Abstract
Autophagy is a fundamental and highly conserved eukaryotic process, responsible for maintaining cellular homeostasis and releasing nutrients during times of starvation. An increasingly important function of autophagy is its role in the cell autonomous immune response; a process known as xenophagy. Intracellular pathogens are engulfed by autophagosomes and targeted to lysosomes to eliminate the threat to the host cell. To counteract this, many intracellular bacterial pathogens have developed unique approaches to overcome, evade, or co-opt host autophagy to facilitate a successful infection. The intracellular bacteria Legionella pneumophila and Coxiella burnetii are able to avoid destruction by the cell, causing Legionnaires’ disease and Q fever, respectively. Despite being related and employing homologous Dot/Icm type 4 secretion systems (T4SS) to translocate effector proteins into the host cell, these pathogens have developed their own unique intracellular niches. L. pneumophila evades the host endocytic pathway and instead forms an ER-derived vacuole, while C. burnetii requires delivery to mature, acidified endosomes which it remodels into a large, replicative vacuole. Throughout infection, L. pneumophila effectors act at multiple points to inhibit recognition by xenophagy receptors and disrupt host autophagy, ensuring it avoids fusion with destructive lysosomes. In contrast, C. burnetii employs its effector cohort to control autophagy, hypothesized to facilitate the delivery of nutrients and membrane to support the growing vacuole and replicating bacteria. In this review we explore the effector proteins that these two organisms utilize to modulate the host autophagy pathway in order to survive and replicate. By better understanding how these pathogens manipulate this highly conserved pathway, we can not only develop better treatments for these important human diseases, but also better understand and control autophagy in the context of human health and disease.
Highlights
Autophagy is an essential cellular pathway which, at its most basic, acts to degrade unwanted molecules and recover nutrients for the cell
In this review we will discuss the role that autophagy plays during infections with L. pneumophila and C. burnetii, focusing on the effector proteins that they use to interfere with the host autophagy system (Table 1)
These studies suggest a complex interaction between L. pneumophila and the host autophagy pathway, encompassing both beneficial and detrimental aspects, that may be influenced by host specific factors and LCV maturation stage
Summary
Autophagy is an essential cellular pathway which, at its most basic, acts to degrade unwanted molecules and recover nutrients for the cell. Autophagy is an important host defence against intracellular pathogens, where it acts to direct invading bacteria to autolysosomes for degradation (a process known as xenophagy) (Rikihisa, 1984; Gutierrez et al, 2004; Nakagawa et al, 2004) Perhaps expectedly, this has led to an evolutionary arms race between host and pathogens, which have developed a range of mechanisms to evade destruction. The plasticity of the Legionella effector repertoire has been well documented, with comparative genomic studies revealing large variability in effector cohorts between Legionella species, with effectors largely unique to each species but presenting significant functional redundancy (Burstein et al, 2016; Gomez-Valero et al, 2019) This is likely a result of its association with a broad range of amoebal hosts, which would drive the evolution of an array of host specific genes that are redundant for infection in human macrophages (Park et al, 2020). In this review we will discuss the role that autophagy plays during infections with L. pneumophila and C. burnetii, focusing on the effector proteins that they use to interfere with the host autophagy system (Table 1)
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