When normal macrophages (green - on the left) become clogged up with cell debris (red - on the right), they lose their ability to engulf TB bacteria.
Image credit: Steven Levitte
The international study, led by the University of Cambridge in the UK, is published in the journal Cell.
It looks at the effect that smoke particles might have on macrophages - literally the "giant eaters" of the immune system. Macrophages act like "vacuum cleaners" for unwanted material, helping to dispose of and recycle billions of dead cells every day.
Tuberculosis (TB) is an infection caused by the bacterium Mycobacterium tuberculosis. It can spread to any organ in the body, but it is most commonly found in the lungs.
TB spreads from person to person through the air and can cause breathlessness, wasting and, eventually, death. Treatments exist and typically last for about 6 months.
Macrophages are the immune system's first line of defense against TB when it first enters the body. The immune cell engulfs the bacterial cell and tries to break it down. In most cases, this is successful - macrophages wipe out the TB bacteria and infection is avoided.
However, sometimes, the TB bacteria manage to avoid being broken down. Moreover, they even use the macrophages to give them a ride deep inside the body and spread infection.
Once it is established, TB then organizes the macrophages into tight clusters called tubercles, or granulomas. At this stage, the macrophages still have not given up, but if they lose this last battle, the bacteria use the structure to spread from cell to cell.
Clogged-up macrophages cannot engulf TB bacteria so well
For their study, the team used zebrafish to observe what happens inside macrophages when they encounter TB bacteria. Zebrafish are particularly useful for this kind of study because they are transparent.
- Global annual deaths to TB dropped 47% between 1990-2015
- TB is curable and preventable
- Worldwide, 9.6 million people fell ill with TB and 1.5 million died from it in 2014.
The researchers genetically screened zebrafish to find out which gene variants made them susceptible to TB. One gene mutation made them particularly susceptible: it causes a deficiency in macrophages.
Macrophages break down unwanted material and they also recycle it. They have special digestion compartments inside them called lysosomes. The researchers found in the TB-susceptible zebrafish, mutant macrophages accumulated undigested material in their lysosomes.
The authors note that this accumulated undigested lysosomal material disrupts the macrophages' ability to recycle, and it also "impairs their migration to, and thus engulfment of, dying cells."
In the next phase of their study, the researchers showed that clogging up the macrophages' lysosomes in the zebrafish with non-biological material - such as tiny plastic beads - has the same result. They could not respond to infection when they were clogged up.
Macrophages become fatter and less agile
Lead investigator Lalita Ramakrishnan, a professor in Cambridge's Department of Medicine, explains that the macrophages, unable to recycle the debris, become "bigger and fatter and less able to move around and clear up other material," and adds:
"This can become a problem in TB because once the TB granuloma forms, the host's best bet is to send in more macrophages at a slow steady pace to help the already infected macrophages."
But the enlarged macrophages cannot move into the TB granuloma. The result is that the macrophages that are already inside the structure burst and form a "soup" in which the bacteria can grow and spread the infection.
Finally, the researchers examined macrophages from the lungs of people who smoke. They found their lysosomes were also clogged up, as they note in their conclusion:
"A majority of their alveolar macrophages exhibit lysosomal accumulations of tobacco smoke particulates and do not migrate to Mycobacterium tuberculosis. The incapacitation of highly microbicidal first-responding macrophages may contribute to smokers' susceptibility to tuberculosis."
The researchers suggest stopping smoking reduces the risk of developing TB because it allows the clogged-up, slow macrophages to die off and gradually be replaced by new, fit cells.
In January 2016, Medical News Today learned it may be possible to make old anti-TB drugs strong again by looking at 3D models of the compounds interacting with the bacteria.