Mycobacterium tuberculosis
Aerobic, non-motile, obligate intracellular acid-fast bacillus (AFB) with a uniquely complex cell wall: ~60% lipids by dry weight, including very-long-chain mycolic acids (C70–C90) that confer intrinsic impermeability, acid-alcohol retention on Ziehl-Neelsen stain, and resistance to most disinfectants. Generation time 15–20 hours dictates months of chemotherapy. Pathogenesis centres on phagosomal maturation arrest inside alveolar macrophages, granuloma formation in the lung, and latency establishment in ~90% of primary infections. Lifetime reactivation risk is 5–10% in immunocompetent hosts but rises sharply with HIV, TNF-α inhibitors, malnutrition, and silicosis. MDR-TB (isoniazid + rifampicin resistance) affects ~400,000 patients annually and requires novel drug regimens including bedaquiline and pretomanid.
Classification & Structure
| Gram reaction | Gram-indeterminate; classified by Ziehl-Neelsen acid-fast stain (retains carbol fuchsin after acid-alcohol decolorisation) due to mycolic acid retention |
| Morphology | Non-motile, non-spore-forming rod, 1–4 µm × 0.3–0.6 µm; may appear beaded; aerobic; generation time 15–20 h vs. 20 min for E. coli |
| Cell wall | Plasma membrane → peptidoglycan → arabinogalactan → mycolic acids (C70–C90) → loosely associated capsule-like layer. ~60% lipids by dry weight. Antibiotic targets: isoniazid (InhA/KasA, mycolic acid synthesis), rifampicin (rpoB, RNA polymerase), ethambutol (EmbB, arabinosyltransferase), pyrazinamide (PncA, multiple targets) |
| Key virulence factors | ESX-1 T7SS (ESAT-6, CFP-10 — phagosome disruption & T-cell antigens); SapM phosphatase (PI3P depletion → phagosome arrest); KatG/SodA/SodC (ROS/RNS neutralisation); Mce4 operon (host cholesterol import); PtpA phosphatase (impairs MHC-II presentation) |
| Genome | 4.4 Mb; GC 65.6%; ~4,000 genes; unusually large lipid metabolism gene family; T7SS systems ESX-1, ESX-3, ESX-5 are major virulence determinants; no plasmids in H37Rv reference strain |
Pathogenesis
1 · Aerosol transmission and alveolar deposition
Droplet nuclei (1–5 µm) from coughing/sneezing of active pulmonary TB cases carry 1–5 bacilli, remain airborne for hours, bypass the mucociliary escalator, and deposit in terminal alveoli. Infectious dose is as low as 1–10 bacilli; ~25–50% of household contacts of smear-positive TB develop latent infection.
2 · Macrophage uptake and phagosome arrest
Alveolar macrophages phagocytose Mtb via mannose receptor, complement receptors CR3/CR4, and FcγRs. Normally the phagosome acidifies (pH ~5.0) and fuses with lysosomes. Mtb prevents this by: depleting PI3P via SapM lipid phosphatase (blocking Rab5→Rab7 conversion); ESX-1-secreted ESAT-6 permeabilising the phagosomal membrane; and using host cholesterol/fatty acids via the mce4 operon as carbon and energy sources.
3 · Granuloma formation and bacterial containment
CD4+ Th1 cells (IFN-γ) and CD8+ CTLs coordinate with macrophages and fibroblasts to form the granuloma: a caseating necrotic core surrounded by epithelioid macrophages, Langhans giant cells, a lymphocyte mantle, and a fibroblast rim. The granuloma walls off but rarely sterilises infection. Mtb within the necrotic core encounters low O⊂2;, acid pH, and nutrient limitation — inducing a dormant (non-replicating) phenotype refractory to most antibiotics.
4 · Latency and reactivation risk
In ~90–95% of immunocompetent primary infections, Mtb is contained as latent TB infection (LTBI) — bacteriologically quiescent but not eradicated. Lifetime reactivation risk is 5–10%; multiplied by HIV (>10%/year without ART), TNF-α inhibitors, high-dose steroids, silicosis, diabetes, and malnutrition. Reactivation produces upper-lobe cavitary disease and is the dominant source of active TB in adults worldwide.
5 · Drug resistance by chromosomal mutation
Mtb acquires antibiotic resistance exclusively by chromosomal mutation (no horizontal transfer of resistance genes). Key mutations: rpoB (rifampicin resistance — proxy for MDR in rapid testing); katG/inhA promoter (isoniazid); embB (ethambutol); rrs/eis (aminoglycosides); gyrA/gyrB (fluoroquinolones); Rv0678 (bedaquiline efflux). MDR-TB (~400,000 cases/year) requires BPaL (bedaquiline + pretomanid + linezolid) or similar 6–24-month novel regimens.
Host Immune Response
Disease Spectrum
| Presentation | Features | Key points |
|---|---|---|
| Primary TB | Usually asymptomatic or mild febrile illness; Ghon complex (primary focus + hilar adenopathy) on CXR | 90–95% self-limited; 5–10% progress to active disease |
| Latent TB (LTBI) | Asymptomatic; positive TST or IGRA (ESAT-6/CFP-10-based); no clinical disease | Treat to prevent reactivation in high-risk groups; 6H isoniazid or 3HP reduces risk 60–90% |
| Reactivation TB | Upper-lobe cavitary disease; chronic cough, haemoptysis, fever, night sweats, weight loss; smear +ve if cavity | Classic "consumption"; dominant presentation in adults; highly infectious |
| Miliary TB | Haematogenous dissemination; millet-seed granulomas in lungs, liver, spleen, meninges; CXR "snowstorm" | Uniformly fatal if untreated; common in immunocompromised and infants |
| Extrapulmonary TB | Pleural (~20%), lymph node (most common extrapulmonary), vertebral/Pott’s disease, renal, pericardial, meningeal | 5–15% of all TB; over-represented in HIV patients |
| MDR-TB / XDR-TB | Resistant to isoniazid + rifampicin (MDR); additional fluoroquinolone + bedaquiline/linezolid resistance (XDR) | ~400,000 MDR cases/year; BPaL regimen; longer treatment, higher toxicity, worse outcomes |
Treatment & Prophylaxis
| Standard DS-TB regimen | 2 months RIPE (rifampicin + isoniazid + pyrazinamide + ethambutol) → 4 months RI. Total 6 months. Shorter 4-month regimens (2HRZE + 2 rifapentine/moxifloxacin) validated for eligible drug-sensitive patients. |
| MDR-TB (BPaL regimen) | Bedaquiline (ATP synthase inhibitor) + pretomanid (nitroimidazole prodrug, multi-target) + linezolid (50S ribosome inhibitor) × 6 months; 90% culture conversion in ZeNix trial. Replaced older injectable-containing regimens. |
| LTBI treatment | Isoniazid 6H (6 months daily); 3HP (rifapentine + isoniazid weekly ×12 doses); 1HP (daily ×28 days, preferred in HIV); reduces reactivation risk by 60–90%. |
| BCG vaccine | Live-attenuated M. bovis; single neonatal dose; 70–80% efficacy against miliary/meningeal TB in children; variable (0–80%) against pulmonary TB in adults. Recommended at birth in high-TB-burden countries. Contraindicated in severe immunodeficiency. |
| Prophylaxis in immunocompromised | Screen for LTBI (IGRA preferred) before anti-TNF therapy, transplant, or immunosuppression. IPT (isoniazid preventive therapy) in all HIV patients with positive LTBI test in high-burden settings. BCG contraindicated in HIV/severe immunodeficiency. |
Cross-Atlas Connections
References
- World Health Organization. Global Tuberculosis Report 2023. who.int/teams/global-tuberculosis-programme
- Dartois VA, Rubin EJ. Anti-tuberculosis treatment strategies and drug development: challenges and priorities. Nat Rev Microbiol. 2022;20(11):685–701. doi:10.1038/s41579-022-00731-y · PubMed 35478222
- Russell DG, Barry CE 3rd, Flynn JL. Tuberculosis: what we don’t know can, and does, hurt us. Science. 2010;328(5980):852–6. doi:10.1126/science.1184563 · PubMed 20466922
- Ehrt S, Schnappinger D. Mycobacterial survival strategies in the phagosome: defence against host stresses. Cell Microbiol. 2009;11(8):1170–8. doi:10.1111/j.1462-5822.2009.01335.x · PubMed 19438517
Contribute to the Pathogen Atlas
This entry covers Mtb biology, granuloma immunology, and TB chemotherapy. Planned expansions include host-directed therapy, TB vaccine pipeline (M72/AS01E, ID93), and bedaquiline resistance mechanisms. Every entry follows the same schema: structured frontmatter, peer-reviewed citations, and cross-atlas links.