Transforming the immune system to combat tuberculosis

Tuberculosis, caused by Mycobacterium tuberculosis, kills 1.6 million yearly. Researchers found that prior exposure to a related bacterium remodels immune defenders. This discovery may lead to a more effective treatment strategy against tuberculosis, according to a study from the University of Massachusetts Amherst and Seattle Children’s Research Institute.

Alissa Rothchild, assistant professor in the Veterinary and Animal Sciences Department at UMass Amherst and the paper’s senior author, said, “We breathe in thousands of liters of air every day. This essential process makes us incredibly vulnerable to inhalation of all sorts of potentially infectious pathogens that our immune systems have to respond to.” 

In our body, we have multiple immune systems. We often think of the adaptive immune system, trained by vaccines. However, the first line of defense is the innate immune system, led by macrophages. They recognize and destroy pathogens, signaling for backup by activating different inflammatory programs.

In the lungs, alveolar macrophages (AMs) are the defenders. However, when infected with Mtb, they don’t initially mount a robust immune response. This weakness becomes a vulnerability that Mtb takes advantage of, causing severe effects.

Rothchild said, “Mtb takes advantage of the immune response. They turn the AM into a Trojan Horse where the bacteria can hide from the body’s defenses.”

Could we enhance the initial response to Mtb in the lungs? Researchers led by Rothchild explored changing the innate immune response. Recent studies hint at the ability to make lasting changes in the innate immune system. However, the mechanisms still need to be fully understood. 

In experiments using two mouse models—one with BCG vaccination and the other with a controlled Mtb infection—the team investigated conditions where the innate immune response could be remodeled.

After exposing mice to Mtb, researchers tested their immune response. The BCG-vaccinated mice activated a specific inflammatory program driven by interferons. Meanwhile, those with a controlled Mtb infection activated a different agenda. 

The experiments revealed changes in the macrophages themselves, suggesting adaptability. According to Rothchild, this shows the potential to use this adaptability to reshape the innate immune system for better tuberculosis defense.

This study, backed by NIH and NIAID, is part of a global effort called IMPAc-TB, aiming to understand immune responses against tuberculosis. Dr. Kevin Urdahl, leading IMPAc-TB, explains that the program seeks to learn how the immune system fights TB, aiding in vaccine development. Rothchild’s findings will contribute to interpreting human cell responses in TB-endemic regions.

The study reveals that the body’s defense against tuberculosis can be strengthened by remodeling the innate immune system, specifically alveolar macrophages (AMs). This adaptability opens up therapeutic possibilities. 

These insights contribute to the IMPAc-TB initiative, aiming to understand immune responses for effective TB elimination and vaccine development. Dr. Kevin Urdahl highlights the importance of these findings for interpreting human cell responses in TB-endemic regions, advancing the fight against tuberculosis.

Journal reference:

1. Dat Mai, Ana Jahn, et al., Exposure to Mycobacterium remodels alveolar macrophages and the early innate response to Mycobacterium tuberculosis infection. PLOS Pathogens. DOI: 10.1371/journal.ppat.1011871.