Tuberculosis (TB) is a persistent global health challenge, caused by a specific bacterium that has impacted human populations for millennia. Historically known as “consumption” or “the white plague,” TB was responsible for a quarter of all deaths in Europe during the 1800s. Despite advancements in medicine, TB remains a leading cause of death from an infectious disease worldwide, with an estimated 10.8 million new infections and 1.25 million deaths in 2023. The rise of drug-resistant forms of the bacterium makes this ancient disease a significant concern.
The Culprit Bacterium
The organism behind tuberculosis is Mycobacterium tuberculosis (MTB). It is a small, rod-shaped bacterium with a remarkably slow growth rate, dividing approximately every 16 to 20 hours, a pace far slower than many other bacteria. This slow growth significantly influences the time required for laboratory culture, diagnosis, and treatment duration.
The bacterium’s unique cell envelope plays a major role in its resilience and ability to evade host defenses. This outer layer is rich in lipids, with mycolic acids making up a substantial portion. Mycolic acids form a thick, waxy coat, providing a robust barrier that contributes to the bacterium’s resistance to many common disinfectants and various antibiotics. This waxy composition also allows MTB to survive in a dry state for weeks outside a host.
Mechanism of Infection
Tuberculosis typically begins when an infected individual with active pulmonary TB releases tiny, airborne droplets containing Mycobacterium tuberculosis through coughing, sneezing, or even speaking. These infectious particles, known as droplet nuclei, are usually between 1 to 5 micrometers in diameter, allowing them to remain suspended in the air for several hours. A susceptible person then inhales these microscopic droplets, which bypass the upper respiratory tract and bronchi to reach the small air sacs of the lungs, called alveoli.
Once in the alveoli, the bacteria are typically engulfed by the body’s primary immune cells in the lungs, known as alveolar macrophages. Instead of being destroyed, Mycobacterium tuberculosis survives and replicates inside these macrophages. This survival within host immune cells marks the establishment of the initial infection. The internalization by macrophages triggers a localized inflammatory response, drawing other immune cells to the infection site.
The Body’s Immune Response and Latency
Following initial infection, the body mounts a specific immune response to contain the pathogen. Immune cells, including macrophages, T lymphocytes, B cells, and neutrophils, aggregate around the infected cells. This coordinated cellular effort leads to the formation of a granuloma, which serves to wall off the bacteria and restrict their replication.
As long as the bacteria are successfully contained within these granulomas, the infected individual experiences no symptoms and cannot transmit the disease. This state is known as Latent TB Infection (LTBI), where Mycobacterium tuberculosis remains dormant but viable within the body, sometimes for decades. However, if the immune system becomes weakened due to factors such as HIV infection, malnutrition, aging, or immunosuppressive medications, the granulomas can break down. When this containment fails, the bacteria can reactivate, multiply, and escape from the granulomas, leading to Active TB Disease, characterized by symptoms and the ability to spread the infection.
Development of Drug Resistance
A significant challenge in controlling tuberculosis is the pathogen’s increasing ability to develop resistance to antibiotics. Drug resistance arises when Mycobacterium tuberculosis undergoes genetic mutations that alter the bacterial targets of the drugs or the pathways involved in drug action. These mutations allow the bacteria to survive exposure to medications that would normally kill them.
Human factors significantly contribute to the emergence and spread of drug-resistant strains. A common cause is when patients do not complete their full, often lengthy, course of TB treatment. Incomplete or inconsistent treatment allows some bacteria with pre-existing, low-level resistance mutations to survive and multiply, leading to a population of drug-resistant organisms.
Multidrug-Resistant TB (MDR-TB) refers to strains resistant to at least the two most powerful first-line drugs, isoniazid and rifampicin. An even more concerning development is Extensively Drug-Resistant TB (XDR-TB), which is MDR-TB that has also acquired resistance to fluoroquinolones and at least one of the three second-line injectable drugs. These highly resistant forms are much harder to treat, often requiring longer courses with more toxic medications and having lower cure rates.