi C et al. 2009; Gostner JM et al. 2013; Vatansever F et al. 2013).
Although macrophages and neutrophils use similar mechanisms for the internalization of targets, there are differences in how they perform phagocytosis and in the final outcome of the process (Tapper H & Grinstein S 1997; Vierira OV et al. 2002). Once formed, the phagosome undergoes an extensive maturation process whereby it develops into a microbicidal organelle able to eliminate the invading pathogen. Maturation involves re-modeling both the membrane of the phagosome and its luminal contents (Vierira OV et al. 2002). In macrophages, phagosome formation and maturation follows a series of strictly coordinated membrane fission/fusion events between the phagosome and compartments of the endo/lysosomal network gradually transforming the nascent phagosome into a phagolysosome, a degradative organelle endowed with potent microbicidal properties (Zimmerli S et al. 1996; Vierira OV et al. 2002). Neutrophils instead contain a large number of preformed granules such as azurophilic and specific granules that can rapidly fuse with phagosomes delivering antimicrobial substances (Karlsson A & Dahlgren C 2002; Naucler C et al. 2002; Nordenfelt P and Tapper H 2011). Phagosomal pH dynamics may also contribute to the maturation process by regulating membrane traffic events. The microbicidal activity of macrophages is characterized by progressive acidification of the lumen (down to pH 4–5) by the proton pumping vATPase. A low pH is a prerequisite for optimal enzymatic activity of most late endosomal/lysosomal hydrolases reported in macrophages. Neutrophil phagosome pH regulation differs significantly from what is observed in macrophages (Nordenfelt P and Tapper H 2011; Winterbourn CC et al. 2016). The massive activation of the oxidative burst is thought to result in early alkalization of neutrophil phagosomes which is linked to proton consumption during the generation of hydrogen peroxide (Segal AW et al. 1981; Levine AP et al. 2015). Other studies showed that neutrophil phagosome maintained neutral pH values before the pH gradually decreased (Jankowski A et al. 2002). Neutrophil phagosomes also exhibited a high proton leak, which was initiated upon activation of the NADPH oxidase, and this activation counteracted phagosomal acidification (Jankowski A et al. 2002).
The Reactome module describes ROS and RNS production by phagocytic cells. The module includes cell-type specific events, for example, myeloperoxidase (MPO)-mediated production of hypochlorous acid in neutrophils. It also highlights differences between phagosomal pH dynamics in neutrophils and macrophages. The module describes microbicidal activity of selective RONS such as hydroxyl radical or peroxynitrite. However, detection of any of these species in the phagosomal environment is subject to many uncertainties (Nüsse O 2011; Erard M et al. 2018). The mechanisms by which reactive oxygen/nitrogen species kill pathogens in phagocytic immune cells are still not fully understood.
Carboxymycobactin and mycobactin exchange their iron loads. This interplay between polar and nonpolar siderophore is unique to Mtb. However, mycobactin can gather iron from nonpolar regions of the host cell by itself too (Madigan et al. 2012).
Due to their abundance in Mycobacteria, lipids fulfill a buffering role in the tolerance of antioxidants. Lipid production is triggered by oxidative stress. The peroxidated lipid can be reduced by AhpC (Chauhan & Mande 2001).
MsrA and MsrB are enzymes that can both reduce the S- and R-stereoisomers of (peptidyl-) methionine sulfoxide. The exact nature of the accompanying thioredoxin is not settled, but it is predicted to be TrxA. The whole methionine-MsrA/B-thioredoxin-and-reductase system is an important part of NO detoxification in Mtb (St John et al. 2001, Lee et al. 2009).
The IrtA transporter has a flavin reductase domain very much like Fre from E.coli that can probably act as ferrisiderophore reductase to relieve incoming loaded mycobactin from its Fe3+ by reducing it to Fe2+. Furthermore Rv2895c, which co-precipitates with IrtB and therefore is probably part of the transporter complex, has such a domain as well (Farhana et al. 2008).
Peroxiredoxin AhpC gets its reducing equivalents through a cascade of proteins via AhpD, a disulfide reductase, DlaT, a lipoylated disulfide reductase, and, finally, from lpdC, the NADH-dependent dihydrolipoyl reductase. The latter two are also part of the pyruvate dehydrogenase complex (Venugopal et al. 2011).
AhpC is an unusual peroxiredoxin - it has three cysteine residues that participate in the reduction of toxic peroxynitrite to nitrite. In a second step, another thioredoxin or the reductase chain AhpD/DlaT/Lpd is needed for reactivation (Guimaraes et al. 2005).
Iron-containing superoxide dismutase is localized both within and without the bacterium where it catalyzes the reduction of superoxide (Zhang et al. 1991).
Copper-containing superoxide dismutase is localized in the plasma membrane of the bacterium where it catalyzes the reduction of superoxide (Wu et al. 1998).
MscR is an alcohol dehydrogenase that can probably reduce nitrosomycothiol with the help of NADH/H+ reducing equivalents to the sulfinamide which then presumably decomposes to the thione and ammonia (Vogt et al. 2003).
The ABC-type transporter IrtA, probably complexed with IrtB and ViuB (Rv2895c), specifically transports iron-loaded mycobactin into the cytosol (Ryndak et al. 2009).
Peroxiredoxin AhpC gets its reducing equivalents through a cascade of proteins via AhpD, a disulfide reductase, DlaT, a lipoylated disulfide reductase, and, finally, from lpdC, the NADH-dependent dihydrolipoyl reductase. The latter two are also part of the pyruvate dehydrogenase complex (Venugopal et al. 2011).
Peroxiredoxin AhpC gets its reducing equivalents through a cascade of proteins via AhpD, a disulfide reductase, DlaT, a lipoylated disulfide reductase, and, finally, from lpdC, the NADH-dependent dihydrolipoyl reductase. The latter two are also part of the pyruvate dehydrogenase complex (Venugopal et al. 2011).
Most gamma-glutamyl transpeptidases (GGT) cleave both glutathione and glutathione conjugates. Mtb GGT cleaves nitrosoglutathione )GSNO) to Cys(NO)-Gly, thus making it soluble for transport into the cytosol (Dayaram et al. 2006).
Mycobactin is the lipophilic siderophore of Mtb. After export into the periplasmic space, it localizes to the bacterium's cell wall. The responsible transporter activity is still unknown (Madigan et al. 2012).
Heme proteins, especially the truncated globin GlbN in Mtb possess oxygen-dependent nitric oxide dioxygenase activity, where the heme that is oxidized to ferriheme in the process will need to be reduced in a second step to activate the protein again. The responsible heme protein reductase is unknown (Ouellet et al. 2002, Pathania et al. 2002).
Carboxymycobactin is the more polar siderophore of Mtb and it is localized, after its secretion, in the phagosomal lumen. The transporters for export and secretion of this molecule are still unknown (Madigan et al. 2012).
Tpx, like AhpC, is a peroxiredoxin with alkylhydroperoxidase, peroxidase, and peroxynitritase activities. Peroxynitrite is detoxified to nitrite (Jaeger et al. 2006, Rho et al. 2006).
The archaeal cofactor F420 reduces toxic nitrogen dioxide that can be produced when NO and oxygen combine. F420 itself is reduced by the enzyme Fgd (Purwantini & Mukhopadyay 2008).
The peroxiredoxin AhpE participates in reducing peroxynitrite to nitrite, but how it is recycled back to the reduced form is still unknown (Hugo et al. 2009).
Glutathione is taken up by the bacterium by an ABC transporter called the oligopeptide importer. OppA determines substrate specificity (Dasgupta et al. 2010).
Mtb bacterioferritin BfrB oxidises Fe2+ to Fe3+, migrates them to its centre, and collects thousands of them as FeO(OH) in the central mineral core from which they can be later remobilised (Harrison & Arrosio 1996, Khare et al. 2011).
Mtb bacterioferritin BfrA oxidises Fe2+ to Fe3+, migrates them to its centre, and collects thousands of them as FeO(OH) in the central mineral core from which they can be later remobilised (Reddy et al. 2012).
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phagocytesThe presence of RONS characterized by a relatively low reactivity, such as H2O2, O2˙− or NO, has no deleterious effect on biological environment (Attia SM 2010; Weidinger A & and Kozlov AV 2015). Their activity is controlled by endogenous antioxidants (both enzymatic and non-enzymatic) that are induced by oxidative stress. However the relatively low reactive species can initiate a cascade of reactions to generate more damaging “secondary� species such as hydroxyl radical (•OH), singlet oxygen or peroxinitrite (Robinson JM 2008; Fang FC et al. 2004). These "secondary" RONS are extremely toxic causing irreversible damage to all classes of biomolecules (Weidinger A & and Kozlov AV 2015; Fang FC et al. 2004; Kohchi C et al. 2009; Gostner JM et al. 2013; Vatansever F et al. 2013).
Although macrophages and neutrophils use similar mechanisms for the internalization of targets, there are differences in how they perform phagocytosis and in the final outcome of the process (Tapper H & Grinstein S 1997; Vierira OV et al. 2002). Once formed, the phagosome undergoes an extensive maturation process whereby it develops into a microbicidal organelle able to eliminate the invading pathogen. Maturation involves re-modeling both the membrane of the phagosome and its luminal contents (Vierira OV et al. 2002). In macrophages, phagosome formation and maturation follows a series of strictly coordinated membrane fission/fusion events between the phagosome and compartments of the endo/lysosomal network gradually transforming the nascent phagosome into a phagolysosome, a degradative organelle endowed with potent microbicidal properties (Zimmerli S et al. 1996; Vierira OV et al. 2002). Neutrophils instead contain a large number of preformed granules such as azurophilic and specific granules that can rapidly fuse with phagosomes delivering antimicrobial substances (Karlsson A & Dahlgren C 2002; Naucler C et al. 2002; Nordenfelt P and Tapper H 2011). Phagosomal pH dynamics may also contribute to the maturation process by regulating membrane traffic events. The microbicidal activity of macrophages is characterized by progressive acidification of the lumen (down to pH 4–5) by the proton pumping vATPase. A low pH is a prerequisite for optimal enzymatic activity of most late endosomal/lysosomal hydrolases reported in macrophages. Neutrophil phagosome pH regulation differs significantly from what is observed in macrophages (Nordenfelt P and Tapper H 2011; Winterbourn CC et al. 2016). The massive activation of the oxidative burst is thought to result in early alkalization of neutrophil phagosomes which is linked to proton consumption during the generation of hydrogen peroxide (Segal AW et al. 1981; Levine AP et al. 2015). Other studies showed that neutrophil phagosome maintained neutral pH values before the pH gradually decreased (Jankowski A et al. 2002). Neutrophil phagosomes also exhibited a high proton leak, which was initiated upon activation of the NADPH oxidase, and this activation counteracted phagosomal acidification (Jankowski A et al. 2002).
The Reactome module describes ROS and RNS production by phagocytic cells. The module includes cell-type specific events, for example, myeloperoxidase (MPO)-mediated production of hypochlorous acid in neutrophils. It also highlights differences between phagosomal pH dynamics in neutrophils and macrophages. The module describes microbicidal activity of selective RONS such as hydroxyl radical or peroxynitrite. However, detection of any of these species in the phagosomal environment is subject to many uncertainties (Nüsse O 2011; Erard M et al. 2018). The mechanisms by which reactive oxygen/nitrogen species kill pathogens in phagocytic immune cells are still not fully understood.
Annotated Interactions