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Review
. 2013 May 15;4(4):307-14.
doi: 10.4161/viru.24290. Epub 2013 Mar 27.

Cellular microbiology and molecular ecology of Legionella-amoeba interaction

Ashley M Richards  1 , Juanita E Von Dwingelo, Christopher T Price, Yousef Abu Kwaik
Affiliations
Review

Cellular microbiology and molecular ecology of Legionella-amoeba interaction

Ashley M Richards et al. Virulence. .

Abstract

Legionella pneumophila is an aquatic organism that interacts with amoebae and ciliated protozoa as the natural hosts, and this interaction plays a central role in bacterial ecology and infectivity. Upon transmission to humans, L. pneumophila infect and replicate within alveolar macrophages causing pneumonia. Intracellular proliferation of L. pneumophila within the two evolutionarily distant hosts is facilitated by bacterial exploitation of evolutionarily conserved host processes that are targeted by bacterial protein effectors injected into the host cell by the Dot/Icm type VIB translocation system. Although cysteine is semi-essential for humans and essential for amoeba, it is a metabolically favorable source of carbon and energy generation by L. pneumophila. To counteract host limitation of cysteine, L. pneumophila utilizes the AnkB Dot/Icm-translocated F-box effector to promote host proteasomal degradation of polyubiquitinated proteins within amoebae and human cells. Evidence indicates ankB and other Dot/Icm-translocated effector genes have been acquired through inter-kingdom horizontal gene transfer.

Keywords: Ankyrin; Ankyrin B; Dot/Icm; Legionnaire; RelA; SpoT; cysteine; effectors AnkB; farnesylation; pneumophila; polyubiquitin; ppGpp; prenylation; proteasomes.

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Figures

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Figure 1. The environmental life cycle of L. pneumophila within protozoa. (1) Flagellated L. pneumophila infect protozoa in the aquatic environment. (2) The LCV evades the default endosomal–lysosomal degradation pathway and becomes rapidly remodeled by the ER through intercepting ER-to-Golgi vesicle traffic and becomes rapidly decorated with polyubiquitinated proteins in an AnkB-dependent manner. (3) Under unfavorable stress conditions, such as nutrient deprivation, amoebae encyst, and bacterial proliferation will not occur due to nutrient limitation. Under growth-permissive conditions for the amoeba, the LCV is decorated with polyubiquitinated proteins, which are targeted for proteasomal degradation leading to elevated cellular levels of amino acids (AA) that power bacterial proliferation of the wild-type strain, while the ankB mutant is defective in this process and is unable to grow despite formation of ER-remodeled replicative LCV. (4) During late stages of infection, the LCV becomes disrupted leading to bacterial egress into the cytosol where the last 1–2 rounds of proliferations are completed. Upon nutrient depletion (see magnified box), RelA and SpoT are triggered leading to increased level of ppGpp, which triggers phenotypic transition into a flagellated virulent phenotype followed by lysis of the amoeba and bacterial escape from the host cell. Excreted vesicles filled with bacteria are also released. The infectious particle is not known but may include excreted Legionella-filled vesicles, intact Legionella-filled amoebae, or free Legionella that have been released from host cell. (5) Transmission to humans occurs via aerosols generated from man-made devices and installations, such as cooling towers, whirlpools, and showerheads.
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Figure 2. Nutritional and metabolic adaptation of L. pneumophila to the intracellular life within amoebae and human cells is facilitated by the AnkB effector and its exploitation of multiple highly conserved eukaryotic processes. The AnkB effector is translocated into host cells by the Dot/Icm type IV secretion system of L. pneumophila, and it is immediately farnesylated by the three host enzymes FTase, RCE1, and ICMT, that are recruited to the LCV by the Dot/Icm system. Farnesylation of AnkB results in its anchoring into the cytosolic face of the LCV membrane where it interacts with the eukaryotic SCF1 ubiquitin ligase complex. The AnkB effector functions as a platform for the docking of K48-linked polyubiquitinated proteins to the LCV. Proteasomal degradation of the K48-linked polyubiquitinated protein generates 2–24 amino acid (AA) peptides that are rapidly degraded by oligo- and amino-peptidases. This generates a surplus of cellular amino acids within the cytosol of L. pneumophila-infected amoebae and human cells. The amino acids are imported into the LCV through various host amino acid transporters present in the LCV membrane, including the neutral amino acid transporter SLC1A5, which imports Cys, and subsequently into L. pneumophila through numerous ABC transporters and amino acid permeases such as the threonine transporter PhtA.
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