- Mycobacterium tuberculosis bacteria invade human macrophages and prevent them from programmed cell death.
- Scientists have found a method to release the bacteria and kill them by a lower concentration antibiotic.
- PPM1A (Protein Phosphatase, Mg2+/Mn2+-dependent 1A) enzyme is a central component of both the antiviral and antibacterial responses of macrophages.
- Inducing this enzyme provoked by M. tuberculosis ends the macrophage's ability to undergo both intrinsic and extrinsic apoptosis.
Mycobacterium tuberculosis bacteria hijack human macrophages, persist inside the cells to evade immune destruction, and then prevent the macrophage from undergoing programmed cell death. This provides a niche where they grow in a protected environment that is hard to reach with antibiotics.
This hijacking which causes disease can now be stopped, according to a recent study by the University of Alabama at Birmingham researchers. In a proof-of-concept experiment, they were able to specifically force M. tuberculosis-infected macrophages into programmed cell death called apoptosis, thereby releasing the sheltered M. tuberculosis bacteria from the macrophage.
The released pathogenic bacteria could then be killed by a lower concentration of rifampicin, one of the front-line tuberculosis antibiotics that is ineffective against the sheltered intracellular bacteria.
Their preclinical findings show, for the first time, that drug-induced selective apoptosis of M. tuberculosis-infected macrophages is achievable. Furthermore, drug-induced apoptosis could also improve the adaptive immune response against the pathogen and potentiate vaccines.
Sun and colleagues in a previous study identified a macrophage enzyme called Protein Phosphatase, Mg2+/Mn2+-dependent 1A (PPM1A) as a central component of both the antiviral and antibacterial responses of macrophages. When M. tuberculosis infects macrophages, they found that it induced the upregulation of PPM1A, which in turn caused "immune paralysis" of the macrophages.
Specifically, the heightened PPM1A levels abrogated the ability of macrophages to send out an "alarm signal" (the efficient production of cytokines and chemokines) in response to pathogen-associated molecules like lipopolysaccharide, it blocked the rush to the "scene of the fire" (migration of macrophages in response to a chemotactic signal of infection from other cells), and it prevented the macrophage's ability to "put out the fire" (by impairing the macrophage's capacity to engulf, or phagocytose, bacteria, the first step in the normal defense against bacterial infections).
In this latest Scientific Reports paper, the UAB researchers greatly expand their understanding of PPM1A's role beyond immune paralysis. They show how the abnormal upregulation of this macrophage enzyme provoked by M. tuberculosis acts as a checkpoint that ends the macrophage's ability to undergo both intrinsic and extrinsic apoptosis.
Apoptosis is a normal, daily event. Between 50 billion and 70 billion cells in an adult undergo apoptotic death every day. Intrinsic apoptosis responds to a signal of cell aging or dysfunction from the inside, and extrinsic apoptosis responds to a 'death signal' from outside the cell.
The normal apoptosis of a macrophage after it has engulfed an invading bacterium leads to priming of cell-mediated immunity, helps to kill the intracellular bacteria and limits harmful tissue inflammation.
M. tuberculosis blocks these events, and when the bacteria are ready to exit the macrophage to disseminate, they induce necrosis, not apoptosis, of the cell, which evades stimulation of an immune reaction.
- Jim Sun et al., A 'release and kill' strategy may aid treatment of tuberculosis, Scientific Reports (2017).