TB or not TB

 In the Shakespearean sense, this is a brief yet knotty tale of granulomas, of organized aggregates of immune cells in which things are not what they seem.

 Viewed through the fog of traditional belief, granulomas, the nodules that are a hallmark of tuberculosis, are heroes in stemming growth of the infecting mycobacteria.

 Now it appears that science’s sunlight has dissolved a century of fog.  Analysis of mycobacteria infections in tiny zebrafish embryos reveals that the early granuloma actually facilitates mycobacterial growth.  

Enough of this overwritten drivel!  “The play’s the thing, ” the bard said. 

In brief, new research has discovered the signaling pathway by which a granuloma encourages TB pathogenesis.  And finding how to block that pathway may lead to new therapies for TB and other serious disorders. 

TB bacteria infect host macrophages in a larval zebra fish and prod epithelial cells to produce MMP9, a signaling protein associated with worsening infection. The MMP9 stained green in this mount, while the macrophages in the tubercle stained red. Credit: J.M. Davis and T. Pozos, University of Washington

In a report of the study in Science, on January 22, 2010, John F. Rawls, Ph.D., assistant professor in the UNC departments of cell and molecular physiology and microbiology and immunology,  joined co-authors from the University of Washingtion.

Their study identified a new molecular pathway that infecting mycobacteria use to coerce disease-fighting cells to switch allegiance and work on their behalf.  

Basically, the bacteria residing with immune cells called macrophages secrete the small protein ESAT-6, long implicated in virulence, which then induces nearby epithelial cells to produce the enzyme Matrix Metalloproteinase 9 (MMP9). 

Here the ball really gets rolling, as MMP9 secretion by epithelial cells is ramped up in the vicinity of an infected TB macrophage.  The enzyme’s action draws in uninfected macrophages to join the infected ones, thereby expanding the granuloma. 

Thus, according to the new research, TB bacteria simultaneously suppress the inflammatory action of macrophages to create a safe haven in them, while nudging epithelial cells to signal for the arrival of more macrophages which, in turn, are inducted into granuloma expansion. 

“The implications of these results extend beyond TB to other types of inflammation,” says Rawls. “This novel signaling cascade from bacterium to epithelium to macrophage could represent a common strategy by which other microorganisms or other factors influence the process of inflammation.” 

And so it is hoped that this discovery could help raise the curtain on some exciting innovative therapies that will bring it down on TB, arthritis, and other inflammatory disorders. Fini.

Les Lang

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