Natural resistance to infection with Legionella pneumophila: chromosomal localization of the Lgn1 susceptibility gene

Abstract

Legionella pneumophila is a strict intracellular pathogen that replicates in the professional phagocytes of the human and guinea pig host. Although murine macrophages from most inbred strains are non-permissive to intracellular replication of L. pneumophila, inflammatory macrophages from the mouse strain A/J are completely permissive to intracellular replication of this bacterium. This genetic difference is controlled by the expression of a single autosomal gene designated Lgn1, with non-permissiveness behaving as completely dominant over permissiveness. We have used a total of 25 AXB/BXA recombinant inbred mouse strains and 182 (A/J x C57BL/6J) x A/J segregating backcross progeny (A/J, permissive; C57BL/6J, non-permissive) to map the Lgn1 gene. Animals were individually typed for tolerance to intracellular replication by in vitro infection of their inflammatory macrophages with L. pneumophila. All animals segregated into two nonoverlapping groups. Examination of the strain distribution pattern of the AXB/BXA strains for Lgn1 initially identified linkage to Chromosome (Chr) 13 markers. Genotyping of the 25 AXB/BXA strains and the 182 backcross progeny for 11 Chr 13 markers established that Lgn1 mapped to Chr 13, with the gene order and intergene distance D13Mit231-(5.5 +/- 1.5)-D13Mit193-(2.2 +/- 0.9)-D13Mit194- (1.1 +/- 0.6)-D13Mit128-(2.6 +/- 1.0)-Lgn1-(2.2 +/- 0.9)-D13Mit70-(3.9 +/- 1.3)- D13Mit73-(7.2 +/- 1.7)-D13Mit53-(0.7 +/- 0.5)-D13Mit32-(0.7 +/- 0.5)-D13Mit77- (0.7 +/- 0.5)-D13Mit78. This portion of Chr 13 is homologous to the distal portion of human Chr 5, 5q11-5q13, suggesting a possible location of a human LGN1 homolog. Understanding the molecular basis of the high permissiveness of A/J macrophage to L. pneumophila may shed light on the survival strategy of this bacterium in highly permissive human phagocytes. This may be achieved by positional cloning of Lgn1, and the identification of the Lgn1 subchromosomal region reported here is a first step towards that goal.