Cell biology of infection by Legionella pneumophila

Abstract

Professional phagocytes digest internalized microorganisms by actively delivering them into the phagolysosomal compartment. Intravacuolar bacterial pathogens have evolved a variety of effective strategies to bypass the default pathway of phagosomal maturation to create a niche permissive for their survival and propagation. Here we discuss recent progress in our understanding of the sophisticated mechanisms used by Legionella pneumophila to survive in phagocytes.

Fig. 1. Intracellular life cycle of L. pneumophila

The L. pneumophila containing vacuole (LCV) bypasses the default endocytic trafficking pathway, which delivers the contents to the lysosomal compartments (left side of the cartoon). Immediately after uptake, the LCV avoids phagolysosomal fusion by modifying its membrane property using materials carried in vesicles originating from the endoplasmic reticulum (ER). It also attracts organelles such as the mitochondrion (mito) and the ribosome (Rb) at different stage of the infection. The bacterial phagosome is transformed into an ER-like compartment, providing a permissive niche for L. pneumophila multiplication. Ubiquitinated proteins (Ub) and the vacuolar ATPases are shown to be present on the LCV membrane.

Fig. 2. Hijacking of the Rab1 activity cycle by L. pneumophila effectors

Rab1 is recruited to the cytoplasmic surface of the L. pneumophila containing vacuole (LCV) by binding to SidM/DrrA, where its activity is controlled by a number of L. pneumophila effectors. 1, SidM/DrrA activates Rab1 by promoting the dissociation of GDI and inducing the exchange of bound GDP to GTP; 2, SidM/DrrA concomitantly modifies Rab1 by AMPylation, which locks the GTPase into the active form by restricting the access by GAPs; 3, SidD reverses the AMPylation of Rab1, thus making it sensitive to GAP; 4, LepB, a Rab1 GAP, completes the cycle by inactivating deAMPylated Rab1; 5–7, AnkX and Lem3, mediating the phosphorylcholination of Rab1 and the reverse reaction, respectively, may affect the binding of GDI. The dash line indicates that Rab1 subjected to AnkX/Lem3-mediated modifications may not occur on the surface of the LCV.

Fig. 3. Close linkage of Legionella genes with functional relevance

Schematic diagram of three pairs of Dot/Icm substrates with functional relevance. Arrows indicate the transcriptional orientation of the genes. Genes in red color codes for proteins that directly target host processes, whereas genes in blues direct the synthesis of proteins that negatively influence their counterparts. Note the short intergenic regions in all cases.

Fig. 4. Manipulation of phosphoinositide lipids by L. pneumophila

Some Legionella effectors present on the LCV such as SidM/DrrA, LidA, SidC and SdcA, probably by binding to PI(4)P. The abundance of phosphoinosite lipids on the LCV is regulated by L. pneumophila effectors, such as SidF, which catalyze the production of PI(4)P by removing the D3 phosphate on PI(3,4)P2. PI(4)P can also be produced from PI(3,4,5)P2 by SidF and the LCV-associated host PI phosphatase OCRL1, which converts PI(4,5)P2 into PI(4)P.