Abstract
Modeling human infectious diseases using the early life stages of zebrafish provides unprecedented opportunities for visualizing and studying the interaction between pathogens and phagocytic cells of the innate immune system. Intracellular pathogens use phagocytes or other host cells, like gut epithelial cells, as a replication niche. The intracellular growth of these pathogens can be counteracted by host defense mechanisms that rely on the autophagy machinery. In recent years, zebrafish embryo infection models have provided in vivo evidence for the significance of the autophagic defenses and these models are now being used to explore autophagy as a therapeutic target. In line with studies in mammalian models, research in zebrafish has shown that selective autophagy mediated by ubiquitin receptors, such as p62, is important for host resistance against several bacterial pathogens, including Shigella flexneri, Mycobacterium marinum, and Staphylococcus aureus. Furthermore, an autophagy related process, Lc3-associated phagocytosis (LAP), proved host beneficial in the case of Salmonella Typhimurium infection but host detrimental in the case of S. aureus infection, where LAP delivers the pathogen to a replication niche. These studies provide valuable information for developing novel therapeutic strategies aimed at directing the autophagy machinery towards bacterial degradation.
Highlights
In the last two decades, it has emerged that autophagy plays a myriad of roles in the immune system, in addition to its long known role as a degradation and recycling process essential for cellular homeostasis [1,2,3]
The production of reactive oxygen species, which is intricately linked with Lc3-associated phagocytosis (LAP), was demonstrated using a bacterial biosensor that showed activity when bacteria were ingested by macrophages of wild type zebrafish but not in Rubicon- or Cyba-depleted hosts
Zebrafish infection models are proving to be valuable additions to cell culture systems and mammalian models for studying how autophagic mechanisms contribute to the innate host defenses or underlie diseases pathologies
Summary
In the last two decades, it has emerged that autophagy plays a myriad of roles in the immune system, in addition to its long known role as a degradation and recycling process essential for cellular homeostasis [1,2,3]. Autophagy represents an efficient effector mechanism of the innate immune system that directs intracellular microbes or damaged phagosomes towards degradation In this process, microbes are trapped by cytoplasmic fragments of membranes (phagophores) that form double membrane vesicles (autophagosomes), which subsequently fuse with lysosomes to degrade the contents [4,5]. SLRs, like p62, collect ubiquitinated host proteins from the cytosol, which can be processed into antimicrobial peptides after fusion with lysosomes This antimicrobial peptide delivery mechanism has been proposed to endow autophagosomes with a bactericidal capacity that is stronger than that of the anti-microbial environment inside phagosomes [20] (Figure 1C). Is an autophagy-related process linked with reactive oxygen production
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