Date Published: February 12, 2019
Publisher: Public Library of Science
Author(s): Won J. Kim, Annette Mai, Nathan J. Weyand, Maria A. Rendón, Koenraad Van Doorslaer, Magdalene So, Steven R. Blanke.
The Gram-negative human pathogen N. gonorrhoeae (Ngo) quickly attaches to epithelial cells, and large numbers of the bacteria remain on the cell surface for prolonged periods. Ngo invades cells but few viable intracellular bacteria are recovered until later stages of infection, leading to the assumption that Ngo is a weak invader. On the cell surface, Ngo quickly recruits CD46-cyt1 to the epithelial cell cortex directly beneath the bacteria and causes its cleavage by metalloproteinases and Presenilin/γSecretease; how these interactions affect the Ngo lifecycle is unknown. Here, we show Ngo induces an autophagic response in the epithelial cell through CD46-cyt1/GOPC, and this response kills early invaders. Throughout infection, the pathogen slowly downregulates CD46-cyt1 and remodeling of lysosomes, another key autophagy component, and these activities ultimately promote intracellular survival. We present a model on the dynamics of Ngo infection and describe how this dual interference with the autophagic pathway allows late invaders to survive within the cell.
Autophagy is critical for cellular homeostasis . Highly conserved from yeast to man, this catabolic process sequesters aging or damaged cytoplasmic contents and organelles in a structure called the autophagosome [2–4]. The autophagosome then fuses with the lysosome to form the autophagolysosome, where lysosomal enzymes degrade the sequestered contents for recycling [2–4]. Cells starved for nutrients also upregulate autophagy to hasten the recycling of their cytoplasmic contents [2, 5].
Autophagy is a well-established host defense mechanism against intracellular pathogens. Cells mount an autophagic response against Group A Streptococci and measles virus via the CD46-cyt1/GOPC pathway, causing their clearance . Cells target Salmonella-containing vacuoles for autophagic degradation in a NDP52-, optineurin-, and p62-dependent manner [10–13]. Conversely, intracellular pathogens have evolved means to counteract autophagic killing. For instance, Legionella evades autophagy using its effectors RavZ and Lpg1137 to cleave LC3 and Syntaxin17, respectively [38, 39]. Shigella flexneri employs VirA and IcsB to inactivate Rab1 and inhibit Atg5, respectively, to avoid being targeted to autophagosomes [40, 41]. For many pathogens, the mechanisms they use to evade autophagic killing are little understood.