Regulation of actin dynamics during Legionella pneumophila infection: a novel function of Naip5 (611.2)

Abstract

Clearance of Legionella pneumophila (Legionella), the causative agent of Legionnaire’s disease, a potentially fatal pneumonia, requires efficient phagolysosomal fusion. Regulation of the host actin cytoskeleton is crucial for proper vesicle trafficking, which in turn promotes efficient phagosome‐lysosome fusion and destruction of invading pathogens. Naip5 is an intracellular NOD‐like receptor (NLR) that detects and promotes the degradation of Legionella via its flagellin. The molecular mechanisms of Naip5‐mediated clearance are unknown. It is this study’s objective to decipher the effect of Naip5 on actin dynamics and its upstream regulators to promote phagosome‐lysosome fusion and restriction of the bacterium.During Legionella infection, Naip5‐/‐ bone marrow‐derived macrophages (BMDMs) exhibited less phagosome‐lysosome fusion events, which was due to lack of caspase‐7 activation. The absence of active caspase‐7 in Naip5 cells inhibited the dephosphorylation (activation) of cofilin, blocking formation of new actin filaments. This lack of F‐actin formation hinders efficient phagolysosomal fusion and therefore allows intracellular replication of Legionella.Taken together, these data establish for the first time that Naip5 regulates actin polymerization during infection with Legionella by activating caspase‐7 to modulate the activation of the upstream regulator of actin: cofilin. Understanding the novel molecular mechanisms of Naip5 regulation of the host cytoskeletal network will provide novel targets to develop therapeutic interventions for numerous infectious diseases.Grant Funding Source: Supported by: R01HL094586