Written by Somdatta Karak At the end of 1929, Germany started a campaign in Lübeck to vaccinate newborns against tuberculosis (TB) using the BCG vaccine. Unfortunately, 251 babies received an oral BCG vaccine contaminated with live TB-causing microbial pathogen Mycobacterium tuberculosis (M.tb). These children were followed up for three years. The study found 90% of these children developed TB disease in the various parts of the digestive system (since the pathogen was ingested) as well as lymph nodes and some even in the lungs and ears. Approximately 31% (77) of the vaccinated children died within the first year of the accident, but none later. At the same time, 16% of them never developed any symptoms. This disaster set many safety protocols in place at that time for vaccine production and dissemination. But to date, scientists are puzzled about this one question - why did the babies react differently to M.tb. This is the basis of other important questions such as how TB spreads in a person, when they access healthcare and how they are treated. And, depending on the kind of TB, the patient experiences vary greatly. Differing impacts of TB Most people today find out they are infected with M.tb when they seek healthcare help because of coughing and breathlessness. It primarily passes through air from infected persons to others as a respiratory pathogen. Most TB patients recover on being treated with a combination of antibiotics, such as rifampicin and isoniazid for at least six months. But the disease can also kill some. Across the world, WHO says 1.5 million people die each year due to TB. At the same time, some people do not develop any symptoms despite being infected or clear out the pathogen very swiftly. These differences motivate scientists to think of devising ways for the treatments to be as personalised and effective as possible for the patients. For this, they look into the details of the workings of the pathogen and the host’s immune system against the pathogen. A host cell offers food and a suitable place for the microbe to survive, reproduce, and spread. On the other hand, the host has immune cells of many kinds that patrol and identify foreign particles, including microbes, that do not belong to its system. Immune cells called macrophages can engulf the foreign particles and put them in compartments called phagosomes. Like suicide bombers, they can degrade the contents within themselves, and eventually blow themselves up too. The neighbouring immune cells consume the broken cell parts to grow in size and number and keep up the defence. Interestingly, studies show unique ways that M.tb hijacks the macrophages. How the body deals with M.tb M.tb houses itself well in the macrophages of the lungs. It goes into the phagosome but doesn’t allow the phagosome to kill it. It feeds on the energy-rich lipids, and scientists argue this might keep the microbes from starving while being trapped in the phagosome. It can create perforations in the macrophages so that they can escape from one and enter the other nearby macrophages. They can create masses of dead macrophages and stay dormant amid them for years. Alternately, they might also enter the bloodstream and reach other body parts. Clinicians have also documented TB in bones, eyes, reproductive tracts, and digestive tracts. When treated with antibiotic drugs, most M.tb die. But some persist and resist the drug. Some persist by making physical changes in response to the drugs. For example, the pathogen alters its metabolic requirements or creates a biofilm of cellulose around itself to protect it from external stresses. And some are able to withstand antibiotics better because of changes at the genetic level. Such changes can happen via random mutations in key genes. For example, if the pathogen’s DNA repair genes don’t function well enough, it raises the possibility of more variants being formed. Among those variants, some give rise to M.tb that do not let the antibiotic enter its cell and bind to its target or it ably throws the antibiotic out of its cell. It is much more challenging to treat persistent and drug-resistant M.tb infections. This is especially a challenge for TB outside the lungs since they are not diagnosed very easily. Scientists are not fully convinced if such cases are indeed M.tb infections. Those are Mycobacterium infections, but the tests do not efficiently differentiate between types of Mycobacterium. On the other hand, a recent study describes in detail how M.tb grows in rodent livers. Irrespective of the reason, there is delay among these patients in seeking medication allows the pathogen more time to grow, spread and cause damage, require a more complex cocktail of antibiotics, and can lead to worse outcomes for the patients. Genetic variations The genetic lineages found in East Asia can also cause TB differently. In this region, there are two prominent M.tb genetic lineages – 1 and 2. Studies estimate that lineage 1 had evolved about 60,000 years back and specialized to live in low-density human populations. It causes fewer fatalities. Scientists hypothesize that the pathogen needed the host to be alive for it to also thrive. Lineage 2, on the other hand, arose later and evolved to live in high-density human populations. It can afford to kill more human hosts, while possibly being transmitted between humans. Just as in the pathogen, food, nutrition and metabolism determine human fitness too. The RATIONS study done among under-nourished TB patients in Jharkhand, India in 2023 showed food rations and micronutrient pills helped the patients gain weight and reduced the chances of death. They also showed that the patients’ household contacts with better nutrition had lesser chances of infection. On the other hand, multiple studies show that other existing health conditions such as diabetes or HIV infection reduce immune action and lead to more complications. Scientists also hint that the growth stage of the macrophages around the pathogen also determines the possibility of getting infected or clearing away the microbe. Reducing TB fatalities TB is a result of a complex interplay between M.tb and human immune cells. We have clues about why TB manifests differently in different people. But we need sustained efforts for these leads to translate into interventions. We need programs, such as The Indian Tuberculosis Genomic Surveillance, that aim to keep an eye on the M.tb variants in the country, their spread patterns and their response to treatments. Such efforts are important since M.tb has reasons to evolve for faster and higher transmissions in our overcrowded cities. Similarly, we need to understand the role of human genes in mediating immunity against TB. Most studies to understand the immune system are done in rodents and don’t necessarily translate for humans. We need to overcome such limitations. Similarly, clinicians and scientists need to work with each other much more closely to report unusual cases and study their bases. Better nutrition and access to healthcare reduce TB fatalities. But to eradicate TB completely, we need more nuanced approaches of diagnostics and therapeutics. That seems still some distance away. Somdatta Karak, PhD, heads science communication and public outreach at CSIR-Centre for Cellular and Molecular Biology, Hyderabad.
