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How does our immune system respond to different stages of tuberculosis?

  • Photo : Purabi Deshpande / Research Matters
    Photo : Purabi Deshpande / Research Matters

Tuberculosis (TB), caused by the notorious bacteria Mycobacterium tuberculosis, is a deadly disease that kills millions each year across the world. Studies have shown that humans first contracted the disease about 6000 to 9000 years ago and since then there have been attempts to understand and describe this disease. Although our knowledge about it has multiplied since the time Robert Koch identified the bacteria, we still have a long way to go before we can effectively eliminate or control the spread of tuberculosis, thanks to the emergence of drug resistance in the bacteria.

In an attempt to understand how the bacterium interacts with our body’s immune system, researchers at the Indian Institute of Science (IISc), Bengaluru, along with their counterparts in other institutes, have analysed the various molecular and immunological responses produced by our body at different stages of the infection.

There are three known clinical manifestations of tuberculosis infection in humans. Pulmonary tuberculosis affects the lungs, and the patient suffers from a chronic cough, spitting sputum with blood, fever, night sweats and weight loss. Extrapulmonary tuberculosis affects other organs like the brain, lymphatic system, genitourinary tract, bones and joints, etc. There is yet another stage, which one in three of us might be in, called latent tuberculosis. Here the bacterium hides in our body without inducing any symptoms in the infected individual. About 5%-10% of subjects with latent tuberculosis can develop full-blown tuberculosis when the bacterium becomes active. The rest can live perfectly normal, healthy lives.

During replication, the bacterium causing tuberculosis, namely Mycobacterium tuberculosis, expresses an array of diverse proteins, some of which are antigenic—that is invoke a response from our immune system.  The array of antigens expressed and their concentration can differ in the three clinical manifestations of tuberculosis infection. The study, published in Nature’s Scientific Reports, and funded by the Department of Biotechnology, Government of India, explores the mechanism behind these differences, which could have implications on the diagnosis of the disease and the development of vaccines.

“Scientists have predicted that certain lymphocytes—cells of our immune system—have functionally different responses in patients with clinically different stages of tuberculosis. However, a definitive analysis of these distinctive features of these cells in patients with active pulmonary TB or extrapulmonary TB versus latent TB infection, especially in infected patients living in India, is lacking”, says Prof. Annapurna Vyakarnam, a visiting Professor at IISc, who led the study. India, along with other southeast Asian countries, contributes to half of tuberculosis-related deaths in the world, making the study more relevant.

The researchers of the study analysed the functionally distinct CD4 T helper cells—an important type of lymphocyte that recognises specific proteins expressed by the TB bacterium. The CD4 cells secrete proteins important for our immunity, called cytokines which can help macrophages (another type of white blood cell) to kill the pathogen. Further, there are also ‘polyfunctional’ T cells that produce many cytokines, thus providing better resistance than CD4 T that secrete a single cytokine.

The researchers found that patients with pulmonary tuberculosis had fewer polyfunctional T cells that respond to four of the antigens expressed by Mycobacterium tuberculosis that the researchers tested compared to subjects with latent TB, who had significantly larger number of polyfunctional T cell in their blood.  The researchers analysed these polyfunctional cells further for the combinations of cytokines expressed.  Specifically, they probed the cells for known cytokine signatures associated with promoting protection versus disease.  They discovered that subjects with latent TB had polyfunctional T cells that expressed a cytokine signature associated with immune protection.  On the other hand, subjects with extrapulmonary TB or pulmonary TB had few polyfunctional cells and the cytokine signature expressed by these cells was pro-inflammatory and associated with disease.  In the case of subjects with pulmonary TB, the researchers found that such cells preferentially accumulated in the lung, at the site of infection.

Our body’s immune system has a ‘memory’ that identifies repeat attacks of pathogens. Memory T cells, as the name suggests, can rapidly respond to an infection to kill a given pathogen. The researchers of the study found that in patients with pulmonary and extrapulmonary tuberculosis, had fewer long lived central memory T cells compared to subjects with latent TB, which are known to be important for long-lived immunity.

But what happens in patients whose immune system is already compromised due to AIDS (Acquired Immunodeficiency Syndrome) or other diseases? “HIV (Human immunodeficiency virus) is known to preferentially infect, replicate and kill CD4 T helper cells. A major consequence of the HIV infection is the increased susceptibility of those with AIDS to TB.  In fact, HIV is the biggest predisposing factor to the increased global prevalence of TB”, explains Prof. Vyakarnam and we are currently engaged in research to better understand how HIV infection disrupts the polyfunctional T cell response to the TB bacterium.

This study plays a vital role in helping scientists design the right kind of vaccine to combat TB. “If one can determine precisely what types of immune cells define patients with latent tuberculosis and establish whether these specific immune cells are lost or decreased in patients with full-blown TB, then this will greatly enhance both diagnosis and vaccine development”, says Prof. Vyakarnam, talking about the importance of such studies. “It also helps in vaccine monitoring where vaccines are tested for their efficacious based on tracking what types of CD4 T helper cells they induce in the host”, she adds

Currently, the only licensed vaccine available to protect against tuberculosis is the Bacillus Calmette–Guérin (BCG) vaccine that is administered to children immediately after birth. BCG is partially protective as it protects infants from TB but a single BCG dose administered immediately after birth is not known to completely protect the host from TB in adulthood. “If we find out what types of immune responses are critical controlled TB infection (i.e. latent asymptomatic TB), we can then reliably design vaccines that specifically enhance or promote the precise combination of CD4 T helper cells implicated in such protective immunity”, remarks Prof. Vyakarnam with the hope that their research can help save millions from the clutches of tuberculosis.