Tuberculosis (TB) remains one of the most significant public health challenges in India and across the globe. Despite the advancements in diagnostic and treatment methods, the rise in antimicrobial resistance has made TB harder to treat. This makes understanding how Mycobacterium tuberculosis (Mtb), the bacteria responsible for TB, evades the human immune response all the more critical. Recent research has focused on identifying the ways Mtb can persist and thrive in hostile environments within the body, helping scientists design more effective treatments.

The Evolutionary Companion of Humans

The Mtb bacteria have coexisted with humans for over 70,000 years, giving them ample time to evolve strategies to survive inside the human body. When Mtb enters the body, it primarily targets the lungs, but it can also spread to other tissues. One of its survival tactics is forming clusters called tubercles, surrounded by protective fatty substances called lipids, allowing it to remain dormant for decades without causing disease. During this dormancy phase, Mtb avoids the immune system’s attacks and resurfaces when the body’s defenses are weakened.

Evading Immune Response Inside Macrophages

A key aspect of Mtb's survival lies in its ability to thrive inside macrophages, the body’s first line of defense against invaders. Macrophages typically engulf pathogens and destroy them through chemical reactions that generate oxidative stress, a condition that alters and breaks down the pathogen’s molecules. However, Mtb has developed a way to resist this process, continuing to live inside these immune cells without being destroyed.

Researchers believe that the bacteria’s large genome, consisting of 4.4 million base pairs, is responsible for its survival. Compared to other respiratory pathogens like Staphylococcus aureus (2.8 million base pairs) and Streptococcus pneumoniae (up to 2.7 million base pairs), Mtb’s larger genome allows it to produce more proteins and adapt to hostile environments.

Cysteine Synthase Enzymes: A Key to Mtb’s Defense

Scientists have zeroed in on a specific group of enzymes known as cysteine synthases, which play a crucial role in Mtb’s ability to survive oxidative stress. These enzymes help synthesize cysteine, an amino acid that plays a key role in producing antioxidants, which counteract the damaging effects of oxidative stress.

A recent study by researchers at the CSIR-Centre for Cellular and Molecular Biology (CCMB) in Hyderabad focused on how these enzymes function within Mtb. They found that two enzymes, CysK2 and CysM, are particularly vital for the bacteria’s survival during periods of oxidative stress and nutritional deficiency. These enzymes enable the bacteria to produce antioxidants and protect themselves from the harmful environment created by macrophages.

The researchers conducted experiments on mice, infecting them with both wild-type Mtb (with functioning cysteine synthases) and mutant Mtb (where the genes for cysteine synthases were knocked out). The results showed that wild-type Mtb survived better inside the mice, highlighting the importance of these enzymes in protecting the bacteria.

Potential for New Treatments

Targeting cysteine synthase enzymes could open up new avenues for TB treatment. Researchers at Vinay Nandicoori’s lab at CCMB tested a list of compounds that inhibit cysteine synthase enzymes. These compounds were found to inhibit Mtb growth, making existing TB drugs, like isoniazid, more potent. Since humans do not produce cysteine synthase enzymes, these inhibitors could become a promising target for new antibiotics that specifically attack Mtb without harming human cells.

The Broader Picture of Mtb Survival Strategies

In addition to cysteine synthases, researchers are exploring other mechanisms that Mtb uses to survive. Some studies focus on how Mtb manipulates phosphate and carbon metabolism to fuel its life cycle. Others investigate how Mtb strengthens its cell wall to resist oxidative stress or tricks host cells into producing molecules that help repair damage caused by the immune system.

An exciting development is the discovery that Mtb can erase the "epigenetic memory" of macrophages. Epigenetic memory allows cells to pass on information about past infections to new cells, which helps the body respond more quickly to recurring infections. By erasing this memory, Mtb weakens the immune system’s ability to fight it.

Future Implications

While these discoveries provide valuable insights into how Mtb evades the immune system, there is still a long way to go before these findings translate into new treatments. More research is needed, particularly using human cells, to understand how these mechanisms function in the human body. However, the progress made in understanding Mtb's survival strategies brings hope that more effective TB treatments could be on the horizon.