An immune defect can make some vulnerable to a rare bacterial infection

Everyone inhales Mycobacterium avium complex (MAC) bacteria from time to time, but most people do not get sick. These bacteria, cousins ​​of the deadly Mycobacterium tuberculosis, tend to live out their harmless little lives in food, soil, water or dust.

Also, there are rare people who get really, really sick.

MAC is an “opportunistic” microorganism, explains Cecilia Lindestham Orlehamn, Ph.D., assistant professor at the La Jolla Institute of Immunology (LJI). Some people have risk factors, e.g cystic fibrosis and structural lung disease, for example, which make them more likely to develop symptoms after MAC exposure. The problem is that no one knows exactly why these factors make such a difference.

Now, Lindestham’s Orlehamn lab has discovered an immune cell defect linked to MAC risk. As reported by her team in Frontiers in Immunologypeople who show symptoms of MAC infection have fewer specialized Th1* cells (the “Th1 star”), which robs them of their ability to mount an effective immune response to the bacteria.

“We think that in these people, this cellular defect is exposed to the MAC,” explains Lindestham Orlehamn, who collaborated closely on the study with the University of Washington staff.

This study may be a step toward identifying biomarkers to predict the risk of lung disease progression and response to treatment in MAC patients.

If the T cells do not fight back

In 2020, Lindestham Orlehamn began researching how T cells fight disease. The hope was that by analyzing T cells from people previously infected with MAC, she would be able to identify key targets or epitopes where MAC-infected cells are vulnerable to attack by the immune system.

T cells are normally critical for fighting infections, but to everyone’s surprise, Lindest Orlehamn’s work showed that the human body has a very limited T cell response to MAC infection, and she was unable to detect MAC-specific epitopes.

It is quite unusual for a T-cell response to a pathogen to be so limited. It was as if the MAC-infected volunteers had almost no “immune memory” of the infection. Instead, Lindestham Orlehamn’s project discovered an unexpected cellular defect that may explain why some people get sick and others don’t. “It was also very interesting,” says Lindestham Orlehamn.

The hidden culprit

When Lindestham Orlehamn looked at global gene expression (which genes are “turned on”) in response to MAC infection, she noticed a stark difference in blood samples from people previously infected with MAC and healthy controls.

People who have had MAC appear to have an immunological defect that results in low numbers of special “helper” immune cells called Th1* cells in the body. Th1* cells normally help warn the body’s pathogen-fighting cells of danger.

Lindestham Orlehamn and her colleagues were among the first to show that Th1* cells are particularly important in fighting mycobacterial attack, both MAC and Mycobacterium tuberculosis.

Their work suggested for the first time that this Th1* defect could lead to increased susceptibility to disease. They suggest that without sufficient Th1* cells, some key immune cells never get the message that the MAC is trying to invade. This means that people susceptible to MAC can have both an overactive innate immune response (with some cells causing inflammation early in the disease process) and an underactive adaptive immune response (lack of activated T cells that actually stop the disease) .

For some people, this lack of immune protection is too much to bear. In people with cystic fibrosis, for example, thick mucus in the lungs can interfere with the ability of T cells to patrol tissues and detect MAC. The lack of Th1* cells could be a double whammy – adding immune system dysfunction to the already weak lung defenses. “That may partly explain it,” says Lindestham Orlehamn.

Next steps to combat MAC

Lindestham Orlehamn now wants to confirm whether there is a defect that leads to a reduction in the number of Th1* cells in humans before exposure to MAC. She plans to study samples taken from people early in the disease’s progression to see if Th1* deficiency is a feature of them as well. She would also like to study samples from people exposed to the same sources of MAC in the environment.

“If you live with someone with MAC, you’re likely to be exposed as well,” she says. “We want to see if we can identify specific T-cell responses in these people and look for differences between those who have the disease and those who don’t.”

This work may help researchers understand exactly how MAC transforms from harmless to highly pathogenic.