Immune System Tracking Improves With Discovery of New Tuberculosis Protein

Researchers at UT Southwestern Medical Center have identified a protein that helps the immune system respond to tuberculosis (TB), one of the world's leading infectious diseases. The findings, published in The Journal of Immunology, revealed that a protein called sorting nexin 5 (SNX5) plays a previously unknown role in helping immune cells alert the body to infection and control damaging inflammation.

The study found that SNX5 is key to a process known as major histocompatibility complex (MHC) class II antigen presentation. During this process, immune cells display fragments of bacteria on their surface to signal other immune cells that an infection is present. Without SNX5, that communication system breaks down, leading to poorer activation of immune cells and increased lung inflammation during TB infection.

The findings show that SNX5 is a previously unrecognized regulator of that process during Mycobacterium tuberculosis infection. By linking a component of the cell's protein-sorting machinery to antigen presentation and inflammation, this work provides new insight into how the immune system responds to tuberculosis."

Beatriz Dias, Instructor of Internal Medicine, UT Southwestern Medical Center

Despite decades of research, tuberculosis remains a major global health challenge, causing more deaths than any other infectious disease. Scientists continue to investigate how the body fights the infection and why disease severity varies among patients.

SNX5 was already known to help move materials within cells and to play a role in the body's defenses against viral infections, but its role in bacterial infections had remained unclear. Therefore, Dr. Dias, study leader Michael Shiloh, M.D., Ph.D., Professor of Internal Medicine and Microbiology at UT Southwestern, and their colleagues decided to investigate its role in TB infections.

They found that mice lacking SNX5 experienced higher mortality after TB infection than mice with normal levels of the protein. Both groups carried similar amounts of TB bacteria. The key difference appeared to be how their immune systems responded to the infection. Mice without SNX5 developed more inflammation in their lungs, which can damage tissue and contribute to worse outcomes.

"This suggests the defect lies not in controlling the pathogen itself but in the body's ability to tolerate infection and limit tissue damage," Dr. Dias said.

Further experiments showed that SNX5 helps the body strike a balance between mounting a protective immune response and preventing excessive inflammation that can damage healthy tissue.

"A better understanding of these pathways may ultimately help identify new approaches to reduce harmful inflammation while preserving protective immune responses during infection," Dr. Shiloh said.

He noted that the project was inspired in part by his collaboration with the late Beth Levine, M.D., at UT Southwestern. Her pioneering work in autophagy, membrane trafficking, and host defense helped shape the study's direction.