After 132 years of study and countless efforts, no toxin had ever been found for the deadly pathogen Mycobacterium tuberculosis.
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Now, Michael Niederweis, Ph.D., professor of microbiology at the University of Alabama at Birmingham, and colleagues have described the first known toxin of this pathogenic bacterium.
This toxin—Tuberculosis Necrotizing Toxin, or TNT—is the founding member of a novel class of previously unrecognized toxins present in more than 600 bacterial and fungal species, as determined by protein sequence similarity. Before the Niederweis discovery, those toxins were identified only as the "Domain of Unknown Function 4237."
Bacteria with those newly recognized toxins include Yersinia pestis, the pathogen that caused the bubonic plague known as the Black Death in Medieval Europe, and Listeria monocytogenes, one of the most virulent and deadly food-borne infections and the cause of Blue Bell Creameries recalls this year.
The lack of an identified toxin in M. tuberculosis had contrasted with nearly all other pathogenic bacteria whose toxins contribute to illness or death.
M. tuberculosis is notable for its survival inside macrophages, the immune cells that ingest and destroy infectious bacteria. The newly identified TNT, Niederweis says, plays a key role to induce necrotic death of the infected macrophage.
Thus, TNT enables the M. tuberculosis bacteria to escape from the macrophage and disseminate to other host cells in a person infected with tuberculosis, thus contributing to the survival of M. tuberculosis and spreading the disease.
"The battle between M. tuberculosis and the human immune system to control the fate of infected macrophages is critical in determining the outcome of the infection," Niederweis wrote.
"The control of host cell death is of utmost importance for the survival, escape and dissemination of M. tuberculosis."
How did this toxin evade discovery for more than a century? First, it is produced in vitro only in very small quantities—the Niederweis lab could detect it only in a cell culture filtrate that was concentrated 1,000-fold, equivalent to concentrating a gallon of milk to about one-third of a teaspoon.
Second, the toxin is deadly only when it is inside the host-cell cytosol; if the toxin is in the bloodstream or is added to the culture medium of in vitro host cells, it has no effect. Third, the toxin has no similarities to any other known toxin.
Niederweis discovered TNT while searching for something completely different. He was hunting for outer-membrane proteins that can act as a door to let nutrients outside the bacteria pass through the extremely impermeable, outer-membrane barrier of M. tuberculosis.
The Niederweis group thought they had found such a porin protein; but it had an unusual property—the end portion of the protein broke off after the pore formed in the outer membrane, and that end portion was extremely toxic, both in simple prokaryotic cells like bacteria and in the more complex eukaryotic cells of yeast, mammals and fish. ■