Light-activated probe reveals how tuberculosis evades immune defenses

Tuberculosis (TB) is an infectious disease that kills more than a million people worldwide every year. The pathogen that causes the disease, Mycobacterium tuberculosis, is deadly in part because of its complex outer envelope, which helps it evade immune responses of infected hosts.

In an ACS Infectious Diseases paper, researchers developed a chemical probe to study a key component of this envelope. Their results provide a step toward finding new ways of inactivating the bacterium.

Because curing TB requires taking drugs for months, which can result in TB resistance to some antibiotics, scientists are working to develop new treatments. One possible target is the bacterium’s outermost layer, called the mycomembrane, which protects the bacteria from stressors. When M. tuberculosis is attacked by a host’s macrophage immune cells, the mycomembrane produces compounds that suppress the infected host’s immune response.

Previously, Ben Swarts, Sloan Siegrist and colleagues developed light-activated chemical probes that mimic some of these compounds and studied how they might interact with a host’s immune cells. Now, the researchers have developed a chemical probe for another mycomembrane component called mycolic acid. They designed the mycolic acid probe to enable the capture of interacting proteins within host immune cells—information that could help scientists better understand how M. tuberculosis survives in the assaulting environment of the host.

In an enzyme immunoassay, the probe stimulated an immune response similar to real mycolic acid in cultured macrophage cells from mice. Using fluorescence scanning, the researchers observed that the mycolic acid probe photo-labeled proteins in the macrophage cells. An immunoblotting technique determined that the probe interacts with a specific receptor—a protein known as TREM2—on macrophage cells, which suppresses immune cell activation.

Swarts and colleagues say their strategy provides researchers with a way to investigate the role of mycolic acids in M. tuberculosis pathogenesis. “Chemical probes can be valuable for discovering and characterizing host–pathogen interactions that are otherwise difficult to investigate,” Swarts explains.

“Knowing the molecular details of how M. tuberculosis cell envelope components manipulate the host response may inform new treatment strategies for TB in the future, such as immunotherapies targeting host proteins.”