Genetic and physical mapping of the mouse host resistance locus Lgn1

Legionella pneumophila is a strict intracellular pathogen that causes an acute form of pneumonia in humans, called Legionnaires' disease. L. pneumophila enters human macrophages through a unique "coiling phagocytosis" mechanism and replicates within the phagosome by inhibiting fusion to endosomes and lysosomes. These replicative phagosomes are morphologically distinct and are associated with endoplasmic reticulum membranes and dotted with ribosomes. The mechanism by which L. pneumophila modulates the fusogenic properties of the phagosome and survives intracellularly remains unknown. In contrast to their human and guinea pig counterparts, mouse macrophages are not permissive to L. pneumophila replication with the exception of mice of the A/J strain, where inflammatory peritoneal macrophages and alveolar macrophages are highly permissive to L. pneumophila replication in vitro (1000-fold increase in viable bacteria during a 72-h infection). The characteristics of L. pneumophila replication observed in A/J macrophages, including the unique inhibition of phagosome maturation, are similar to those observed in human cells. Segregation analyses in informative backcross populations derived from susceptible (A/J) and resistant (C57BL/6J) progenitors have indicated that permissiveness of A/J macrophages to intracellular replication of L. pneumophila is determined by a single recessive gene designated Lgn1, which maps on Chromosome (Chr) 13. Understanding the molecular mechanism of action of Lgn1 may provide important clues on the intracellular survival strategy of L. pneumophila, and possibly on a new antimicrobial mechanism of the macrophage effective against L. pneumophila. (DBO)