PgmNr Z637: Macrophage epithelial reprogramming underlies mycobacterial granuloma formation and promotes infection.

Authors:
Mark Cronan 1 ; Rebecca Beerman 1 ; Allison Rosenberg 1 ; Matthew Johnson 1 ; Joseph Saelens 1 ; Stefan Oehlers 1 ; Dana Sisk 1 ; Kristen Jurcic Smith 1 ; Le Trinh 2 ; Scott Fraser 2 ; John Madden 1 ; Joanne Turner 3 ; Jason Stout 1 ; Sunhee Lee 1 ; David Tobin 1


Institutes
1) Duke University, Durham, NC; 2) University of Southern California, Los Angeles, CA; 3) The Ohio State University, Columbus, OH.


Abstract:

Mycobacterium tuberculosis infection in humans triggers formation of granulomas, tightly organized immune cell aggregates that are the central structure of tuberculosis. Infected and uninfected macrophages interdigitate, assuming an altered, flattened appearance. Although pathologists have described these changes for over a century, the molecular program that mediates this transition is unclear. We find that mycobacterial infection results in macrophage induction of canonical epithelial molecules, driving formation of granulomas. Using the zebrafish-Mycobacterium marinum model and intravital microscopy, we identify bona fide adherens junction formation between granuloma macrophages and nucleation of this process via interactions with host epithelium. Macrophage-specific disruption of E-cadherin function results in disordered granuloma formation, decreased bacterial burden, and enhanced long-term survival of infected animals, suggesting that a canonical mycobacterial granuloma may be fundamentally host-detrimental.  In human clinical samples, granuloma macrophages are similarly transformed, paralleling E-cadherin-dependent mesenchymal-to-epithelial transitions in development and cancer, processes that profoundly regulate cell fate and function.



ZFIN Genetics Index
1. cdh1