Is tolerating TB a better way to go than resisting it?

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Researchers have discovered that rather than fighting to resist tuberculosis, the body’s tolerance to the bacteria causing TB, Mycobacterium tuberculosis (or Mtb), is the key mechanism for preventing the spread of the infection.

More surprisingly, they found that having excessive levels of T cells, which are known as soldiers of our immune system, could cause more harm than good.

Historically, our view of host defense against infection was that we must eliminate pathogens to eradicate disease. However, this perspective has recently been challenged as scientists have taken a lesson from plant biologists about an ancient strategy involving the ability to “tolerate” rather than “resist” infection to maintain health.

This concept, referred to as “disease tolerance”, provides an opportunity to develop new strategies that mitigate the consequences of infection.

Since the discovery of Mtb over a century ago, researchers have made great progress in defining strategies that facilitate elimination of the bacteria. For instance, the discovery of antibiotics was a major breakthrough in the treatment of active TB. However, greater than 90 percent of TB-infected individuals tolerate the bacteria without any treatment.

Maziar Divangahi, a pulmonary immunologist and associate director of the Translational Research in Respiratory Diseases Program at the Research Institute of the McGill University Health Centre, and a member of the McGill International TB Centre in Montreal, has been trying to explain why the vast majority of people infected with Mtb can tolerate the infection without developing disease. Clinicians refer to this condition as “latent tuberculosis”, and it affects a quarter of the global population.

“TB is a perfect example of disease tolerance,” he says.

“We always thought that having more T cells would provide better protection against TB. Instead, we found that it could imbalance disease tolerance causing extensive tissue damage and ultimately killing the host,” says Divangahi, lead author of the new study in Science Immunology, as well as the associate director of the Meakins-Christie Laboratories.

Our body’s defense system is divided into two arms: one is resistance, which aims to eliminate the pathogen, while the other is tolerance, which is designed to control the tissue damage caused by the infection.

“While disease tolerance is an established field of research in simple organisms such as plants, our understanding of this host defense strategy in humans is very limited,” says Divangahi.

Although immunologists and vaccinologists have made progress in the study of host resistance to infectious diseases, little is known about the mechanisms of disease tolerance in humans.

Divangahi’s team determined that a protein in the mitochondria called cyclophilin D (CypD) acts as a key checkpoint for T cell activation. Through collaboration with Russell Jones from McGill University, an expert in T cell biology, they identified that CypD is required for controlling T cell metabolism.

“T cells are traditionally considered to be important in eliminating Mtb,” says Divangahi. “However, we found that increasing T cell activation in mice by eliminating a metabolic checkpoint unexpectedly compromised host survival without any impact on the growth of Mtb.”

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“In contrast to conventional thinking, we show that T cells are essential for regulating the body’s tolerance to Mtb infection,” explains one of the study’s first authors, Nargis Khan, who is currently a postdoctoral fellow in Divangahi’s lab.

Given the widespread drug resistance to various Mtb strains, the limited pipeline of effective antibiotics, and the lack of an efficient vaccine, alternative approaches to treat TB are urgent.

“If we could understand the mechanisms of ‘natural immunity’ that controls TB in 90-95 percent of infected individuals,” says Divangahi,”we will able to design a novel therapy or vaccine to substantially reduce the worldwide burden of this ancient disease.”

Grants from the Canadian Institutes of Health Research (CIHR) supported this work.

Source: McGill University