The cells have machines that move toxins across them. The ESX-4 type VII secretion system is used to transport the potent exotoxin of M. tuberculosis, which kills more than 1 million people a year. Credit: University of Alabama.
Six years ago, Michael Niederweis described the first known toxin of the deadly pathogen, which had gone undetected for more than a century.
The University of Alabama at Birmingham and their colleagues have described the mechanism of the toxin's production and transportation, which is the major factor in the virulence of the pathogen.
The report published in Nature Communications identifies key secretion systems used by Mtb, which makes them candidate targets for therapeutic use.
Mtbbacteria are trapped inside phagosomes when they are inhaled into a human lung. Mtb prevents the phagosome from merging with a lysosome. Instead, Mtb grows inside the phagosomes and breaks out of the phagosomes into the cytosol of the macrophage, which it uses to kill the macrophage.
First, the toxin needs to be moved across the bacteria's cytoplasmic membrane, and then it needs to be moved across the bacteria's outer membrane to be exported. To do this,bacteria use a wide variety of specialized secretion systems, which are basically machines that recognize and transport the bacterial toxins or other proteins involved in a variety of bacterial functions.
Most of the major pathogens have been described, but there has been one exception.
Niederweis, David Pajuelo, Uday Tak, and others have used a comprehensive genetic analysis to learn which of the five type VII secretion systems in Mtb is used. They discovered which three secretion systems are needed to help the phagosome. The damage sieves allow the TNT to enter the macrophage, where it depletes the NAD+ and causes death.
The five type VII secretion systems in Mtb are known as ESX-1, ESX-2, ESX-3, ESX-4 and ESX-5. Each of the secretion systems has a complex of between seven and 15 genes. There were no roles for ESX-2 and ESX-4 up to now.
CpnT is a largerprotein that begins its journey as a part of TNT. When CpnT reaches the outer membrane, the toxins break away from the largerProtein. Both export to the cell surface and the production of CpnT/TNT need the ESX-4 system. This is the first known function for the ESX-4 system.
The researchers at the University of Alabama found that the two other ESXs are required to act in concert with one another to break the phagosomal membrane and allow the transfer of TNT into the Mtb.
"Our study shows that the only known exotoxin of Mtb is required for the secretion of the two previously uncharacterized type VII secretion systems, ESX-2 and ESX-4," said Niederweis.
In the Nature Communications paper, the researchers propose a model for the production, export, and secretion of Mtb, and they point out the steps of this process that are still unclear.
The discovery that the ESX-2 and ESX-4 systems need to act in concert with the ESX-1 system to permeabilize the phagosomal membrane raises important questions about the regulation of these activities. The study will definitely encourage further research in the areas of Mtb biology.
David Pajuelo and his team wrote about the toxy secretion and trafficking of Mycobacterium tuberculosis. There is a DOI: 10.1038/s41467-021-26925-1.
Nature Communications is a journal.
The only known exotoxin of the pathogen is found in the Mycobacterium tuberculosis.
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