Research Article: Activation of Focal Adhesion Kinase by Salmonella Suppresses Autophagy via an Akt/mTOR Signaling Pathway and Promotes Bacterial Survival in Macrophages

Date Published: June 5, 2014

Publisher: Public Library of Science

Author(s): Katherine A. Owen, Corey B. Meyer, Amy H. Bouton, James E. Casanova, Vojo Deretic.

http://doi.org/10.1371/journal.ppat.1004159

Abstract

Autophagy has emerged as an important antimicrobial host defense mechanism that not only orchestrates the systemic immune response, but also functions in a cell autonomous manner to directly eliminate invading pathogens. Pathogenic bacteria such as Salmonella have evolved adaptations to protect themselves from autophagic elimination. Here we show that signaling through the non-receptor tyrosine kinase focal adhesion kinase (FAK) is actively manipulated by the Salmonella SPI-2 system in macrophages to promote intracellular survival. In wild-type macrophages, FAK is recruited to the surface of the Salmonella-containing vacuole (SCV), leading to amplified signaling through the Akt-mTOR axis and inhibition of the autophagic response. In FAK-deficient macrophages, Akt/mTOR signaling is attenuated and autophagic capture of intracellular bacteria is enhanced, resulting in reduced bacterial survival. We further demonstrate that enhanced autophagy in FAK−/− macrophages requires the activity of Atg5 and ULK1 in a process that is distinct from LC3-assisted phagocytosis (LAP). In vivo, selective knockout of FAK in macrophages resulted in more rapid clearance of bacteria from tissues after oral infection with S. typhimurium. Clearance was correlated with reduced infiltration of inflammatory cell types into infected tissues and reduced tissue damage. Together, these data demonstrate that FAK is specifically targeted by S. typhimurium as a novel means of suppressing autophagy in macrophages, thereby enhancing their intracellular survival.

Partial Text

Serovars of Salmonella enterica are facultative intracellular Gram-negative entero-pathogens that cause a spectrum of human diseases ranging from localized gastroenteritis to typhoid fever. Pathogenic Salmonella strains use two Type III secretion systems (T3SS), encoded within Salmonella Pathogenicity Islands I (SPI-1) and 2 (SPI-2) to translocate distinct arrays of virulence proteins into host cells. Although there is some functional overlap, effectors translocated via T3SS-1 facilitate bacterial penetration of the intestinal epithelium, while effectors translocated via T3SS-2 promote intracellular survival [1], [2]. Expression of T3SS-2 occurs 2–5 hours after entry of the bacteria into host cells and is necessary for remodeling of the phagosome into a specialized bacterial replication niche, the Salmonella containing vacuole (SCV) [2]. If local host defenses are insufficient to limit infection to the intestinal tract, bacteria disseminate systemically, first colonizing the mesenteric lymph nodes (mLNs), followed by the liver and spleen.

Autophagy is a dynamic process that broadly impacts multiple immunological functions. At the level of innate immunity, autophagy is a strategy employed by host cells for the capture and elimination of intracellular pathogens (xenophagy). Not surprisingly, successful pathogens have evolved numerous ways to protect themselves from autophagic degradation. Recent evidence indicates that Salmonella can actively suppress autophagy to promote its intracellular survival in epithelial cells [37]. Here we show that S. typhimurium also inhibits autophagic processing in macrophages, through a pathway mediated by focal adhesion kinase and its downstream signaling partner Akt.

 

Source:

http://doi.org/10.1371/journal.ppat.1004159

 

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