How Tuberculosis Challenges Our Immune System

 Figure 1. Lung TB (“Tuberculosis (TB) - Interventional Pulmonology Clinic,” 2023)

Tuberculosis (TB) is a deadly infectious disease caused by the bacterium Mycobacterium tuberculosis. It is a slow-growing, acid-fast bacillus with a mycolic acid-rich lipid cell wall. This unique feature enhances its survival inside host cells, making it one of the most adaptable human pathogens (Mohammadnabi et al., 2024). In 2023, TB affected 10.8 million people worldwide and caused an estimated 1.25 million deaths. Most cases were reported in the WHO South-East Asia Region (45%), with Africa (24%) and the Western Pacific (17%), highlighting the continued prevalence in resource-limited countries.  Alarmingly, TB has returned as the leading cause of death from a single infectious pathogen, surpassing HIV/AIDS and even COVID-19 (WHO, 2024).  

There are two forms of TB known as latent and active. Latent TB is asymptomatic and non-transmissible, but the bacteria can remain dormant in the body for years. Active TB occurs when the immune response fails to control the infection, resulting in symptoms such as persistent cough, chest pain, fever, night sweats, hemoptysis (coughing up blood), and weight loss (Luies & du Preez, 2020) (Figure 2).

 Figure 2. The Symptoms of Active TB (Alsayed & Gunosewoyo, 2023)

Although the lungs are the primary site of infection, TB can also affect the spine, kidneys, and brain (Rahlwes et al., 2023). Tuberculosis spreads through the air when someone with active pulmonary TB coughs, sneezes, or talks, releasing tiny droplets (aerosols) that carry the bacteria. Inhaling these aerosols allows the bacteria to reach the alveoli, where the infection begins. Although TB is curable and preventable, it remains a significant threat due to late diagnosis, incomplete treatment, and emerging drug resistance (Mohammadnabi et al., 2024; Vu et al., 2024). 

Host Immune Response to TB

Once inhaled, M. tuberculosis targets alveolar macrophages (immune cells responsible for engulfing pathogens). The bacterium enters through receptors like fibronectin-binding proteins and uses virulence factors to facilitate entry and survival inside macrophages. It then resides and replicates slowly, leading to latent TB. When immunity is compromised, latent TB may reactivate and progress to active TB (Mohammadnabi et al., 2024; Zhuang et al., 2024).

The immune response to M. tuberculosis includes both innate and adaptive immunity. Alveolar macrophages, dendritic cells, and neutrophils detect the bacteria through pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), and respond by releasing signalling molecules such as tumor necrosis factor-alpha (TNF-α) and interleukins (IL-12 and IL-1β). Neutrophils and natural killer cells also play a role by destroying infected cells and producing a key cytokine, interferon-gamma (IFN-γ), which helps control the infection (Abbasnia et al., 2024; Zhuang et al., 2024). 

After two to three weeks, adaptive immunity is activated. Dendritic cells process TB antigens and present them to T cells (thymus-derived lymphocytes) in the lymph nodes, triggering the adaptive response. The CD4+ T-helper cells become activated and release IFN-γ and IL-2 to further activate macrophages, enhance phagocytosis, and initiate granuloma formation (Figure 3). Granulomas are tight clusters of immune cells that surround and isolate the bacteria to prevent them from causing widespread damage. Meanwhile, CD8+ cytotoxic T-cells can directly kill infected host cells to prevent the bacteria from spreading (Vu et al., 2024).

Figure 3. Disease Progression in TB (Luies & du Preez, 2020)

How TB Evades the Immune System

M. tuberculosis has evolved several strategies to overcome the immune system and persist inside the host. When the bacterium is engulfed by macrophages, it blocks the normal process of phagosome-lysosome fusion that would typically destroy it. It achieves this by perforating the phagosomal membrane and interfering with the host’s fusion machinery using virulence factors, such as ESAT-6 and CFP-10, and proteins like PknG (protein kinase G) and SapM (Ramon-Luing et al., 2023).

In addition, M. tuberculosis regulates the way infected host cells die. Instead of allowing apoptosis, the bacterium triggers necrosis and necroptosis. These forms of cell death result in the rupture of the infected cell, releasing viable bacteria into nearby tissues and promoting further spread (Vu et al., 2024). One of the key molecules involved in this process is tuberculosis necrotizing toxin (TNT), which depletes NAD⁺ and activates necroptosis (Rahlwes et al., 2023).

During latent infection, M. tuberculosis reduces its metabolic activity and ceases replication, entering a dormant state. This helps it evade immune detection and resist antibiotics, which typically target actively dividing cells (Mohammadnabi et al., 2024).  Additionally, M. tuberculosis weakens the immune response by downregulating the MHC (major histocompatibility complex) class II expression, making it harder for the immune system to recognize and attack infected cells. Furthermore, it promotes the expansion of regulatory T cells (Tregs), which usually prevent autoimmunity but, in TB, suppress protective immune responses (Zhuang et al., 2024). Moreover, M. tuberculosis induces indoleamine 2,3-dioxygenase (IDO) enzyme activity, which breaks down tryptophan (an amino acid vital for T cell growth), thereby weakening T cell responses and impairing the body’s ability to eliminate the infection (Yang et al., 2023).

M. tuberculosis also manipulates the host immune system through epigenetic regulation. It alters DNA methylation patterns and modifies histone proteins, suppressing MHC class II expression, further weakening antigen presentation (Abbasnia et al., 2024). At the same time, they promote the production of IL-10, an anti-inflammatory cytokine that reduces immune activity (Vu et al., 2024). Together, these strategies help M. tuberculosis create ideal environment to survive and persist in the body for years.

Screening, Diagnosis and Treatment of TB

Screening for TB is essential for early detection and controlling transmission, especially in high-risk populations.  The Tuberculin Skin Test (TST) and Interferon Gamma Release Assays (IGRAs) are the most widely used screening methods that detect the body’s immune response to M. tuberculosis. To diagnose active TB, sputum smear microscopy is simple and rapid, while culture remains the gold standard despite its slow turnaround (Zhuang et al., 2024). Modern molecular tests like GeneXpert MTB/RIF offer rapid results and can detect drug resistance (Rahlwes et al., 2023; Zhuang et al., 2024). Chest X-rays are useful, especially for detecting pulmonary TB (Mohammadnabi et al., 2024). One of the biggest challenges in TB diagnosis today is identifying the difference between active TB and latent infection (LTBI). However, advanced “omics” technologies (genomics, proteomics, and metabolomics) are enabling scientists discover host biomarkers that could make TB diagnosis faster and more accurate (Kanabalan et al., 2021) (Figure 4).

Drug-sensitive TB is usually treated with a six-month course of isoniazid, rifampicin, pyrazinamide, and ethambutol, while drug-resistant TB needs longer therapy using newer drugs, including bedaquiline (Yang et al., 2023; Zumla et al., 2013). Early screening, accurate diagnosis and strict adherence to treatment are critical to controlling the disease and preventing its transmission.

Figure 4. Omics in TB diagnosis (Kanabalan et al., 2021)

References

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