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

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.

Host Serine/Threonine Kinases mTOR and Protein Kinase C-α Promote InlB-Mediated Entry of Listeria monocytogenes

“…However, two previous reports indicated that mTORC1 promotes intracellular replication of the Gram-negative bacterium Salmonella enterica serovar Typhimurium (37,38). These studies demonstrated that intracellular Salmonella avoids autophagic killing by stimulating the recruitment and activation of mTORC1 on vacuoles containing bacteria.…”

Salmonellae interactions with host processes

“…The reactivation and recruitment of mammalian target of rapamycin (mTOR) to SCVs, which occurs following the acute and transient amino acid starvation response that is induced on infection, inhibits the induction of autophagy and possibly provides an escape mechanism for the bacteria 146 . It has been suggested that in macrophages, an unknown SPI-2 effector is involved in the recruitment of focal adhesion kinase to the SCV, which can then activate mTOR through Akt 147 . Furthermore, it is likely that autophagic targeting of damaged or altered SCVs influences antigen presentation, as well as adaptive and autoimmunity, and a deeper understanding of this process should expand our knowledge of chronic human diseases.…”

Legionella pneumophila S1P-lyase targets host sphingolipid metabolism and restrains autophagy

“…Furthermore, it has been shown that autophagy acts as a cell-autonomous defense mechanism against intracellular bacteria, contributing to antibacterial immunity by regulating the inflammatory immune response and routing engulfed intracellular bacteria toward lysosomal degradation (12,13). Many pathogens are able to evade autophagy, although the molecular mechanisms at play remain largely uncharacterized (14)(15)(16)(17)(18)(19)(20). Among these pathogens L. pneumophila is known to escape cellular attack by blocking autophagy defenses (21).…”