INTRODUCTION — The human host serves as the only natural reservoir for Mycobacterium tuberculosis. The ability of the organism to efficiently establish latent infection has enabled it to spread to nearly one-fourth of the world's population . According to the 2021 World Health Organization report, in 2020, an estimated 9.9 million new cases of tuberculosis (TB) and 1.3 million deaths among people without human immunodeficiency virus (HIV) infection were reported worldwide . The progression from latent TB infection to active disease remains poorly understood. Given the magnitude of the health problem and the emergence of drug-resistant strains of the organism, a better understanding of the immunology of this disease and the development of an effective vaccine are highly desirable. (See "Epidemiology of tuberculosis".)
The immunology of M. tuberculosis will be reviewed here. The microbiology and pathogenesis of this infection, including virulence factors, tropism for the lungs, and latency factors, are discussed separately. (See "Tuberculosis: Natural history, microbiology, and pathogenesis".)
IMMUNOLOGY — The majority of individuals in the general population who become infected with M. tuberculosis never develop clinical disease . This demonstrates that the innate and adaptive immune response of the host in controlling TB infection is effective. Mycobacterial and host factors that adversely affect these two arms of the immune system contribute to latent tuberculosis infection (LTBI) and active disease.
Innate immunity — The pathophysiology of innate immune response during first encounter of M. tuberculosis with lung cells remains poorly characterized. In the average human alveolus, there are more than 28,000 epithelial cells (pneumocytes) and about 50 macrophages [4,5]. Mouse studies have shown that after about 14 days of infection, the predominant cell type infected with M. tuberculosis is the myeloid dendritic cell rather than the alveolar macrophage . Thus, during the very early phase of lung infection, the interaction of M. tuberculosis with lung epithelial cells may affect later dendritic cell and alveolar macrophage migration and ultimately clinical outcome. Little is known about what happens during this early phase.
Once M. tuberculosis comes into contact with dendritic or alveolar macrophages, the interaction of these cells with M. tuberculosis first involves recognition by these cells of microbe-associated molecular patterns (MAMPs) or pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) located on the cell surface or in the cytosol . Distinct sets of macrophage PRRs recognize distinct sets of PAMPs of M. tuberculosis. These PRRs serve to trigger innate immune response against molecules recognized to be foreign to the host cell. The recognition of M. tuberculosis by a group of PRRs called toll-like receptors (TLRs) triggers cell signal transduction that induces a proinflammatory response that is supposed to control the infection . However, M. tuberculosis has evolved to subvert these host responses for its own survival in the host.
Toll-like receptors — TLR is a mammalian homologue of the toll receptor in the insect Drosophila that plays a role in conferring immunity of the insect against yeast infections . TLRs exhibit pattern recognition of organism group characteristic molecules, such as the lipopolysaccharide of gram-negative organisms, peptidoglycan of gram-positive organisms, double-stranded ribonucleic acid (RNA) of viruses, and lipoteichoic acids of yeasts [10-12]. (See "Toll-like receptors: Roles in disease and therapy".)
TLR2 and TLR4 are important for the recognition of M. tuberculosis PAMPs [10,13]. M. tuberculosis is killed by activation of the TLR2 by the bacterial lipoprotein (19-kD) in both mouse and human macrophages . However, the killing in the mouse macrophage was dependent on the intracellular nitric oxide pathway, while in the human macrophage, it was independent of this pathway . That is, the human TLR2 activation by the 19-kD lipoprotein killed M. tuberculosis, but no nitric oxide production could be demonstrated.
Further characterization of the mechanism of killing of M. tuberculosis in human macrophages has identified that TLR1/2 activation up-regulates expression of the vitamin D receptor as well as vitamin D-1-hydroxylase . The expression of vitamin D receptor-related genes leads to an increased expression of cathelicidin, an antimicrobial peptide, which is then responsible for inhibition of growth of M. tuberculosis.
TLR2 and TLR4 require MyD88, an intracellular adapter protein required for inducing early innate immune response to pathogens . However, in murine macrophages, M. tuberculosis can activate macrophages via an MyD88-independent pathway . Furthermore, M. tuberculosis infection of MyD88-deficient C57BL/6 mouse is fatal despite an intact adaptive immune response . When the mice were vaccinated with Mycobacterium bovis Bacillus Calmette-Guérin (BCG), they were protected from M. tuberculosis infection, indicating that the adaptive immune response functioned normally in this MyD88-deficient mouse. The adaptive immune response was not sufficient to compensate for the innate immune defect in unvaccinated mice, suggesting that the innate immune response plays a substantive role in protection against TB, at least in the mouse model .
Genetic polymorphism found in TLR2/4 has been shown to affect infection outcomes in some populations. TLR4 polymorphism among individuals in India has been reported to be associated with increased severity of TB, while, in other populations, no such association has been found [19,20]. Such differential host response may also be affected by M. tuberculosis strain differences. Human studies have shown that some M. tuberculosis strains preferentially activate TLR2, whereas others activate TLR4 .
Other cell surface pattern recognition receptors — In addition to TLRs, there is a multitude of cell surface receptors that recognize M. tuberculosis PAMPs. They include C-type lectins, which comprise a family of Ca2+-dependent glycan-binding proteins such as mannose receptors, DC-SIGN (receptor for lipoglycan lipoarabinomannan), dectin-1 (its ligand not determined), dectin-2 (binds to mannose-capped lipoarabinomannan), collectin-11 (receptor for mannose-capped lipoarabinomannan), and macrophage-inducible C-type lectin or Mincle, which binds mycobacterial glycolipid trehalose dimycolate (TDM); and scavenger receptors (eg, macrophage receptor with collagenous structure or MARCO, which is also a receptor for TDM), reviewed elsewhere [22-30].
Cytosolic surveillance pathway — Cytosolic surveillance pathway (CSP) is activated by a variety of PAMPs that engage cytosolic PRRs or sensors that lead to innate immune responses involving induction of Type I interferons [31,32]. PRRs or ligands that recognize M. tuberculosis PAMPs include nucleotide oligomerization domain (NOD)-like receptors (NLRs; which recognize muramyl dipeptide), cyclic GMP-AMP synthase (engaged by M. tuberculosis deoxyribonucleic acid [DNA]), and stimulator of interferon genes (STING), which is activated by bacterial second messenger cyclic-di-nucleotide [33-36]. CSP activation per se, however, does not always to lead to effective control of M. tuberculosis infection. M. tuberculosis has evolved to evade these host antibacterial innate immune responses.
Evasion mechanisms — After the tubercle bacterium gets taken up by macrophages, it uses several strategies to evade early intracellular antimicrobial mechanisms inside these target cells. Some of the mechanisms previously thought to contribute to these strategies include:
●Resistance to reactive oxygen intermediates (ROIs)
●Inhibition of phagosome-lysosome fusion
●Inhibition of phagosome acidification
●Escape from the phagosomal compartment into the cytoplasmic space
During the initial stages of infection, tubercle bacilli stimulate the migration of neutrophils and mononuclear phagocytes to the site of infection. M. tuberculosis possesses a variety of products that enable it to constitutively resist ROIs produced by these cells, which are usually toxic to other pathogens. Lipoarabinomannan serves as a scavenger for oxygen intermediates . Entry of the organism into macrophages via complement receptors (CR1 and CR3) does not stimulate ROI production [38,39]. Cyclopropanated mycolic acids of the cell wall may help the organism resist hydrogen peroxide . Furthermore, mycolic acids can inhibit the expression of interleukin (IL)-12, monocyte chemotactic protein 1 (MCP-1), and tumor necrosis factor (TNF)-alpha in a toll-like receptor 2 (TLR-2)-dependent manner in macrophages . Thus, drugs targeted against mycolic acid biosynthesis can exert an antibacterial effect early in the phase of M. tuberculosis infection or during transition from latent infection to active disease, when mycolic acid synthesis is most active.
In Escherichia coli and Salmonella, the oxyR gene serves as a regulatory element in response to oxidative stress. In contrast, the oxyR homologue in M. tuberculosis contains numerous deletions and is believed to be nonfunctional [42,43]. The constitutive anti-ROI products of M. tuberculosis described above may obviate the need for such a gene in this organism.
M. tuberculosis taken up by macrophages can interfere with phagosome maturation. Phagosome maturation requires the conversion of Rab5 into GTP-bound Rab7 and the production of phosphatidylinositol 3-phosphate (PI3P) in the phagosomal membrane . Two secreted bacterial products PtpA (a tyrosine phosphatase) and NdkA (a GTPase) are believed to be involved in Rab7 inactivation [45,46].
Fusion of lysosomes with phagosomes leads to the release of microbicidal lysosomal contents. However, M. tuberculosis can inhibit phagosome-lysosome fusion inside murine peritoneal macrophages more than one week after infection [47,48]. When the macrophages were observed only two hours after infection in another study, 85 percent of the phagosomes containing M. tuberculosis or BCG strains were fused, but the number of such phagosomes declined over time in cells infected with live H37Rv or Ra strains of M. tuberculosis . M. tuberculosis strains incubated with an antibody raised against BCG did not inhibit fusion, but they remained viable inside macrophages . Thus, while there is evidence that M. tuberculosis can inhibit phagosome-lysosome fusion, the relevance of this mechanism in ensuring intracellular survival is not clear.
Both Mycobacterium avium and M. tuberculosis can inhibit vacuolar acidification [50,51]. They do this by selectively excluding the proton-ATPase from the phagosome. While this inhibitory mechanism may be important during the initial encounter of the organism with macrophages, it is not clear how much of a role this plays in the ultimate intracellular fate of the pathogen. Macrophages activated by cytokines can acidify phagosomes, but the acidification itself may not contribute to significant killing of mycobacteria inside such cells .
M. tuberculosis is also known to interfere with antigen presentation by major histocompatibility complex (MHC) class II molecules, which is important for priming CD4 T cells . Such interference could lead to resistance of M. tuberculosis to acquired immunity in the host and, hence, may contribute to bacterial persistence, a characteristic feature of this organism. M. tuberculosis products suggested to inhibit macrophage presentation of MHC class II molecules include lipoarabinomannan, 25 kDa glycoprotein, and a 19 kDa lipoprotein [37,54,55].
The traditional view is that when M. tuberculosis is engulfed by macrophages or dendritic cells, it resides inside the phagosomal compartment and that it does not escape into the cytosol. However, data suggest that the organism can enter the cytosol and that this is dependent on two major secreted M. tuberculosis proteins, early secretory antigenic target 6 (ESAT-6) and culture filtrate protein (CFP)-10, encoded by the Esx-1 locus . ESAT-6 has been shown to have a membranolytic effect in vitro [57,58]. In the cytosol, mycobacterial cell wall component N-glycolyl muramyl dipeptide is believed to induce the production of type I interferons by binding to the intracellular PRR nucleotide oligomerization domain 2 (NOD2) and that the induction of type I interferons is dependent on intact Esx-1 system [59,60]. ESAT-6 may promote access to the cytosol of other M. tuberculosis immunostimulatory products that activate the NLRP3 inflammasome complex that promotes caspase-I-dependent secretion of type I interferons . The effect of type I interferon production on outcome M. tuberculosis infection outcome is not clear.
Reactive nitrogen intermediates — Several studies have focused on the role of reactive nitrogen intermediates (RNI) in clearing infection before acquired immunity develops. In mice, RNIs are the only known macrophage effector molecules associated with killing of M. tuberculosis. A murine macrophage cell line expressing RNI but defective in ROI expression was able to kill a virulent strain of M. tuberculosis after stimulation with interferon (IFN)-gamma .
Additional evidence for the importance of RNI in controlling M. tuberculosis infection in mice is illustrated by the following observations:
●Mortality in mice infected with M. tuberculosis is increased when inducible nitric oxide synthase (NOS2 or iNOS), which leads to RNI expression, is blocked by nitric oxide synthase inhibitors .
●IFN-gamma is a potent stimulus of NOS2 expression in mice. Mice with disrupted IFN-gamma or NOS2 genes become highly susceptible to M. tuberculosis infections [64,65].
Human macrophages do not express NOS2 when exposed to IFN-gamma, and NOS2 expression in peripheral blood-derived macrophages is difficult to demonstrate. However, several studies have provided evidence for NOS2 expression by alveolar macrophages obtained from bronchial alveolar lavage (BAL) fluid of patients with TB [66-68].
Thus, human NOS2 may require factors other than those that stimulate NOS2 expression in murine macrophages. RNIs may play an important role in the initial (innate immunity) as well as the later control (acquired immunity) of M. tuberculosis infection.
There is epidemiologic evidence supporting the importance of RNIs in TB control. A study in New York City found that the most common drug-susceptible strain of M. tuberculosis circulating in the city (C strain) during the early 1990s was resistant to RNIs generated in vitro and was associated with injection drug use . This strain was used to identify a novel gene called noxR1. Expression of this gene in nonpathogenic strains of E. coli or Mycobacterium smegmatis led to increased resistance to RNIs and ROIs in vitro .
Another protein, alkyl hydroperoxidase subunit protein, expressed by gene ahpC of M. tuberculosis also protects human cells from necrosis and apoptosis caused by RNIs . AhpC is believed to detoxify peroxynitrite, a potent oxidant generated from the reaction of nitric oxide and superoxide anion (O2-) . Peroxynitrite-induced damage has been suggested to be repaired by methionine sulfoxide reductase encoded by msrA . Another gene noxR3 of M. tuberculosis has been reported to protect Salmonella typhimurium against oxidative and nitrosative stress .
Interferon-gamma — In human macrophages, the effect of IFN-gamma in killing M. tuberculosis has not been demonstrated definitively. In one study, for example, cells preincubated with IFN-gamma enhanced the intracellular proliferation of M. tuberculosis; in comparison, killing of another intracellular organism, Leishmania, was increased .
However, the coadministration of IFN-gamma with calcitriol (the most active metabolite of vitamin D), which causes monocytes to mature in vitro, leads to intracellular killing of M. tuberculosis . Calcitriol independently stimulates NOS2 production and suppresses growth of M. tuberculosis inside the human macrophage-like cell line, HL-60 .
Transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha) has been demonstrated to be an essential mediator of IFN-gamma-dependent control of M. tuberculosis in murine macrophages infected in vitro and in mice disrupted in HIF-1alpha . Furthermore, nitric oxide has been demonstrated to contribute to HIF-1alpha activation and also inhibit nuclear factor-kappa-B activity to prevent macrophage proinflammatory responses, which suggests that nitric oxide may serve as a signaling molecule that activates macrophages instead of or in addition to being an antibacterial factor .
Other cytokines — In addition to the role that IFN-gamma plays in M. tuberculosis control described above, other cytokines also contribute. One important cytokine is TNF-alpha. Its role in controlling latent infection with M. tuberculosis in humans has been dramatically demonstrated by multiple reports of reactivation TB occurring in individuals treated for rheumatoid arthritis or Crohn disease with anti-TNF-alpha (infliximab) or TNF-alpha receptor (etanercept) antibodies [80-82]. TNF-alpha is also important for proper granuloma formation (see below). Persistently infected mice treated with neutralizing anti-TNF-alpha antibody develop granuloma disorganization, which eventually kill the mice . IFN-gamma and IL-12 levels in these mice are not affected. Mice deficient in this cytokine or TNF-alpha receptor are highly susceptible to M. tuberculosis infection [84,85].
The role of other cytokines in outcome after M. tuberculosis infection is less clear. IL-10 produced by macrophages has an antiinflammatory effect. However, IL-10-disrupted mice are not any more resistant to M. tuberculosis infection than wild-type mice . The role of another suppressive cytokine transforming growth factor-beta in infection outcome in mice or humans remains unresolved .
Nutrient deprivation — Nutrient limitation by macrophages is another innate immunity-related tool for control of M. tuberculosis. M. tuberculosis engulfed into a phagosomal compartment must access nutrients and carbon source for its persistence. Macrophages limit access of glucose and lipids to M. tuberculosis residing inside phagosomal compartments, but M. tuberculosis has developed a strategy to utilize lipids derived from host cell's triacylglycerol and cholesterol, which accumulate in the phagosome as lipid droplets . Cells containing such lipid droplets are often referred to as foamy macrophages. Vitamin D, however, can prevent M. tuberculosis-induced lipid droplet accumulation .
Further study suggests that lipid droplets in activated macrophages form as part of a host defense mechanism and that M. tuberculosis can access lipids in the absence of lipid droplets . It has been suggested that IFN-gamma-driven, HIF-1alpha-dependent signaling pathway redistributes macrophage lipids into lipid droplets and that this is a host-protective adaptive immune response against M. tuberculosis.
Cellular immunity — Cellular immunity may contribute to the protective response against TB, but the specific correlates of such protective response have not yet been well established in human cell-mediated immunity.
Macrophages as well as other phagocytic cells such as dendritic cells carry phagocytized M. tuberculosis to draining lymph nodes where they present M. tuberculosis antigens to T cells. The presentation of antigens to T cells induces cellular immune response. This occurs two to six weeks after infection with M. tuberculosis. This response can be demonstrated clinically by the development of a delayed-type hypersensitivity (DTH) response to intradermally injected tuberculin or purified protein derivative (PPD). One study of T cell responses in persistently anergic patients with documented pulmonary TB demonstrated that T cells produced IL-10 but not IFN-gamma and failed to proliferate in vitro following stimulation with PPD . By contrast, T cells from PPD-positive patients produced both IL-10 and IFN-gamma and displayed a dramatic proliferative response to PPD stimulation.
The DTH response per se does not correlate with protection against TB, since numerous BCG vaccination trials have demonstrated that disease can occur in those who mount a DTH response . As a result, the protective T cell response must be distinguished from the T cell response associated with DTH.
IFN-gamma release assays have been developed; these are in vitro, whole blood-based tests to measure T cell activation. The assays are an alternative to the tuberculin skin test for detection of latent M. tuberculosis infection in human hosts [93-97]. The test measures IFN-gamma released into blood from T cells when they are activated by M. tuberculosis antigens in vitro. The tests use antigens specific to M. tuberculosis including ESAT-6 and CFP-10 [93,94]. These proteins are encoded by genes located within the region of difference 1 (RD1) of the M. tuberculosis genome and are absent in vaccine strain BCG or M. bovis. This enables the test to differentiate those latently infected with M. tuberculosis from those vaccinated with BCG. (See "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults".)
The importance of T cells in the protective immune response against TB was first demonstrated in mice; adoptive transfer of T cells from BCG-immunized mice protected irradiated recipient mice from infection [98,99]. Other animal studies showed that this protective response was mediated by CD4-bearing T cells [100,101]. If it is assumed that the DTH response is mediated by CD4+ Th1 cells, the wide range of protection (0 to 80 percent) demonstrated by numerous BCG trials suggest that CD4+ T cells are not sufficient for protection and that other cells must be involved . However, the greatly increased risk of TB with HIV infection, in which CD4+ T cells become depleted, suggests that these cells are important for protection against TB in humans. CD4+ T cells exert their effector function by producing IFN-gamma, which activates macrophages. This response is important, particularly during early phase of an infection. In one study, in CD4-disrupted mice, levels of IFN-gamma in the lungs, while diminished early in infection, reached levels found in wild-type mice after about three weeks, suggesting that other cell types (CD8+ cells) can compensate for the decreased cytokine expression by CD4 T cells . Finally, in addition to the role of cytokines produced by CD4+ cells, apoptosis of infected cells by CD4+ T cells may contribute to controlling infection. However, published reports on the role of apoptosis in M. tuberculosis infection control remain equivocal [103,104].
Cytotoxic T lymphocytes (CTLs) have been implicated in protection against M. tuberculosis, and active investigation into the details of this mechanism is ongoing.
●Mice with disruption of the beta-2 microglobulin gene fail to control infection with a virulent strain of M. tuberculosis (Erdman) despite having intact CD4+ and cytolytic gamma-delta T cells . A beta2-microglobulin-deficient mouse is unable to present antigens through MHC class I and class I-like molecules.
●Another study using different strains of gene-disrupted mice found that perforin contributed only partially to the protective ability of CTLs, but beta-2-microglobulin-dependent T cell populations distinct from CD8(+) T cells contributed to immunity against M. tuberculosis infection. Protection was also associated with transporter associated with antigen processing (TAP) pathways, but TAP-independent mechanisms also played a role .
●Mice immunized with Mycobacterium vaccae can generate CD8+ T cells that express IFN-gamma and that are lytic to macrophages infected with M. tuberculosis .
●Live mycobacteria activate more CD8+ T cells than dead organisms or PPD .
Antigen-presenting pathways other than MHC class I or class II that stimulate this type of CTL response have been explored. One such pathway, CD1-restricted CTL stimulation, involves MHC-like cell surface molecules that process and present nonpeptide antigens to T cells . In patients with active TB, two types of T cells that recognize M. tuberculosis lipid and lipoglycan antigens presented by CD1b-bearing cells were found, "double negative" (DN) CD4-/CD8- T cells and CD8+ T cells . These cells were both capable of lysing macrophages (CD-1 bearing cells) infected with M. tuberculosis .
However, cell lysis would not necessarily lead to protection in the absence of bacterial killing. CTL-mediated cell lysis involves two pathways: a degranulation pathway that generates perforin and granzymes, and a Fas-FasL-dependent pathway that induces apoptosis of the target cell [110,111]. Studies with perforin gene-disrupted mice showed that this pathway was not essential for early protection against M. tuberculosis infection [112,113]. Another study showed that perforin-disrupted mice eventually did succumb to infection at a later time point, suggesting that the protection is partially dependent on perforin . Coculturing DN and CD8+ T cell lines with CD1 cells infected with M. tuberculosis revealed that DN CD1-restricted cells had no effect on the viability of the organism, while CD8+ CD1-restricted T cells reduced the number of colony forming units by 35 to 50 percent .
This bacterial killing is mediated by granulysin, a protein found in the granules of human CTLs and natural killer cells, but not in murine cells . Granulysin is present in CD1-restricted CD8+ T cells but not in CD1-restricted DN T cells. Granulysin, a member of the saposin-like protein family, induce blister-like lesions on the surface of M. tuberculosis .
There also appears to be a role for CD8+ alpha beta TCR+ cells, which recognize antigens bound to MHC class I. In one study, for example, two human TCR alpha beta+ CD8+ T cell lines specific for M. tuberculosis antigens recognized lipid antigens when presented by CD1a or CD1c antigen-presenting cells and displayed both cytotoxicity and cytokine responses .
5'-adendomsinephosphosulfate reductase (CysH), an enzyme essential for the production of reduced sulfur-containing metabolites, has been shown to be important for M. tuberculosis during the chronic infection phase . Resistance to nitrosative and oxidative stress (RNI and ROI) may be the mechanism of this protection .
Granuloma formation — In addition to the specific cell-mediated protective response involved in M. tuberculosis elimination, granuloma formation is an important mechanism of the host to control infection. Granuloma formation requires balanced expression of cytokines and chemokines, including RANTES (Regulated on Activation, Normal T cell Expressed, and Secreted), MIP1-alpha, MIP1-beta, MCP-1, MCP-3, MCP-5, and IP10 [117,118]. Chemokine receptors also determine proper formation of granulomas and, with M. tuberculosis infection, the expression of CCR5 (receptor for RANTES, MIP1-alpha, and MIP1-beta) increases in macrophages . CCR2-disrupted mice are more susceptible to M. tuberculosis than the wild-type mice . CCR2 is a receptor for MCP-1, -3, and -5. MCP-1-disrupted mice, however, are not susceptible .
M. tuberculosis disrupted in an operon called mce1 was shown to become hypervirulent in the mouse model of TB . This hypervirulence was associated with aberrant proinflammatory cell migration to the site of infection in the mouse lungs and poor granuloma formation. The mce1 operon mutant was unable to stimulate MCP-1 and TNF-alpha expression by murine macrophages . Disruption of the mce1 operon may alter the cell wall architecture and thus exert an effect on host granulomatous response . Indeed, an untargeted metabolomics analysis of the cell wall lipids of the mce1 operon mutant showed more than 400 lipids that were significantly altered from those of wild-type M. tuberculosis , indicating that changes in cell wall lipid contents affect host immune response. M. tuberculosis mutant defective in trans-cyclopropanation of mycolic acids induced larger sized granulomas in mouse lungs than did the wild-type M. tuberculosis . These observations suggested that alteration in the cell wall lipid composition or its remodeling can greatly affect host immune response and that a certain level of proinflammatory response induced by M. tuberculosis itself is necessary for proper granuloma formation that is protective both to the host and the bacterium. Thus, the granuloma is not only a host protective factor but may serve as a shelter constructed by the tubercle bacterium itself for its long-term survival in the host and that bacterial cell wall lipids may play an important role in this host-pathogen homeostatic interaction.
Humoral immunity — Early studies regarding role of humoral immunity in TB protection have shown mixed observations and include the following range of findings:
●Passive transfer experiments of serum from BCG-vaccinated animals or M. tuberculosis-infected animals and humans to other animals have provided conflicting evidence of protection .
●Antibodies against a variety of mycobacterial antigens, including lipid and carbohydrate products, can be demonstrated in both asymptomatic PPD-positive persons and in patients who develop active disease.
●M. tuberculosis strains incubated with an antibody raised against BCG promoted phagosome-lysosome fusion, but the viability of such strains inside macrophages was not affected .
●Transgenic mice unable to make immunoglobulin (Ig)M become more susceptible to M. tuberculosis .
More recently, detailed analysis of antibody Fc functional profiles, binding to receptor FcγRIII, and Fc glycosylation patterns has shown that individuals with LTBI and active TB disease exhibit distinct patterns of these antibody profiles . Antibodies from individuals with LTBI showed enhanced phagolysosomal maturation, inflammasome activation, and macrophage killing of intracellular M. tuberculosis , suggesting that a subset of antibodies in M. tuberculosis-infected persons may indeed play a role in protection.
With better understanding of antibody functional repertoires, the role of humoral immunity in protection against TB is undergoing re-evaluation.
Immunologic correlates of protection — Understanding correlates of protection against a pathogen is critical for the development of an effective vaccine. Much of our understanding of immunologic correlates of protection against active TB has come from mouse model studies, as described above. Extrapolating such data to human immune response to M. tuberculosis infection has raised more questions than answers about which component of the human immune response is required to be induced by a vaccine to confer protection against TB. Based on available data, we do not have a good understanding of which component of human immune responses can be considered a measure of protection against TB.
Issues related to vaccines for prevention of TB are discussed further separately. (See "Prevention of tuberculosis: BCG immunization and nutritional supplementation".)
Mycobacterial lipids — M. tuberculosis lipid products have been associated with TB pathogenesis since 1947, when Middlebrook suggested that a growth morphology called "cording" was associated with virulent tubercle bacilli . Subsequently, the toxic effect of petroleum ether extractable "cord factor" from M. tuberculosis was characterized in a murine model . This cord factor was eventually identified as glycolipid trehalose dimycolate (TDM) . Although studies have shown that "cording" is not necessarily restricted to virulent mycobacteria, structural changes in TDM elicit distinct mammalian host immune responses.
TDM is comprised of mycolic acids covalently bound to trehalose. Mycolic acids are beta-hydroxyl fatty acids with an alpha-alkyl side chain; the M. tuberculosis cell wall contains three classes of this fatty acid: alpha-, keto-, and methoxy-mycolates . Alpha-mycolic acid has two cyclopropane rings, which are in the cis configuration, while the keto- and methoxymycolates have one ring in either cis or trans configuration . The cyclopropanation status of mycolic acids is important for pathogenesis in the mouse model as illustrated by the following findings:
●M. tuberculosis strains lacking keto-mycolates grow poorly inside THP-1 cells .
●Absence of keto- or methoxy-mycolates in M. tuberculosis leads to attenuation of infection in a murine model .
●M. tuberculosis strains disrupted in the cyclopropane synthase gene, pcaA, are attenuated in mice. pcaA is required for cord formation and for the synthesis of the proximal cyclopropane ring of alpha-mycolic acid. TDM prepared from this mutant is less inflammatory .
●M. tuberculosis disrupted in cyclopropane-mycolic acid synthase 2 (cmaA2), a gene responsible for the trans-cyclopropanation of mycolic acid in the cell wall, is hypervirulent in BALB/c mice . Lipid extracted from this mutant is hyper-proinflammatory.
In addition, phthiocerol dimycocerosates (PDIM) are important for growth of M. tuberculosis in mouse lungs (although not in mouse spleen or liver) . PDIM is thought to protect M. tuberculosis against the bactericidal activity of reactive nitrogen intermediates . A mutation in a lipoprotein (LppX), needed for the export of PDIM, led to attenuation of the mutant in a mouse infection model .
M. tuberculosis grown in detergent-free medium produces biofilm and extracellular matrix of the biofilm has been shown to include mycolic acids . Whether M. tuberculosis makes biofilm in vivo during its natural course of infection is not known. The mce1 operon of wild-type M. tuberculosis is repressed during the early phase of infection in mice  and a strain of M. tuberculosis disrupted in this operon over-expresses mycolic acids [124,142,143]. Thus, it is conceivable that M. tuberculosis makes biofilm in vivo. Mycolic acids have been shown to inhibit proinflammatory cytokine expression by human alveolar epithelial cells (A549) and murine RAW cells . Furthermore, the mce1 operon mutant shows reduced expression of mmpL8, mmpL10, stf0, pks2, and papA2 genes involved in transport and metabolism of lipids associated with proinflammatory response .
Nonpolar lipids extracted from M. tuberculosis disrupted in the mce1 operon enhanced the mRNA expression of lipid-sense nuclear receptors (LSNRs) TR4 and PPAR-gamma and dampened the murine macrophage expression of genes encoding TNF-alpha, IL-6, and IL-1 beta . As described above, the mce1 operon mutant varies by more than 400 lipid species and contains >10-fold greater amount of mycolic acids in its cell wall compared with the wild type M. tuberculosis [124,142]. PPAR-gamma ligands have been reported to inhibit monocyte production of TNF-alpha, IL-6, and IL-1 beta , and keto-mycolic acids of M. tuberculosis activate TR4 to modulate foamy macrophage biogenesis in granulomas . Thus, profound changes in cell wall lipid contents of M. tuberculosis can affect cytokine profiles via LSNRs.
These observations suggest that M. tuberculosis cell wall lipids play an important role in the early interaction of this organism with the host immune response and that the cell wall lipids ultimately determine clinical outcomes. Clinical isolates of M. tuberculosis with changes in lipid composition can affect the distribution of organisms in a community, as illustrated by a large outbreak of TB in Tennessee and Kentucky in 1994 through 1996 caused by strain CDC1551 . CDC1551 produced an enhanced proinflammatory cytokine response in mice, which was traced to changes in its cell wall lipids .
Another outbreak-associated strain, HN878, expresses a highly active lipid species called phenolic glycolipid (PGL), not detected in M. tuberculosis strain CDC1551 or laboratory strain H37Rv . PGL inhibits proinflammatory cytokine release by macrophages [149,150], but a later study showed that PGL itself does not mediate hypervirulence .
●The majority of individuals in the general population who become infected with Mycobacterium tuberculosis never develop clinical disease; this demonstrates that the innate and adaptive immune response of the host in controlling tuberculosis (TB) infection is effective. Factors that adversely affect the immune system contribute to development of latent TB infection and active disease. (See 'Immunology' above.)
●Components of innate immunity thought to be involved with defense against TB infection include direct or indirect killing via reactive nitrogen intermediates, interferon (IFN)-gamma and other cytokines, use of toll-like receptors as well as other pattern recognition receptors for M. tuberculosis molecules, and other factors. (See 'Innate immunity' above.)
●Cellular immunity may contribute to the protective response against TB, but the specific correlates of such protective response have not yet been well established in human cell-mediated immunity. The role of humoral immunity in the protective response against TB remains uncertain. (See 'Cellular immunity' above and 'Humoral immunity' above.)
●Granuloma formation is an important host mechanism to control infection, but it is also a host response induced by M. tuberculosis itself for its own protection against host antibacterial effector molecules; it requires expression of cytokines and chemokines as well as M. tuberculosis cell wall remodeling. (See 'Granuloma formation' above.)
●M. tuberculosis cell wall lipids play an important role in the early and later interaction of the organism with the host immune response and determination of clinical outcome. (See 'Mycobacterial lipids' above.)
ACKNOWLEDGMENT — We are saddened by the death of Lee W Riley, MD, who passed away in October 2022. UpToDate acknowledges Dr. Riley's past work as an author for this topic.
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