Mycobacterium tuberculosis Overview

Objectives

• Describe the properties, pathogenesis, and clinical significance of Mycobacterium tuberculosis as respiratory pathogens.

Mycobacterium tuberculosis

• Mycobacterium tuberculosis was first identified by Robert Koch.
• There are more than 100 species of mycobacteria.
• The name "mycobacteria" means fungus-like bacteria, derived from their mold-like appearance when grown in liquid media.
• They are also called acid-fast because they resist decolorization by dilute mineral acids due to the rich lipid content (mycolic acids, waxes, and phosphatides) in their cell walls.

Morphology

• Size: 3 microns in length and 0.3 microns in width.
• Shape: Straight or slightly curved rod.
• Arrangement: Singly, pairs, or small clumps.
• Nonmotile, nonsporing, and non-capsulated.
• Staining reaction: Ziehl Neelsen staining.
• Acid fastness, beaded forms commonly seen.
• Fluorescent stain: Auramine Rhodamine stain.

Pathogenesis - Mode of Infection

• Almost all M. tuberculosis infections result from inhaling droplet nuclei (infectious particles) from a person with pulmonary TB (coughing, sneezing, talking).
• These dried droplet nuclei remain airborne and reach the terminal air passages.
• The infection occurs by inhaling aerosolized bacilli contained in droplet nuclei of expectorated sputum.
• Coughing, sneezing, etc., release about 3000 droplet nuclei.
• Processing clinical specimens in the lab and other procedures can lead to infection.
• Ingestion can also occur by infected milk (e.g., M. bovis).

Transmission

• Person-to-person via the air.
• Less frequently through ingestion of unpasteurized milk products.
• Laboratory accidents can also lead to infection.

Environmental Factors

• Concentration of infectious droplet nuclei: Higher concentration increases transmission probability.
• Space: Exposure in small, enclosed spaces increases transmission risk.
• Ventilation: Inadequate local or general ventilation reduces dilution and removal of infectious droplet nuclei.
• Air circulation: Recirculation of air containing infectious droplet nuclei increases transmission risk.
• Specimen handling: Improper procedures generate infectious droplet nuclei.
• Air pressure: Positive air pressure in infectious patient rooms can cause M. tuberculosis to flow to other areas.

Virulence Mechanisms

• Ability to survive within macrophages.
  • Phagosome acidification: Mycobacterial urease helps prevent acidification, limiting the effectiveness of bactericidal enzymes.
  • Phagosome-lysosomal fusion: The organism produces an exported repetitive protein to prevent fusion, allowing it to escape degradative enzymes in the lysosome.
• Cord formation (trehalose dimycolate): Correlates with virulence. A cord factor inhibits leukocyte migration and causes chronic granulomas.
• LAM (lipoarabinomannan): Inhibits macrophage activation by interferon gamma.
• The organism secretes various antioxidants (superoxide dismutase, catalase) to detoxify reactive oxygen species generated by phagocytes.
• Phosphatidase plays a role in caseous necrosis.

Immunology

• TB requires a cellular immune response for control.
• Effective immune response relies on CD4+ T cells and cytokines (interleukin-12, interferon-gamma, tumor necrosis factor).
• CD4+ Th1 cells secrete interferon-gamma, crucial for the protective immune response against M. tuberculosis.
• Activated macrophages accumulate high concentrations of lytic enzymes and reactive metabolites, increasing mycobactericidal competence.
• Epithelioid cells (characteristic of tuberculous granuloma) are highly stimulated macrophages.
• Langhans giant cells are fused macrophages oriented around TB antigens.
• Cellular immune responses also cause tissue damage and pulmonary cavity formation.

Mechanism

• After inhalation, M. tuberculosis must bypass mechanical barriers (ciliated respiratory epithelial cells, mucins) to reach alveolar spaces.
• In alveoli, M. tuberculosis is phagocytized by alveolar macrophages.
• Alveolar macrophages sometimes successfully kill M. tuberculosis through phagosome maturation and lysosome fusion.
• Alternatively, M. tuberculosis may release virulence factors to delay phagosome maturation.
• M. tuberculosis uses several strategies to survive within macrophages while delaying or preventing an effective immune response

Primary Tuberculosis

• Initial infection, unrestrained replication for weeks in the initial focus and lymphohematogenous metastatic foci.
• Delayed adaptive cellular immunity development (4-8 weeks).

Pathogenesis of Tuberculosis

• After 3 weeks of infection, cell-mediated immunity develops, forming epithelioid granulomas (with T cells, macrophages, and giant cells); central caseation and peripheral fibrosis (called Ghon focus).
• Ghon focus location: Upper part of the lower lobe or lower part of the upper lobe is typical.
• Ghon's complex: If Ghon's focus involves adjacent lymphatics and hilar lymph nodes, it is known as Ghon's complex or primary complex.
• Ranke complex: If Ghon's complex undergoes fibrosis and calcification, it is referred to as a Ranke complex.

Macrophages and Granulomas

• Macrophages, epithelioid cells, T lymphocytes, and fibroblasts aggregate to form granulomas with lymphocytes surrounding infected macrophages.
• Fused macrophages form giant multinucleated cells in the alveolar lumen.
• Granulomas prevent dissemination of M. tuberculosis.
• Bacteria can become dormant in granulomas, leading to latent infection.

Spread of Mtb in the Body

• A tubercle can erode into a bronchus, emptying caseous contents and spreading organisms to other lung portions, or the gastrointestinal tract if swallowed.

M.tuberculosis as an Opportunistic Organism

• Decreased immunity (e.g., HIV, chronic steroid use) increases susceptibility to tuberculosis.
• Children, elderly, and pregnant women are more prone due to a weaker immune system.
• TB is closely linked to overcrowding and malnutrition.

Burden of Tuberculosis

• M. tuberculosis infects about one-quarter of the world's population.
• Approximately 10.4 million new TB cases and 1.7 million deaths in 2016.
• Leading cause of death worldwide (above HIV).
• Immunocompromised individuals (e.g., HIV-infected) are at high risk for TB.

Atypical Mycobacteria

• Mycobacterium tuberculosis, M. leprae, and other atypical mycobacteria (e.g., M. avium-intracellulare complex, M. kansasii) cause tuberculosis-like disease.
• Mycobacterium chelonae is a rapidly growing atypical mycobacterium.
• More than 170 Mycobacterium species exist.

Clinical Significance of Tuberculosis

• Pulmonary TB: Chest pain, coughing up blood or sputum, fatigue, weight loss, anorexia, fever, night sweats.
• Extrapulmonary TB : Central nervous system (tuberculous meningitis), lymphatic system (scrofula), genitourinary system, bones and joints (Pott disease).

Scrofula

• Cervical lymphadenitis (swollen, nontender lymph nodes, usually unilateral) caused by TB.