Macrophage Autophagy and Bacterial Infections

Abstract

Autophagy is a well-conserved lysosomal degradation pathway that plays key roles in bacterial infections. One of the most studied is probably xenophagy, the selective capture and degradation of intracellular bacteria by lysosomes. However, the impact of autophagy goes beyond xenophagy and involves intensive cross-talks with other host defense mechanisms. In addition, autophagy machinery can have non-canonical functions such as LC3-associated phagocytosis. In this review, we intend to summarize the current knowledge on the many functions of autophagy proteins in cell defenses with a focus on bacteria-macrophage interaction. We also present the strategies developed by pathogens to evade or to exploit this machinery in order to establish a successful infection. Finally, we discuss the opportunities and challenges of autophagy manipulation in improving therapeutics and vaccines against bacterial pathogens.

Keywords: autophagy; bacteria; inflammation; macrophage; pathogen; phagocytosis; xenophagy.

Figure 1

Roles of autophagy machinery in macrophage antibacterial defenses. Autophagy machinery plays several functions in innate immunity to bacterial infection such as: (A) xenophagy: selective capture and lysosomal degradation of cytosolic and vacuolar pathogens. Xenophagy requires formation of an autophagosome and depends on ULK1, autophagy-related (Atg)14, Beclin-1, Atg5-12, and autophagy receptor proteins such as p62 (A.1). Bacterial compartment is captured by autophagosome either via ubiquitination (A.2, 3) or host glycan recognition by galectins (A.3). (B) LC3-associated phagocytosis (LAP): LC3 is conjugated onto the membrane of phagosome containing bacteria to promote fusion with lysosome. LAP depends on Rubicon, Beclin-1, and Atg5-12. (C) Induction of autophagy enables production and delivery of antimicrobial peptides to bacterial compartments. (D) Autophagy machinery reduces the expression of scavenger receptors to limit phagocytosis of some intracellular pathogens. (E) Autophagy controls inflammation by limiting inflammasome activation. PAMP, pathogen-associated molecular pattern; DAMP, damage-associated molecular pattern; AMP, antimicrobial peptide; ROS, reactive oxygen species; mDNA, mitochondrial DNA.

Figure 2

Autophagy evasion strategies adopted by bacterial pathogens inside macrophages. To evade autophagy in macrophages bacterial pathogens have developed a wide array of strategies such as: (A) masking of microbial surface to avoid recognition. (B) Manipulation of macrophage signaling pathways involved in autophagy regulation. (C) Direct cleavage of autophagy proteins or signaling lipid. (D) Limitation of autophagy machinery expression or function by miRNA regulation. (E) Inhibition of autophagosomes/lysosome fusion. PI3P, phosphatidylinositol 3-phosphate; LC3-PE, LC3 lipidated with phosphatidylethanolamine.