Studies zero in on biology TB bacteria use to evade immune response Premium

India's focus on tuberculosis research, including antimicrobial resistance, Mtb survival mechanisms, and potential new antibiotics.

Tuberculosis (TB) is a major focus in India’s healthcare goals. The country is steadily improving its ability to diagnose and track TB patients and help them adhere to the long course of antibiotics required to treat it. But with increasing antimicrobial resistance in Mycobacterium tuberculosis (Mtb), the pathogen that causes TB, many existing antibiotics aren’t working as effectively to kill it. So researchers are studying Mtb to identify its important proteins and then design new drugs that can act against them.

This is not an easy problem to solve. The pathogen has co-evolved with humans for millennia. Researchers have found the Mtb complex was present as long as 70,000 years ago. Such a long relationship between the two species has allowed the microbe ample time to evolve and trick the human immune system in many ways.

One of them is its ability to grow in macrophages. The first line of human immune cells that destroy many other invading microorganisms are actually Mtb’s home. Macrophages are designed to engulf foreign particles, including microbes. They can initiate a plethora of chemical reactions involving peroxides, free radicals, and other compounds that break down the engulfed particle or microbe. These reactions often collectively induce a state called oxidative stress and alter the chemical nature of molecules, including the DNA, the RNA, and/or the proteins of life-forms, rendering them dysfunctional or even literally broken up. Macrophages also use diverse strategies to starve the engulfed microbes of essential nutrients, eventually killing them.

But these techniques don’t work against Mtb. Mtb keeps itself protected in clusters called tubercles (hence the name of the disease) surrounded by lipids (fatty substances) in the lungs. Though it’s a respiratory pathogen, it has been known to spread to various other tissues. It can also stay dormant in the cells for a long time, up to a few decades, without causing disease or spreading to other people.

Researchers believe Mtb’s many survival abilities are a result of its large genome, consisting of 4.4 million base pairs. To compare, the respiratory bacteria Staphylococcus aureus has 2.8 million base pairs and Streptococcus pneumoniae, 1.9 million to 2.7 million. 

A larger genome means more proteins. Scientists are yet to understand the role of many Mtb proteins — but they believe Mtb’s genetic and protein machinery allows it to lead an independent life once it finds a home inside the macrophages.

Scientists are intrigued by whatever allows Mtb to survive and persist in the macrophage’s hostile environment and are on the lookout for proteins that shield it. One category of proteins called the cysteine synthase enzymes is of particular interest. They help cells synthesise cysteine, a sulphur-containing amino acid. Cells use cysteine to make antioxidants, whereby the sulphur disrupts the reactions that cause oxidative stress.