Tuberculosis: Microbiology, pathogenesis, and immunology

Authors:: David Lewinsohn, MD, PhD; Dylan Kain, MD; Nicole Parrish, PhD, MHS, D(ABMM)
Section Editor:: C Fordham von Reyn, MD
Deputy Editor:: Elinor L Baron, MD, DTMH

Literature review current through: May 2024.

This topic last updated: Mar 05, 2024.

INTRODUCTION — The human host serves as a natural reservoir for Mycobacterium tuberculosis. M. tuberculosis causes tuberculosis (TB) and is a leading infectious cause of death in adults worldwide [1]. (See "Epidemiology of tuberculosis".)

The microbiology, pathogenesis, and immunology of TB will be reviewed here. Other issues related to TB infection and disease are discussed separately (see related topics).

NATURAL HISTORY OF TUBERCULOSIS — Most commonly, tuberculosis (TB) is transmitted via aerosol droplets generated when a person with the disease involving the lungs or airways (especially when involving the larynx) coughs, sneezes, talks, or even breathes. Inhalation of aerosolized droplets containing M. tuberculosis by a susceptible, previously uninfected individual leads to deposition in the lungs with a spectrum of possible outcomes:

●No TB infection – M. tuberculosis bacilli do not establish infection. With repeated exposure, it has been estimated that only approximately 5 percent of individuals remain uninfected [2].

●TB infection (previously termed latent TB) – The term TB infection (table 1) refers to evidence of specific cell-mediated immunologic response following exposure to M. tuberculosis (eg, positive tuberculin skin test [TST] and/or interferon-gamma release assay [IGRA]) in the absence of signs or symptoms of illness.

Following M. tuberculosis exposure, TB infection occurs in a variable percentage of individuals based on the nature and duration of exposure. With repeated, prolonged exposure, TB infection occurs in approximately 90 to 95 percent of individuals with intact immunity [2]. Worldwide, an estimated 1.7 billion individuals are infected with M. tuberculosis [3].

●Reactivation TB disease (previously termed active TB) – Reactivation TB disease refers to onset of symptomatic TB disease, years following a period of contained TB infection. Among individuals with no underlying medical problems, the lifetime risk of reactivation disease is 5 to 10 percent [4-6]. This risk is markedly increased in individuals with immunosuppressive conditions, including HIV infection, immunosuppressive medications, and the extremes of age [1].

●Primary TB disease – A subset of disease in which the onset of TB disease develops as a consequence of new infection. This usually occurs within the first two years following M. tuberculosis exposure and infection in a previously naïve host. Primary TB most commonly occurs in young children and in immunocompromised individuals; it is thought to occur in approximately 5 percent of individuals with intact immunity [7].

The above categories are usually regarded and managed as discrete outcomes; however, data suggest that there is continuous spectrum from asymptomatic infection to clinical, communicable TB disease. As an example, in "subclinical TB disease," individuals have positive sputum acid-fast bacilli (AFB) tests (nucleic acid amplification [NAA] test, smear, or culture) for M. tuberculosis or have imaging features consistent with TB disease, in the absence of symptoms; testing for infection by TST or IGRA was not studied in this context [8-10].

The natural history of TB is discussed further separately. (See "Pulmonary tuberculosis: Clinical manifestations and complications", section on 'Natural history'.)

MICROBIOLOGY

M. tuberculosis complex — Mycobacterium tuberculosis is a member of a complex of closely related mycobacteria. The M. tuberculosis complex consists of the species M. tuberculosis, M. bovis, M. bovis Bacille-Calmette Guérin (BCG), M. africanum, M. caprae, and M. microti, all of which belong to the genus Mycobacterium; unvalidated species include M. orygis, M. mungi, M. canettii, and M. surricatae.

Identification of M. tuberculosis provided by a clinical laboratory usually refers to detection of M. tuberculosis complex; most laboratories do not have the advanced technology required for subspeciation within the complex. In addition, with the exceptions of M. bovis and M. bovis BCG (the vaccine strain of Mf. bovis), which are intrinsically resistant to pyrazinamide, treatment does not vary between members of the complex, so subspeciation is not needed for the purposes of antimicrobial therapy.

In addition to the M. tuberculosis complex, the genus Mycobacterium, includes more than 200 other species, referred to collectively as non-tuberculous mycobacteria or nontuberculous mycobacterium (NTM) [11]. (See "Overview of nontuberculous mycobacterial infections".)

Cell wall and envelope — The cell wall and envelope are distinguishing features of organisms belonging to the genus Mycobacterium and are unlike any other structures found in prokaryotic organisms. In addition to the peptidoglycan layer (which is contained by the cell envelope of other Gram-negative and Gram-positive bacteria), there are two additional macromolecules which make up the core of the mycobacterial cell wall; these are arabinogalactan and mycolic acids; together they are covalently linked to each other and the peptidoglycan.

Mycolic acids are alpha-alkyl, beta-hydroxy fatty acids which can vary in chain length as well as the number and type of functional groups present. In general, mycobacteria have mycolic acids which are 70 to 90 carbons in length, the ends of which are intercalated by additional hydrophobic lipids of up to an average of 30 to 50 carbons. Taken together, the cell wall and envelope present a formidable permeability barrier to nutrients as well as antibiotics; they also provide for the unique 'acid-fast' staining characteristics observed with this genus.

Lipoarabinomannans, M. tuberculosis cell wall glycolipid components, may be detected in urine of patients with tuberculosis disease and have been endorsed for diagnostic purposes by the World Health Organization (WHO) in patients with advanced human immunodeficiency virus (HIV) disease [12]. (See "Diagnosis of pulmonary tuberculosis in adults", section on 'Urine antigen test in HIV infection'.)

Staining characteristics — The cell wall components give the genus Mycobacterium its unique staining properties.

●Light microscopy

•Limitations of Gram stain – Mycobacteria may appear Gram-positive with a Gram stain; however, the appearance of the bacilli is likely to be variable and may have the appearance of beaded rods. Thus, Gram stain is not suitable for visualization of mycobacteria using light microscopy.

•Ziehl-Neelsen and Kinyoun methods – The Ziehl-Neelsen and Kinyoun methods are more mycobacterial-specific than Gram stain as they reveal the 'acid-fast' characteristics of the cell wall. The term 'acid-fast' refers to the ability of the cell wall components to form stable complexes with the primary stain and resist decolorization with harsh acid-alcohol or mineral acids resulting in an 'acid-fast' bacillus (AFB).

The Ziehl-Neelsen procedure uses the application of heat during the staining process to facilitate uptake of the dye through the hydrophobic cell wall and envelope. However, application of heat can also generate infectious aerosols. For this reason, the Ziehl-Neelsen staining procedure should be done ideally under BSL-3 conditions. Since not all laboratories have such capabilities, the Kinyoun procedure (which does not require the application of heat), is often used as a 'cold' acid-fast staining alternative.

Use of light microscopy for detection of AFB has limitations. Specimens must contain at least 10⁴ colony forming units (CFU)/mL, the lower limit of detection for most light microscopes, to yield a positive smear [13].

●Fluorescence microscopy – Fluorescence microscopy using fluorochrome dyes (such as auramine-O or auramine-rhodamine) permits more rapid assessment of a greater number of microscopic fields using a lower power objective lens, improving sensitivity over the Ziehl-Neelsen by 10-fold to 10³ colony forming units (CFU)/mL.

Microscopic detection of mycobacteria (by light or fluorescence techniques) cannot distinguish M. tuberculosis from non-tuberculous mycobacteria.

Growth characteristics — A distinguishing feature of M. tuberculosis is its relatively slow growth rate. In artificial media, the generation time is about 20 to 24 hours (as opposed to 20 minutes for organisms such as Escherichia coli). Culture growth may require two to six weeks, depending on the cultivation systems used.

Laboratory isolation — Culture remains the most sensitive and effective method for detection of M. tuberculosis; as few as 10¹ to 10² bacilli/mL can be detected.

Most clinical laboratories use a combination of cultivation techniques to recover M. tuberculosis from clinical specimens, including broth-based and solid agar-based methods. The most common broth-based media is Middlebrook 7H9 supplemented with oleic acid, bovine albumin, dextrose, and catalase. Solid media includes Middlebrook 7H10, 7H11, and 7H11 selective agars as well as Löwenstein-Jensen agar (which is an egg-based agar containing malachite green) which helps to inhibit normal flora present in clinical specimens.

Most mycobacteria grow more rapidly in broth-based media. Primary isolation from clinical specimens relies heavily on largely two automated broth culture detection systems: the Mycobacterial Growth Indicator Tube (MGIT, Becton Dickinson) and the VersaTREK system (VersaTREK Diagnostic Systems). Both of these platforms are approved by the United States Food and Drug Administration (FDA) for isolation of mycobacteria from clinical specimens as well as antibiotic susceptibility testing of first-line TB drugs (isoniazid, rifampin, ethambutol, and pyrazinamide). A third culture detection system, the MB/BacT Alert 3D (bioMérieux) has not been approved for antimicrobial susceptibility testing.

●In the MGIT platform, the culture tubes are monitored continuously by the instrument and contain a fluorescence oxygen sensor which fluoresces as the organisms grow and begin to diminish the oxygen present in the tube. Once fluorescence level reaches a critical threshold, the instrument indicates the presence of a positive culture. The tubes can also be read manually using a Wood's lamp or a transilluminator as the UV light source; this allows laboratories with inadequate resources for purchase of the MGIT system to utilize the tubes. In addition, mycobacterial cultures can be incubated at alternative temperatures (other than the standard MGIT setting of 35˚to 37˚C) which is essential for recovery of certain NTM species.

●The VersaTREK system senses pressure changes in the space above the broth medium resulting from gas production or consumption due to microbial growth.

●The MB/BacT Alert 3D system uses a colorimetric carbon dioxide sensor in each bottle to detect mycobacterial growth.

Organism identification — Positive cultures (from broth or agar) are smeared to verify the presence of AFB. Once confirmed, laboratories utilize a number of techniques to evaluate for M. tuberculosis.

The Gene Xpert MTB/RIF assay is a nucleic acid amplification test that detects the M. tuberculosis complex as well as rifampin resistance. It is approved by the United States FDA only for respiratory secretions (sputum) obtained from patients who have been on antimycobacterial therapy for fewer than three days. Xpert is not FDA approved for testing culture growth; identification of M. tuberculosis from culture growth by MALDI-TOF (mass spectrometry) requires a sufficient density of organisms in the culture medium. (See "Diagnosis of pulmonary tuberculosis in adults", section on 'Molecular testing'.)

Antibiotic susceptibility testing — First-line drugs (isoniazid, rifampin, ethambutol, and pyrazinamide) are tested on either the MGIT or the VersaTREK systems; both are FDA approved for that purpose. These systems test the first-line drugs using a single concentration for which a result of 'susceptible' or 'resistant' has been established.

Susceptibility testing of second- and third-line agents is usually done with a broth microdilution method, which provides a minimum inhibitory concentration for which no interpretation (such as susceptible, intermediate, or resistant) has been defined. Such testing is usually performed at larger reference laboratories or academic centers. In addition, whole genome sequencing and targeted next generation sequencing for organism identification and detection of resistance may be performed.

Many laboratories lack the capacity to provide susceptibility testing for antimicrobial agents including moxifloxacin, bedaquiline, pretomanid, and linezolid. Such testing can be done at the United States Centers for Disease Control (CDC), which has a molecular detection of drug resistance program (MDDR) available through state public health laboratories for genomic detection of resistance to second-line agents and newer drugs [14].

PATHOGENESIS — The mechanisms responsible for infection by Mycobacterium tuberculosis, its containment, and its "reactivation" to cause disease remains poorly understood. This is due in large part to complex and interacting systems specific to the characteristics of the infecting organism and the immune response of the individual human host. This section will address some factors thought to be important for the organism's ability to cause disease and human host response factors that may be responsible for host expression of infection and disease.

Virulence factors — Mycobacterial virulence factors facilitate pathogen survival within the host, including entering mammalian cells, reproductive growth, and defense against the host immune response [15,16].

M. tuberculosis has evolved many virulence factors to assist in survival and propagation [17]. These virulence factors may be categorized based on the mechanism by which they facilitate the success of M. tuberculosis. Some of the major virulence factors are discussed below [18].

●Survival outside host and access into the airway

•Many cell wall components facilitate survival in the environment, retarding desiccation of the organism and allowing airborne transmission of M. tuberculosis.

●Intracellular survival

•M. tuberculosis avoids immune system detection by surviving within antigen presenting cells, airway cells and other cell types. Its virulence factors facilitate phagocytosis, prevent phagosomal maturation arrest, subvert autophagy, and prevent M. tuberculosis killing within the cell [19-26].

•M. tuberculosis also uses virulence factors to manipulate cell death pathways (apoptosis, pyroptosis, and ferroptosis) to its advantage [23-31]. Its virulence factors also aid in phagosomal escape, for transmission to other individuals [32].

●Granuloma formation and extracellular survival

•Granuloma formation in M. tuberculosis infection has an evolutionary role for both M. tuberculosis and the host [33,34]. It allows the host to contain and prevent dissemination of the infection, and most hosts remain asymptomatic. However, at the same time, it facilitates bacilli "dormancy" permitting re-emergence and activation to produce disease and allow transmission up to decades later, when local containment breaks down and organism proliferation follows with disease reactivation.

•Cell wall components, including lipids and glycolipids, play a major role in extracellular survival; they protect the bacilli from host antimicrobial molecules, as well as the hostile environment within granulomas [35,36].

●Dissemination in the host

•Dissemination in the host is facilitated through several mechanisms, including direct spread via tissue destruction as well as via more distant spread via lymphatics or bloodstream; this is thought to occur via travel of infected antigen presenting cells [37].

•Necrosis is an important means of local tissue destruction and can be induced by virulence factors such as tuberculosis necrotizing toxin (TNT), PE11, and PE25/PPE41 [38-44].

●Immune manipulation

•M. tuberculosis has evolved mechanisms to both suppress and enhance the immune system.

•It has many virulence factors that bind pattern recognition receptors (PRR) that can facilitate phagocytosis, but also may antagonize those PRRs and prevent subsequent immune activation.

•M. tuberculosis has developed many systems that manipulate the cytokine response to infection, including reduced pro-inflammatory IL-12, TNFα, IL-6, and IL-1β production [44-64] or increased anti-inflammatory IL-10 production [65,66].

•M. tuberculosis has developed mechanisms to dampen the adaptive immune response, both by preventing phagosomal acidification and presentation of antigens to T cells, but also by directly inhibiting T cell activation and T cell receptor (TCR) signaling through specific virulence factors [67,68].

●Transmission

•M. tuberculosis has evolved complex mechanisms to facilitate transmission to subsequent hosts. These include necrosis at sites of bacterial proliferation in the setting of active TB disease, allowing bacilli in the lungs to escape into airways where they can then be aerosolized.

•The process of M. tuberculosis aerosolization can occur via breathing but is dramatically increased through coughing. Virulence factors have been shown in animal models to stimulate the cough reflex [69,70].

Variability in virulence — Variability in M. tuberculosis virulence can broadly be categorized into two categories: host-specific factors and bacterial-specific factors.

●Host specific factors – Host specific factors that influence variability in M. tuberculosis virulence include genetic factors and acquired factors. Acquired factors are discussed separately. (See "Epidemiology of tuberculosis", section on 'Risk factors'.)

Some major genetic predispositions are discussed below [71].

•Interferon mutations – Inborn errors in interferon-gamma, a condition known as Mendelian susceptibility to mycobacterial disease (MSMD), encompasses many mutations that impair the production of interferon-gamma (IL12RB, IL12RB1, NEMO, ISG15, IRF8, TYK2, SPPL2A) or the response to interferon-gamma (STAT1, IRF8, CYBB, IFNGR1, IFNGR2) [72]. These mutations predispose an individual to M. tuberculosis as well as other mycobacterial infections. (See "Mendelian susceptibility to mycobacterial diseases: An overview" and "Mendelian susceptibility to mycobacterial diseases: Specific defects".)

•Human leukocyte antigen (HLA) mutations – Several genome-wide association studies have identified some HLA variants associated with TB risk [73-75].

•Toll-like receptor (TLR) mutations – Mutations in TLR1, 2, 4, 8, 9, and 10 have all been associated with increased risk of TB [76-82].

•Vitamin D – Mutations in vitamin D receptor and vitamin D binding protein have been associated with increased susceptibility to TB [83,84].

•Tumor necrosis factor (TNF) – Mutations in TNF, a critical cytokine in M. tuberculosis control, have been associated with susceptibility to TB disease [80,85-88].

•Other – Many other genes have been associated with increased risk of TB, or increase risk of severe or disseminated TB including: TWF2 [89], DUSP14 [90], IL17F [91], CYP7A1 [92], IRGM [93], CCL5 [94], CCL13 [95], ADRB2 [96], CYBA [97], IFITM3 [98], and MR1 [98].

●Bacterial-specific factors – M. tuberculosis can be classified into 7 distinct phylogenic lineages (L1-7) [99]. Lineages have been found to have differences in associated risk of infection, transmission, and dissemination.

•Widely distributed lineages – Lineages L2-L4 are widely distributed and generally are considered "modern" lineages.

L2, which includes the Beijing strain (HN878) has been shown to be hypervirulent [100]. This is thought to be attributable in part to pks15/1 mutations in phenolic glycolipids, which have also been associated with hypervirulence in ancestral subspecies.

An outbreak with high rates of disseminated disease was found to be caused by a modern lineage; however, the strain possessed a full length EsxM protein export system (typical of ancestral strains), rather than a shortened EsxM (typical of modern lineages) [101]. This full-length EsxM contributed to this strain’s increased dissemination.

•Localized lineages – Lineages L1 and L5-7 are more localized to certain regions of the world. L5 and L6 lineages (M. africanum lineages) are mainly found in West Africa, are less transmissible in humans, and have been found to be less virulent in animal models [102].

IMMUNOLOGY — For most individuals, the innate and adaptive immune response is effective at controlling tuberculosis (TB) infection; most individuals with TB infection never develop clinical disease [2].

The pathophysiology of the host immune response during the initial encounter of M. tuberculosis with human lung cells remains poorly understood. Components of the host immune response include innate immunity, granuloma formation, and adaptive immunity. There is also growing recognition of the importance of immune system components that bridge the innate and adaptive immune response.

Understanding immune correlates of protection also is critical for vaccine development. It is uncertain which component of the human immune response must be induced by a vaccine to confer protection against TB, and what stage (from initial infection to expression of disease) should be targeted. Issues related to vaccines for prevention of TB are discussed further separately. (See "Prevention of tuberculosis: BCG immunization and nutritional supplementation".)

Innate immunity — Components of innate immunity thought to be involved with host defense against M. tuberculosis include:

●Use of receptors for M. tuberculosis molecules – The recognition of M. tuberculosis by toll-like receptors (TLRs) triggers signal transduction that induces a proinflammatory response to control the infection [103]. However, M. tuberculosis has evolved to subvert these host responses for its own survival in the host. (See "Toll-like receptors: Roles in disease and therapy".)

There are a number of different TLR pathways. As an example, activation of TLR1/2 induces expression of the vitamin D receptor, leading to increased expression of cathelicidin (an antimicrobial peptide) which inhibits in vitro growth of M. tuberculosis [104].

TLR4 polymorphism among individuals in India has been reported to be associated with increased severity of TB; in other populations, no such association has been found [105,106]. Such differential host response may also be affected by M. tuberculosis strain differences. Some M. tuberculosis strains preferentially activate TLR2, whereas others activate TLR4 [107].

There are a number of other cell surface pattern recognition receptors; their role (if any) in organism-cellular interactions is unclear [22].

●Direct or indirect killing via reactive nitrogen intermediates – Reactive nitrogen intermediates (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 during the early 1990s (C strain) was resistant to RNIs generated in vitro [108]. This strain was used to identify a novel gene called noxR1.

Bridging innate and adaptive immune response — Immune system components that bridge the innate and adaptive immune response include cellular and non-cellular components.

●Cytokines

•Interferon (IFN)-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 [109]. However, coadministration of IFN-gamma with calcitriol (the most active metabolite of vitamin D) causes monocytes to mature in vitro and leads to intracellular killing of M. tuberculosis [110].

•Tumor necrosis factor (TNF)-alpha – TNF-alpha is important for proper granuloma formation. The role of TNF-alpha in controlling M. tuberculosis infection has been demonstrated by multiple reports of reactivation TB disease among individuals treated for rheumatoid arthritis or Crohn disease with anti-TNF-alpha blockers [111-113]. (See "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors".)

●Other cytotoxic granules and cytokines – Other cytotoxic granules and cytokines include IL-26 [114], granulysin [115], granzyme A [116], granzyme B, and perforin [117] have all demonstrated killing ability against M. tuberculosis.

The role of other cytokines in M. tuberculosis infection is less clear. IL-10 produced by macrophages has an anti-inflammatory effect; however IL-10 disrupted mice are not more resistant to M. tuberculosis infection that wild-type mice [118]. The role of transforming growth factor-beta (another immunosuppressive cytokine) in infection outcomes also remains unresolved [119]. Several studies have suggested a possible role for IL-17 in M. tuberculosis defense [120-123]; however, this remains less well established with some suggestion that over-expression is detrimental [124].

●Trained immunity – Memory components of the immune system are generally attributed to the adaptive immune response, and traditionally they have not been considered a feature of the innate immune system.

However, evidence has emerged that certain stimuli, including Bacille-Calmette Guérin (BCG) vaccination, can lead to epigenetic changes in innate cells (such as monocytes) that allow them to better respond to subsequent exposures, a process referred to as trained immunity. Trained immunity from BCG vaccination has been shown to improved protection against M. tuberculosis in mice [125] and has been suggested as one explanation for BCG-induced protection against TB in humans [126].

●Donor-unrestricted T cells (DURTs) – DURTs (including CD1-resricted T cells, MR1-restricted T cells, γδ T cells, and iNKT and MHC class 1b-reactive T cells) are a group of T cells that possess features of both the adaptive and innate immune system and are able to quickly produce cytolytic enzymes [127]. Instead of recognizing peptide antigens presented from the polymorphic MHC I or MHC II, they recognize peptide and non-peptide antigens presented from monomorphic proteins. Since they are restricted by monomorphic proteins, they are often referred to as donor-unrestricted T cells.

Granuloma formation — A certain level of host proinflammatory response induced by M. tuberculosis is necessary for proper granuloma formation. The granuloma serves as a host protective factor as well as a shelter for long-term survival of the tubercle bacterium within the host. Granuloma formation requires balanced expression of cytokines and chemokines (including TNF-alpha and others) [128,129].

M. tuberculosis cell wall lipids play an important role in the early interaction of the organism with the host immune response. (See 'Virulence factors' above.)

Clinical isolates of M. tuberculosis with alterations in their lipid composition can affect community transmission; this was illustrated by a large outbreak of TB in Tennessee and Kentucky between 1994 and 1996 caused by strain CDC1551 [130].

Issues related to granuloma formation in the natural history of infection are discussed further separately. (See "Pulmonary tuberculosis: Clinical manifestations and complications", section on 'Natural history'.)

Adaptive immunity — Adaptive immunity is a critical component of the host immune response against M. tuberculosis. Macrophages and phagocytic cells carry phagocytized organisms from the lung to draining lymph nodes, where they present M. tuberculosis antigens to T cells, inducing an adaptive immune response; this occurs two to six weeks after infection.

Clinical assays for evaluation of cellular immunity to M. tuberculosis antigens include the tuberculin skin test (TST) and IFN-gamma release assays. (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)" and "Use of the tuberculin skin test for diagnosis of tuberculosis infection (tuberculosis screening) in adults" and "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults".)

Components of the adaptive immune response include:

●CD4 T cells – 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 [131,132]. Other animal studies showed that this protective response was mediated by CD4-bearing T cells [133,134].

•If the delayed hypersensitivity response is mediated by CD4 Th1 cells, the wide range of protection (0 to 80 percent) demonstrated by numerous BCG trials suggests that CD4 T cells are not sufficient for protection [135]. However, the greatly increased risk of TB among patients with human immunodeficiency virus (HIV) infection, in which CD4 T cells become depleted, suggests that these cells are important for protection against TB in humans.

•CD4 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 of CD4-disrupted mice, levels of IFN-gamma in the lungs were diminished early in infection but later 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 [136].

•In addition to the role of cytokines produced by CD4 cells, apoptosis of infected cells by CD4 cells may contribute to controlling infection.

●CD8 T cells – The role of CD8 T cells has in protection against M. tuberculosis has been demonstrated by the following observations:

•Beta-2-microglobulin-dependent T cell populations distinct from CD8 cells contribute to immunity against M. tuberculosis infection. Protection has been associated with transporter antigen processing (TAP) pathways, but TAP-independent mechanisms also appear to play a role [137].

•Live mycobacteria activate more CD8 cells than dead organisms or purified protein derivative [138].

•CD8 cells are critical in protection against TB dissemination to lymph nodes [127].

●Humoral immunity – Studies regarding role of humoral immunity in TB protection have demonstrated the following range of findings:

•Passive transfer of serum from BCG-vaccinated animals or M. tuberculosis-infected animals and humans to other animals have provided conflicting evidence of protection [139].

•Antibodies against a variety of mycobacterial antigens, including lipid and carbohydrate products, can be demonstrated in both asymptomatic TST-positive individuals and in patients who develop TB disease.

•M. tuberculosis strains incubated with an antibody raised against BCG promote phagosome-lysosome fusion, but the viability of such strains inside macrophages was not affected [140].

•Household contacts of patients with TB disease in Uganda who remained interferon-gamma release assays (IGRA) negative were found to have class-switched immunoglobulin G (IgG) antibodies to common M. tuberculosis antigens, suggesting they had developed antibody response to TB, despite lack of an IFN-gamma response to [141].

•Intravenous BCG has been observed to induce more immunoglobulin M (IgM) in the plasma and lungs of rhesus macaques than intradermal BCG, and IgM titers in the plasma and lung strongly correlated with reduced bacterial burden on subsequent M. tuberculosis challenge [142].

SUMMARY AND RECOMMENDATIONS

●Natural history – Inhalation of aerosolized droplets containing M. tuberculosis leads to deposition in the lungs, with a spectrum of possible responses, often grouped into one of the following possible outcomes (see 'Natural history of tuberculosis' above):

•No TB infection – Immediate clearance of the organism

•TB infection (previously termed latent TB) – TB infection (table 1) refers to containment of viable organisms via host immunity, in the absence of signs or symptoms of illness.

-Reactivation TB disease – Reactivation TB disease refers to onset of symptomatic TB disease, years following a period of contained TB infection.

•Primary TB disease – A subset of TB disease with onset within one to two years of infection.

●Microbiology

•Cell envelope – The cell wall and envelope are distinguishing features of organisms belonging to the genus Mycobacterium and account for the unique 'acid-fast' staining characteristics observed with this genus. In addition to the peptidoglycan layer (which is contained by the cell envelope of other bacteria), two additional macromolecules make up the core of the mycobacterial cell wall: arabinogalactan and mycolic acids. (See 'Cell wall and envelope' above.)

•Staining – Light microscopy to detect acid-fast bacillus (using Ziehl-Neelsen or Kinyoun stain) is the most commonly used technique for TB diagnosis. A specimen must contain at least 10⁴ colony forming units (CFU)/mL to yield a positive smear. Microscopy of specimens stained with a fluorochrome dye (such as auramine O) is a more sensitive and efficient technique. (See 'Staining characteristics' above.)

•Growth characteristics – A distinguishing feature of M. tuberculosis is its relatively slow growth rate. In artificial media the generation time is about 20 to 24 hours. Culture growth may require two to six weeks, depending on the cultivation systems used. (See 'Growth characteristics' above.)

•Organism identification – Once the organism is isolated, identification is based upon morphologic and biochemical characteristics. Molecular tools (such as the Gene Xpert MTB/RIF assay) and mass spectrometry have obviated many of the conventional tests. (See 'Organism identification' above.)

●Virulence factors – Virulence factors facilitate transmission and pathogen survival within the host, including entering mammalian cells, reproductive growth, and defense against the host immune response (see 'Virulence factors' above):

●Immunology – Components of the host immune response include:

•Innate immunity – Components of innate immunity thought to be involved with host defense against M. tuberculosis include use of receptors for M. tuberculosis molecules and killing via reactive nitrogen intermediates. (See 'Innate immunity' above.)

•Bridging the innate and adaptive immune response – Immune system components that bridge the innate and adaptive immune response include cellular and non-cellular components. (See 'Bridging innate and adaptive immune response' above.)

•Granuloma formation – A certain level of host proinflammatory response induced by M. tuberculosis is necessary for proper granuloma formation. The granuloma serves as a host protective factor as well as a shelter for long-term survival of the tubercle bacterium within the host. (See 'Granuloma formation' above.)

•Adaptive immunity – Macrophages and phagocytic cells present M. tuberculosis antigens to T cells, inducing a cellular immune response. Clinical assays for evaluation of cellular immunity to M. tuberculosis include the tuberculin skin test and IFN-gamma release assays. (See 'Adaptive immunity' above.)

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Topic 8023 Version 34.0

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Tuberculosis: Microbiology, pathogenesis, and immunology

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