Nature Communications: Dhiraj Kumar latest study on overcoming major hurdles in tuberculosis control

Mycobacterium tuberculosis (Mtb) continues to infect, cause illness (tuberculosis) and kill a large number of individuals globally. Among numerous factors that thwart any tuberculosis control program, lack of an effective vaccine and long duration of treatment are the two most critical.

The latest Open Access article published by D. Kumar and collaborators is now available on Nature Communications.

Anti-tuberculosis (TB) drugs, while being highly potent in vitro, require prolonged treatment to control Mycobacterium tuberculosis (Mtb) infections in vivo. We report here that mesenchymal stem cells (MSCs) shelter Mtb to help tolerate anti-TB drugs. Through this research, we propose that targeting the unique immune-privileged niche, provided by MSCs to Mtb can have a major impact on tuberculosis prevention and cure.

Tuberculosis is a serious disease affecting a significant population of the world, particularly in the developing and under-developed settings. The causal organism Mycobacterium tuberculosis is an ancient pathogen of the human hosts, a belief, which was further reinforced upon their discovery in the Egyptian mummies. Millions of people are infected and several hundred thousand die of TB annually all over the globe. The complexities of the disease severely limit our efficiency in executing the three major arms of disease control i.e. prevention, diagnosis, and treatment.

Despite drugs (like antibiotics) being available against Mtb, which show very high efficacy to kill the pathogen in petri dishes and culture tubes, the treatment outcomes are compromised due to the need to take the drugs for 6-9 months. Similarly, while BCG, the only commercially available vaccine against TB has served as an effective vaccine against some form of childhood tuberculosis, its efficacy in controlling TB in adults remain questionable.

Human lung biopsy samples. From: Mesenchymal stem cells offer a drug-tolerant and immune-privileged niche to Mycobacterium tuberculosis
Human lung biopsy samples. From: Mesenchymal stem cells offer a drug-tolerant and immune-privileged niche to Mycobacterium tuberculosis

In this study, we show that mesenchymal stem cells, the cells of special repair capacity which are present through out our body, provide a safe heaven to the Mtb allowing them escape both drugs as well as host immune response. The study establishes some new paradigms in tuberculosis prevention and control.

In this study we report that some of the classical immune effectors, well known for their function in controlling Mtb, have quite contrasting effects on Mtb when they are present within the adult stem cells. Instead of killing the pathogen, these immune effectors, also known as cytokines, help them survive and grow better within these cells. Through a series of experiments, this study identifies an interesting mechanism through which MSCs are able to provide a safe shelter to this pathogen. The presence of MSCs which were infected with Mtb were also observed in the human lung granulomas or lesions where the bacteria reside, underscoring the relevance of this observation.

This study shows ways to improve treatment outcomes and also how to potentially make vaccines more efficacious against TB, possibly reducing the treatment time and treatment outcomes. Secondly, the blunting of IFNγ and TNFα on the MSC-resident Mtb effectively suggests why most anti-TB vaccines fail. That is because all known vaccine candidates as well as the BCG, rely on generating a strong immune response which produces lots of IFNγ. However since this cytokine is not effective on MSC-resident Mtb, these vaccines will require additional support to make them efficacious.

While there is no clear path available, smart inclusion of PGE2 inhibitors in high-risk areas could dramatically reduce the chances of new TB cases among BCG-vaccinated individuals.

Nature Communications 11, 16 June 2020: Mesenchymal stem cells offer a drug-tolerant and immune-privileged niche to Mycobacterium tuberculosis

Read more about the research activity of the Cellular Immunology Group, ICGEB New Delhi.