Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (Mtb), is a leading cause of death by an infectious agent globally, claiming the lives of over 1.6 million people annually. Researchers from the University of Massachusetts Amherst and Seattle Children’s Research Institute have made a surprising discovery about the immune system’s response to Mtb. They found that prior exposure to a specific genus of bacteria, Mycobacterium, remodels the body’s first-line defenders in the immune system.
These findings suggest that targeting all aspects of the immune response through an integrated treatment approach could be more effective in combatting tuberculosis.
According to Alissa Rothchild, the senior author of the paper and assistant professor in the Veterinary and Animal Sciences Department at UMass Amherst, humans inhale thousands of liters of air each day, making them vulnerable to inhaling various potentially infectious pathogens that the immune system must respond to.
When discussing immunity, the focus is often on the adaptive immune system, which develops immunity through prior exposure to pathogens and creates protective antibodies. Vaccines play a crucial role in teaching the adaptive immune system what to recognize and protect against.
However, the body’s first responders to pathogens are macrophages, a crucial part of the innate immune system. These macrophages are known as alveolar macrophages (AMs) in the lungs. They reside in the lung’s alveoli, the small air sacs where oxygen passes into the bloodstream. Previous research by Rothchild has shown that AMs do not mount a strong immune response when initially infected by Mtb.
Mtb exploits this weak response and replicates inside the AMs, effectively hiding from the body’s defenses. Targeting this initial step of infection and enhancing the AMs’ response could potentially change the course of tuberculosis. Rothchild wonders if the body’s innate immune response can be modified to make AMs more effective in fighting Mtb.
To investigate potential remodeling of the innate immune response, researchers conducted an experiment using two different mouse models. The first model involved the Bacillus Calmette-Guérin (BCG) vaccination, widely used as the only vaccine for tuberculosis. In the second model, researchers induced a contained Mtb infection that had previously shown protection against subsequent infections.
The mice were later exposed to aerosolized Mtb, and infected macrophages were analyzed through RNA sequencing. The researchers found significant differences in the RNA of the macrophages from each model. While both sets of AMs displayed a stronger pro-inflammatory response compared to those from unexposed mice, the BCG-vaccinated AMs activated a specific type of inflammatory program driven by interferons, while the AMs from the contained Mtb infection exhibited a qualitatively different inflammatory program.
Further experiments demonstrated that different exposure scenarios resulted in changes to the AMs themselves, and some of these changes were influenced by the lung environment.
These findings indicate that macrophage response is highly adaptable, and there is potential to harness this adaptability to remodel the innate immune system to effectively fight tuberculosis.
The study forms part of the larger IMPAc-TB (Immune Mechanisms of Protection Against Mycobacterium Tuberculosis) program, a global, cross-species effort aimed at comprehensively understanding immune responses to eliminate tuberculosis. Dr. Kevin Urdahl, one of the paper’s co-authoras and lead Principal Investigator for the IMPAc-TB consortium, explained that the program’s goal is to uncover how the immune system controls or eradicates Mtb to facilitate the development of effective vaccines.
The findings from Rothchild’s team will contribute to the interpretation and understanding of results obtained from human alveolar macrophages in individuals recently exposed to Mtb in tuberculosis-endemic regions. This research takes us one step closer to developing more effective vaccines and treatment strategies to combat tuberculosis, a persistent global health threat.
1. Source: Coherent Market Insights, Public sources, Desk research
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