Researchers discover new portal for Mycobacterium tuberculosis to enter the body

In tracking one of the world’s deadliest pathogens, researchers from University of Texas Southwestern Medical Center, Dallas, TX, may have found a new way that tuberculosis gains entrance into the human body—microfold cell (M-cell) translocation—and have published their new study online in the journal Cell Reports.

Each year, 8 million cases of tuberculosis and 1.3 million deaths worldwide are caused by Mycobacterium tuberculosis (Mtb). Historically, Mtb was believed to enter the body through inhalation, which led to active infection. But research has also shown that approximately 10% of all cases of active tuberculosis involve isolated infection of cervical lymph nodes—mycobacterial cervical lymphadenitis, or scrofula—which begs the question of whether inhalation is necessary for active infection.

M-cells are highly specialized epithelial cells overlying the lymphoid follicles of the small and large intestines, and are charged with the transportation of antigens and microorganisms from the airway or mucosal surfaces to the underlying lymphoid tissue.

“The current model of disease is that when Mtb bacteria are inhaled, they reach the end of the lung – the alveolus – and then are ingested by a macrophage, a type of white blood cell that swallows and kills invading bacteria,” said lead researcher Michael Shiloh, MD, assistant professor, Internal Medicine and Microbiology, UT Southwestern.

In multiple mouse models, Dr. Shiloh and fellow researchers demonstrated that Mtb enters through M-cells and initiated infection. Upon intranasal Mtb infection, M-cell depleted mice demonstrated reduced invasion, reduced or delayed dissemination of Mtb to the lymph nodes, as well as reduced mortality. Then, researchers demonstrated that translocation of Mtb across two M-cell Transwell models was rapid and transcellular.

“Our study shows that once Mtb bacteria are inhaled, they also can enter the body directly through M-cells that line the airway tissue, and then travel to the lymph nodes and beyond. This is a key finding that suggests disease onset outside of alveolar macrophages is not only possible, but also important in the pathogenesis of tuberculosis infection,” explained Dr. Shiloh.

These findings, he added, may finally shed light on scrofula, an ancient condition also known as “King’s evil,” in which tuberculosis does not infect the lungs, but rather, the lymph nodes of the neck. Scrofula still occurs today, especially in immunocompromised patients.

In addition, their findings may be pivotal in finding agents that could prevent Mtb from entering the body, figuratively closing the M-cell door.

Dr. Shiloh and colleagues are now working on finding human cell-surface receptors form MtB involved with Mtb’s M-cell translocation, and further elucidating how M-cells move Mtb from the cell surface to its bottom.

“Understanding these mechanisms in vivo would allow for targeted blockade of bacterial transport via vaccinations or medications, which could ultimately lead to new ways to prevent or treat airway infectious diseases,” concluded Dr. Shiloh.

This study was supported by grants from the National Institutes of Health.