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The host and microbial grounds that control the stromal-autonomous immune response

As macrophages express the broadest set of inflammasome-forming sensors and are a cellular target for many successful pathogens, it has been widely accepted to study inflammasome regulation and importance in this cell type. Yet, many cell types also express conserved or unique inflammasome-forming sensors that can mediate completely different functions to those described in macrophages. For instance, macrophage NLRP6 nucleate an inflammasome response upon lipoteichoic acid (LTA) sensing (Gram-positive bacteria lipid), yet epithelial cells use NLRP6 to induce to secrete mucus at the intestinal barrier. In addition, intestinal epithelial cells specifically express Nlrp9b, an RNA inflammasome sensor. Finally, exposure of pathogens to (skin, intestinal or alveolar) epithelial cells leads to an inflammasome-triggered cell shedding, and not to an inflammasome-mediated cell pyroptosis, ensuring efficient microbial rejection. For all these reasons, we anticipate that stromal cells (i.e. epithelial cells) might play yet unknown, but of most importance, immune functions against bacterial pathogens. 

Specifically, successful Mycobacterium tuberculosis (Mtb) infection mainly relies on hijacking the microbicidal response of alveolar macrophages. However, there are key and yet unanswered issues regarding the means by which Mtb can reach alveolar macrophages, present in the lower airway tract. Airway epithelial cells (AECs) are the major cell type lining the respiratory tract. They prevent microbes entry into the alveoli thanks to an innate host-defense system that enables mucociliary clearance. Recent major advances in stem cell biology have resulted in the development of organoïds, which enable the generation and maintenance of complex epithelium in vitro. Thus, airway organoids (AO) constitute a unique model to decipher Mtb-AEC interactions. Thanks to an already ongoing collaboration with the groups of Drs. H. Clevers and P. Peters, we successfully established AO at IPBS, micro-injection of Mtb in AO and live-imaging on a spinning disk microscope, in the IPBS BSL-3 facility. 

Our objective is now to establish the AO as a model for Tuberculosis by addressing Mtb fitness in AO and to study the role of AECs in mounting both inflammasome and cell-autonomous immune response toward Mtb as well as the immune and bacterial consequences.


Figure : Airway organoids (AO) to assess the stromal-autonomous immune response of epithelial cells upon Mtb infection: A. Bright field images of AO in culture; B. Fluorescence image of AO stained for the actin cytoskeleton (Phalloidin-Texas Red) and nuclei (Hoescht) acquired with an Olympus/Andor CSU-X1 spinning disk microscope; C. AO micro-injected with Mtb H37Rv expressing eGFP. Mtb-injected AO were stained with cell mask (deep red) to visualize AEC plasma membrane and live imaging was performed on an Andor/Olympus spinning disk microscope for 5 days. Picture illustrates Mtb interaction with AEC extruded inside the lumen of the AO and packed with the secreted mucus. © Céline Cougoule (IPBS, CNRS/UT3)


Principal Investigators: Céline Cougoule, Etienne Meunier
Other personnels: Stephen Adonaí León Icaza, Pierre-Jean Bordignon


Collaborations: Dr. Olivier Neyrolles, Dr. Geanncarlo Lugo, Dr. Christel Verollet
Dr Peter J. Peters, Maastricht MultiModal Molecular Imaging Institute (M4I), Maastricht, Netherlands
Dr Hans Clevers, Hubrecht Institute, Utrecht, Netherlands