Membrane Vesicles Shed byLegionella pneumophilaInhibit Fusion of Phagosomes with Lysosomes

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Abstract
When cultured in broth to the transmissive phase,Legionella pneumophilainfects macrophages by inhibiting phagosome maturation, whereas replicative-phase cells are transported to the lysosomes. Here we report that the ability ofL. pneumophilato inhibit phagosome-lysosome fusion correlated with developmentally regulated modifications of the pathogen's surface, as judged by its lipopolysaccharide profile and by its binding to a sialic acid-specific lectin and to the hydrocarbon hexadecane. Likewise, the composition of membrane vesicles shed byL. pneumophilawas developmentally regulated, based on binding to the lectin and to the lipopolysaccharide-specific monoclonal antibody 3/1. Membrane vesicles were sufficient to inhibit phagosome-lysosome fusion by a mechanism independent of type IV secretion, since only ∼25% of beads suspended with or coated by vesicles from transmissive phase wild type ordotAsecretion mutants colocalized with lysosomal probes, whereas ∼75% of beads were lysosomal when untreated or presented with vesicles from theL. pneumophila letAregulatory mutant orE. coli. As observed previously forL. pneumophilainfection of mouse macrophages, vesicles inhibited phagosome-lysosome fusion only temporarily; by 10 h after treatment with vesicles, macrophages delivered ∼72% of ingested beads to lysosomes. Accordingly, in the context of the epidemiology of the pneumonia Legionnaires' disease and virulence mechanisms ofLeishmaniaandMycobacteria, we discuss a model here in whichL. pneumophiladevelopmentally regulates its surface composition and releases vesicles into phagosomes that inhibit their fusion with lysosomes.

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