Aaron Wyatt Lecture: Stephanie Shames

Unintended consequences: Augmentation of cell-intrinsic immunity by a Legionella Pneumophila effector protein

Host defense against intracellular bacterial pathogens is mediated largely by macrophages, which become highly microbicidal under inflammatory conditions – a phenomenon termed cell-intrinsic immunity. We discovered that cell-intrinsic restriction of the pulmonary pathogen Legionella pneumophila (Lp) - the etiological agent of Legionnaires’ Disease - is induced through the activity of the effector LegC4 - one of >300 effectors delivered into host cells by Lpthrough a Dot/Icm type IV secretion system. LegC4 and promotes virulence in Lp’s protozoan hosts, but, paradoxically, is deleterious to Lp in mammalian hosts. We found that LegC4 targets mammalian proteasome activator (PA)28ab, which is upregulated under inflammatory conditions to facilitates ubiquitin-independent proteasomal degradation of oxidant-damaged proteins. Our new work shows that PA28ab depletion phenocopies host defense induced by LegC4 in cultured macrophages and in a mouse model of Legionnaires’ Disease in vivo. Our data support a novel mechanism whereby PA28ab targeting by a pathogen effector augments cell-intrinsic host defense against intracellular bacterial pathogens.