MONDAY, JUNE 18, 2018

Researchers show how TB survives in host cells

A team of Emory University researchers has shown that M. tuberculosis and several of its close relatives use a family of host enzymes called ABL-family tyrosine kinases to enter into host cells and survive.
The researchers also showed that imatinib, an Abl-family inhibitor, limits TB infection, and works just as successfully against antibiotic resistant strains. In addition, when given alongside traditional front-line antibiotics, the drugs worked synergistically to increase their effectiveness.
By targeting the host — not the mycobacteria itself — the researchers were able to reduce the host's mycobacteria load and target antibiotic-resistant strains, all while enhancing the effectiveness of front-line antibiotics.
"This study implicates host tyrosine kinases in entry and intracellular survival of M. tuberculosis and M. marinum and suggests that imatinib may have therapeutic efficacy against tuberculosis," Daniel Kalman, the lead investigator of the study, said.
The researchers found that M. tuberculosis and its relatives exploit ABL within the host cell to gain entry, and then again once inside the cell. This prevents the formation of phagolysosomes which typically fuse with lysosomes that contain enzymes that can break down their contents.
"Once inside the cell, tuberculosis hangs out in phagocytic cells in a compartment called the phagosome," Kalman said. "But what the Mycobacterium does once inside the phagosome is very crafty. It stops the phagosome from fusing with the lysosome, where the bacteria could be killed, and instead replicates and isolates itself."
Imatinib is known commercially as Gleevec and is already FDA approved.
"Inhibiting ABL with Gleevec disrupts this carefully orchestrated bacterial survival mechanism, and tips the balance back in our favor," Kalman said. "Because Gleevac targets the host rather than the pathogen it is less likely to engender resistance compared with conventional antibiotics. And by reducing bacterial load, imatinib will likely reduce the possibility of M. tuberculosis developing resistance against co-administered conventional antibiotics, which could extend the lifespan of these drugs."
It is estimated that close to one-third of the world's population — more than two billion people — are infected with Mycobacterium tuberculosis. According to the World Health Organization, five to 10 percent of infected people eventually develop active tuberculosis and can transmit the bacterium to others. Nearly two million die from the disease each year. The current treatment regimen for TB is long and arduous, making patient compliance difficult. As a result, some strains of the bacteria have become resistant to most or all of the available antibiotics.