Tuberculosis Pathogenesis

• Obligate human pathogen.
• Approximately 1/3 of the world population is infected, and there are 8-10 million new cases each year.

– Of these, 5-10% will develop tuberculosis disease, which kills 1-4 million people annually.

• Individuals with HIV or other immune deficiencies are more likely to develop severe infection; because of this, co-infection with HIV and tuberculosis is a major public health concern in areas where both infections are endemic.
• Transmitted from human to human via respiratory aerosols
• Microbes are inhaled and travel to the lungs, where they are engulfed by alveolar phagocytes.

Mycobacterium tuberculosis* has evolved to highjack the innate immune response and to delay the adaptive immune response. – Disease development is the outcome of host and bacterial interactions that produces chronic inflammation.

• Occurs in primary or secondary pulmonary infections.
• It is especially likely in individuals with impaired cellular immunity.
• Miliary tuberculosis occurs when the resulting lesions are very tiny (like millet seeds); infection can by systematic or localized within a specific organ.
• Isolated tuberculosis with larger lesions can also occur.
• Extrapulmonary infections can occur in any organ, but are particularly common in the liver, spleen, kidney, adrenal glands, bone marrow, lymph nodes, and the meninges.

• Bacille Calmette-Guerin (BCG) vaccine is administered to children in areas where tuberculosis is endemic.

– Vaccine is made with attenuated Mycobacterium bovis. – Significant limitations: it is only effective against some forms of childhood tuberculosis, and is not effective against pulmonary tuberculosis, which is the most prevalent form of the disease. Skin and blood tests can determine if Mycobacterium tuberculosis* is present in the body. – These tests do not distinguish between latent and active infections; individuals who've had the Mycobacterium bovis vaccine will test positive.

• Chest x-rays can show cavitation and pulmonary tissue damage.

Mycobacterium tuberculosis* is resistant to antibiotics – Long-term, multi-drug therapy is necessary. – "Extensively drug-resistant" strains (XDR TB) are on the rise in some regions. Occurs when a new host first encounters Mycobacterium tuberculosis* Alveolar macrophages engulf Mycobacterium tuberculosis* bacteria and sequesters the bacteria within a vacuole. – Recall that part of the innate immune response involves phagocytosis of microbes, followed by phago-lysosome fusion to expose the microbes to bactericidal lysozymes. Mycobacterium tuberculosis* prevents phago-lysosome fusion, thus evading destructive enzymes. – Allows fusion with nutrient-filled vesicle to facilitates its own replication within the macrophage.

• Infected macrophage responds by secreting IL-12 and Tumor Necrosis Factor alpha (TNF-alpha).
• These cytokines recruit other immune cells to the area:

– Natural killer cells, CD4+ T cells, and Monocytes.

• The CD4+ T cells differentiate to become Helper T cells that release Interferon gamma, which is a cytokine that activates macrophages.

– Interferon gamma triggers the following antibacterial effects: Phagolysosome maturation, production of oxygen reactive species and nitric oxide, antimicrobial defensin recruitment, autophagy, and macrophage differentiation to form epithelioid cells. – Not surprisingly, patients with low production of TNF-alpha and/or interferon-gamma are more susceptible to severe Mycobacterium tuberculosis infection.

• Macrophage activation and the other effects of interferon-gamma promotes intracellular killing.

Mycobacterium tuberculosis* can induce macrophage apoptosis to escape killing.

• The monocytes recruited by IL-12 and TNF can also be infected; thus, instead of fighting bacterial spread, the newly arrived monocytes promote its success.
• The host's response to Primary infection leads to chronic inflammation and granuloma formation.

Granuloma formation Chronic inflammation produces granulomas, aka, tubercles

• Granulomas are hallmarks of primary tuberculosis infection that reflect interactions between the adaptive immune response and invading bacteria.
• They comprise aggregations of immune cells that wall-off bacteria in areas of the lungs and lymph nodes.

– Necrotic center comprises apoptotic macrophages and Mycobacterium tuberculosis. – Center is surrounded by layers of epithelioid macrophages and Langhans giant cells (fused epithelioid cells). – B-cells, T-cells, and neutrophils also surround the necrotic center. – Outer fibrous layer encircles the granuloma.

• In a histological sample of infected lung tissue, we can see multiple granulomas with caseous ("cheese-like") necrotic centers. Compare these areas with the remaining alveolar tissue, and consider how granulomas interfere with gas exchange in the lungs.

Primary tuberculosis infection is typically characterized by lesions in the lower lobes of the lung (Ghon foci*) and in the hilar lymph nodes, which drain the lungs. – Collectively, the pulmonary and lymph node lesions are referred to as the Ghon complex.

• The Ghon complex can calcify and become a fibrotic Ranke complex, which reflects latent infection.

– Early studies stressed the benefits of granuloma formation to the host – bacterial spread is prevented by layers of host tissues. However, we now recognize that those layers of cells also prevent the host immune system or clinical therapies from reaching the bacteria, which allows infection to persist in a dormant state. – Ultimately, the dormant bacteria can reactivate to cause secondary infection. Secondary Infection Tuberculosis infection in an individual who has previously been exposed to Mycobacterium tuberculosis*

• Occurs upon reactivation of dormant bacteria or re-infection from a new source.
• Secondary infection is characterized by lesions in the upper lobes of the lungs and does not involve the lymph nodes (in contrast to primary infection lesions).
• Many lesions heal spontaneously, and can leave behind fibrotic scars.
• Others lead to caseation and cavitation.

– Bacteria replicate within the lesions and are released in sputum along with fragments of necrotic lung tissue. – The contaminated sputum constitutes the is the primary route of Mycobacterium tuberculosis transmission between humans.