Autophagy Evasion and Endoplasmic Reticulum Subversion: The Yin and Yang ofLegionellaIntracellular Infection

Abstract

The gram-negative bacterial pathogen Legionella pneumophila creates a novel organelle inside of eukaryotic host cells that supports intracellular replication. The L. pneumophila-containing vacuole evades fusion with lysosomes and interacts intimately with the host endoplasmic reticulum (ER). Although the natural hosts for L. pneumophila are free-living protozoa that reside in freshwater environments, the mechanisms that enable this pathogen to replicate intracellularly also function when mammalian macrophages phagocytose aerosolized bacteria, and infection of humans by L. pneumophila can result in a severe pneumonia called Legionnaires' disease. A bacterial type IVB secretion system called Dot/Icm is essential for intracellular replication of L. pneumophila. The Dot/Icm apparatus delivers over 300 different bacterial proteins into host cells during infection. These bacterial proteins have biochemical activities that target evolutionarily conserved host factors that control membrane transport processes, which results in the formation of the ER-derived vacuole that supports L. pneumophila replication. This review highlights research discoveries that have defined interactions between vacuoles containing L. pneumophila and the host ER. These studies reveal how L. pneumophila creates a vacuole that supports intracellular replication by subverting host proteins that control biogenesis and fusion of early secretory vesicles that exit the ER and host proteins that regulate the shape and dynamics of the ER. In addition to recruiting ER-derived membranes for biogenesis of the vacuole in which L. pneumophila replicates, these studies have revealed that this pathogen has a remarkable ability to interfere with the host's cellular process of autophagy, which is an ancient cell autonomous defense pathway that utilizes ER-derived membranes to target intracellular pathogens for destruction. Thus, this intracellular pathogen has evolved multiple mechanisms to control membrane transport processes that center on the involvement of the host ER.

The respiratory microbiome in bronchial mucosa and secretions from severe IgE-mediated asthma patients

“…Legionella is able to replicate intracellularlly in macrophages that have phagocytized aerosolized bacteria, and several studies have shown that Legionella pneumophila creates endoplasmic reticulum (ER)-like vacuoles that support intracellular replication. Through this mechanism the bacteria are able to interfere host autophagy processes, which is an ancient cell autonomous defense pathway based on ER-derived membranes to target intracellular pathogens for destruction [55–58]. The presence of Legionella in our BB samples could be explained by this mechanism, but future studies focused on the chronic presence of these bacteria in the respiratory system will be needed to confirm these findings and their medical implications.…”

MTOR-Driven Metabolic Reprogramming Regulates Legionella pneumophila Intracellular Niche Homeostasis

“…One potential MTOR-independent LCV expansion mechanism could be a direct membrane acquisition from other intracellular compartments. Indeed, early secretory vesicles tether and directly fuse with the LCV [6,68] thus it was tested whether the secretory compartment contributes to LCV expansion during MTOR suppression. To this end, Myd88-/- BMMs infected with Δ flaA bacteria were treated for 3hrs with PP242 and brefeldin A to disperse the Golgi compartment or nocodazole to block microtubules-dependent vasicular trafficking during the late LCV expansion phase (Fig 8i).…”

Biological Diversity and Evolution of Type IV Secretion Systems

“…This suggests that Legionella spp., typically have large substrate repertoires, although the effector set can be quite distinct from species to species (Gomez-Valero, submitted). The functions of effectors that have been revealed up to now target many cellular pathways and different eukaryotic organelles, including cell uptake and exit, endocytosis, vesicle trafficking, autophagy, mitochondria, cytoskeleton, ubiquitination/proteasome, ribosome, transcription factors, and the nucleus (Escoll et al 2016; Finsel and Hilbi 2015; Qiu and Luo 2017; Sherwood and Roy 2016). (see Chapter “ Subversion of Host Membrane Dynamics by the Legionella Dot/Icm Type IV Secretion System ”).…”