THE ROLE OF THE NON-CANONICAL INFLAMMASOME IN INNATE IMMUNITY

ABSTRACT
Legionella pneumophila is an infectious bacterium that causes Legionnaire’s disease and remains a major cause
of morbidity and mortality in the immunocompromised individuals such as the elderly and cancer patients.
Macrophages are the main immune cells that can clear Legionella after activation of the canonical Nlrc4/Naip5
inflammasome. Caspase-11 is a component of the non-canonical inflammasome and mice lacking caspase-11
allow significant Legionella replication in their macrophages. Down-regulation of the homologous caspase in
human macrophages increases their permissiveness to Legionella. Our preliminary data show that caspase-11
is necessary for fusion of the Legionella-containing vacuole with the lysosomes via a mechanism that requires
the polymerization and depolymerization of actin. Using state-of-the-art techniques including 3D confocal
microscopy and high resolution SIM-S microscopy, RNA seq and proteomics analyses, we identified new
molecules that are cleaved by caspase-11 and regulate restriction of Legionella in macrophages. This proposal
will investigate the molecular mechanisms leading to caspase-11-mediated clearing of Legionella infection.

Grant Number: 5R01AI159452-05
NIH Institute/Center: NIH
Principal Investigator: Amal Amer