Autophagy-A Story of Bacteria Interfering with the Host Cell Degradation Machinery

Abstract

Autophagy is a highly conserved and fundamental cellular process to maintain cellular homeostasis through recycling of defective organelles or proteins. In a response to intracellular pathogens, autophagy further acts as an innate immune response mechanism to eliminate pathogens. This review will discuss recent findings on autophagy as a reaction to intracellular pathogens, such as Salmonella typhimurium, Listeria monocytogenes, Mycobacterium tuberculosis, Staphylococcus aureus, and pathogenic Escherichia coli. Interestingly, while some of these bacteria have developed methods to use autophagy for their own benefit within the cell, others have developed fascinating mechanisms to evade recognition, to subvert the autophagic pathway, or to escape from autophagy.

Keywords: autophagy; innate immune response; pathogens; pattern recognition receptors; xenophagy.

Figure 1

Overview of the autophagy pathway. Autophagy can be subdivided into following stages: (A) signal induction, which is regulated by the serine threonine kinases AMPK (AMP-activated kinase) and mTOR (mammalian target of rapamycin complex 1) (B) phagophore nucleation, which is induced by the Beclin1-containing phosphatidylinositol 3-kinase (PI3K) class III complex (C) vesicle expansion and autophagosome formation, which is governed by two ubiquitin-like conjugation systems, namely, ATG5-ATG12 and LC3 (microtubule-associated protein light chain 3). (D) autophagosome and lysosome fusion and (E) degradation and recycling. All stages are described in detail in their chapters, respectively (created with biorender.com).

Figure 2

Autophagic elimination of invading bacteria. Cytoplasmic bacteria and bacteria within phagosomes can be degraded through autophagy. After sequestration, the autophagosome fuses with a lysosome to form an autophagolysosome. Some bacteria can escape from the phagosome. These intracellular bacteria are polyubiquitinated and recognised by autophagy receptor proteins to deliver them directly to the phagophores (shown on the left). Bacteria captured in phagosomes are degraded in a process called LC3-associated phagocytosis (LAP; shown on the right) (created with biorender.com).

Figure 3

Autophagy as an antibacterial defence mechanism. Autophagy can be induced following the uptake of bacteria into the host cell during phagocytosis or after the escape of the bacteria from the phagosomes into the cytosol. Internalised bacteria can induce xenophagy or LAP by different mechanisms, such as competing for amino acids or by stimulating pattern recognition receptors (PRRs) (created with biorender.com).

Figure 4

Bacterial evasion or subversion of autophagy pathways. (A) Francisella tularensis escapes from the phagosome to replicate in the host cytoplasm. Afterwards, it enters the autophagy pathway and replicates in autophagosomes. (B) Staphylococcus aureus inhibits the autophagosome lysosome fusion through p38 MAPK phosphorylation. Then, it either replicates in autophagosomes or escapes from the autophagosome in an unknown mechanism. (C) Yersinia sp. block the fusion with lysosomes. Thus, Yersinia creates a replicative niche in autophagosomes. (D) After infection of host cells, O. tsutsugamushi induces autophagy, but the bacteria can prevent their uptake into the autophagosome. (E) Anaplasma phagocytophilum secretes Anaplasma translocated substrate-1 (Ats-1) to induce autophagy. However, the bacteria-containing inclusions fuse with autophagosomes to form amphisomes, delivering nutrients for bacterial replication. (F) Ehrlichia chaffeensis translocates Ehrlichia translocated factor-1 (Etf-1) to induce Rab5-regulated autophagy. This leads to the generation of amphisomes to provide nutrients for bacterial growth. (G) While intestinal epithelial cells induce autophagy after invasion of Adherent-invasive E. coli (AIEC) due to NOD2 activation, AIEC upregulates host microRNAs to subvert autophagy. (H) After Adhesion, Enterohaemorrhagic E. coli (EHEC) expresses its Type III secretion system (T3SS), leading to the translocation of translocated intimin receptor (Tir), which activates Protein kinase A (PKA) and thus blocks autophagy formation. LC3-II is displayed as red dots, and bacterial effector proteins are in blue (created with biorender.com).