Legionella pneumophila pathogenesis: A fateful journey from amoebae to macrophages

Legionella pneumophila first commanded attention in 1976, when investigator s from the Centers for Disease Control and Prevention identified it as the culprit in a massive outbreak of pneumonia that struck individuals attendin g an American Legion convention(84). It is now clear that this gram-negativ e bacterium flourishes naturally in fresh water as a parasite of amoebae, b ut it can also replicate within alveolar macrophages. L. pneumophila pathog enesis is discussed using the following model as a framework. When ingested by phagocytes, stationary-phase L. pneumophila bacteria establish phagosom es which are completely isolated from the endosomal pathway but are surroun ded by endoplasmic reticulum. Within this protected vacuole, L. pneumophila converts to a replicative form that is acid tolerant but no longer express es several virulence traits, including factors that block membrane fusion. As a consequence, the pathogen vacuoles merge with lysosomes, which provide a nutrient-rich replication niche. Once the amino acid supply is depleted, progeny accumulate the second messenger guanosine 3',5'-bispyrophosphate ( ppGpp), which coordinates entry into the stationary phase with expression o f traits that promote transmission to a new phagocyte. A number of factors contribute to L. pneumophila virulence, including type II and type IV secre tion systems, a pore-forming toxin, type TV pill, flagella, and numerous ot her factors currently under investigation. Because of its resemblance to ce rtain aspects of Mycobacterium, Toxoplasma, Leishmania, and Coxiella pathog enesis, a detailed description of the mechanism used by L. pneumophila to m anipulate and exploit phagocyte membrane traffic may suggest novel strategi es for treating a variety of infectious diseases. Knowledge of L. pneumophi la ecology may also inform efforts to combat the emergence of new opportuni stic macrophage pathogens.