Mycobacterium tuberculosis and immune system evasion
In my morning browsing of Science Daily Microbiology, I came across this headline, which describes one of the mechanisms by which the acid-fast bacterium M. tuberculosis is able to persist in the body despite our immune response against the pathogen. The ability of M. tuberculosis to evade the immune system helps to explain the chronic and episodic nature of tuberculosis disease manifestations.
The body normally responds to the presence of many pathogens by recruiting white blood cells, or phagocytes, to the site of infection. These cells then envelop the pathogens, and begin to digest the bacteria with specialized enzymes. This ultimately results in destruction of the pathogen, and clearance of the organisms from the body. There are a number of pathogens that are able to subvert this process though, which leads to our natural defenses being unable to clear an infectious agent. M. tuberculosis is an example of an organism that is able to evade immune system clearance, by blocking the ability of phagocytes to destroy the bacterial cells.
The lower respiratory system receives a constant influx of material from the atmosphere, yet the lobes of the lungs have very few microorganisms present, and there is no normal microbial flora associated with the lower respiratory system. This is in contrast to the upper respiratory system (the bronchiae, for example.) which has a significant number of organisms in the absence of any disease symptoms. This is due to the action of macrophages, a type of white blood cell that constantly moves through the tissue of the lungs searching foreign material that may be present. If a macrophage finds an M. tuberculosis cell though, the bacterium is phagocytosed by the macrophage, but is not killed by the process. The way that the bacterium accomplishes this is actually pretty neat! Some organisms are able to evade the process of phagocytosis by having a surface that is not amenable to engulfment by a white blood cell, and structures such as the bacterial capsule serve in this role. This is not what happens with TB. When a macrophage contacts an M. tuberculosis cell, it is able to engulf it just fine, however the bacterial cell is able to block the ability of the macrophage to deliver the killing digestive enzymes from cellular organelles called “lysosomes.”
The precise mechanism by which the tuberculosis bacteria are able to do this is not completely clear, but involves a number of specific proteins that virulent strains of the bacterium possess. The end result is that the bacteria get engulfed by macrophages, and then are able to grow inside the macrophage, which in turn allows the bacterium to evade other anti-microbial responses by the body. This means that in many cases, the body is unable to effectively clear the infection once it starts, leading to the chronic nature of many tuberculosis infections.
So back to the Science Daily article: researchers at Linkoping University in Sweden have developed a method for looking at living mycobacteria inside of a macrophage. Note that for the electron micrograph above, the bacterial cells are clearly visible in the picture on the right, but recall that electron microscope is not useful for looking at living cells. The researchers have added a gene for luciferase to the bacterium. This is the same enzyme that causes fireflies to glow, and enables the bacteria to glow when they are inside of a macrophage. It also, unlike many other glowing gene reporters, requires the bacterium to be alive in order to glow. The scientists are now able to visualize and assess the viability of M. tuberculosis cells inside of macrophages, and the amount of light shed corresponds to the number of bacteria inside of a macrophage. It is their hope that they will be able to use this experimental system to rapidly screen potential inhibitors of mycobacteria, either by blocking the ability of the bacterium to prevent phagocytic killing or by blocking the ability of the bacterium to multiply inside macrophages. A long way away from developing a cure for tuberculosis, but a novel way of potentially treating these infections that affect an estimated one third of all the people on Earth.
BONUS: What are some other mechanisms that the human body has for coping with tuberculosis?