Single gene effects in mouse models of host: pathogen interactions

Inbred mouse strains have been known for many years to vary in their degree of suscepti- bility to different types of infectious diseases. The genetic basis of these interstrain differences is sometimes simple but often complex. In a few cases, positional cloning has been used successfully to identify single gene effects. The natural resis- tance-associated macrophage protein 1 (Nramp1) gene (Slc11a1) codes for a metal transporter ac- tive at the phagosomal membrane of macrophages, and Nramp1 mutations cause susceptibility to My- cobacterium, Salmonella, and Leishmania. Fur- thermore, recent advances in gene transfer tech- nologies in transgenic mice have enabled the func- tional dissection of gene effects mapping to complex, repeated parts of the genome, such as the Lgn1 locus, causing susceptibility to Legionella pneumophila in macrophages. Finally, complex traits such as the genetically determined suscepti- bility to malaria can sometimes be broken down into multiple single gene effects. One such example is the case of pyruvate kinase, where a loss-of- function mutation was recently shown by our group to be protective against blood-stage infection with Plasmodium chabaudi. In all three cases reviewed, the characterization of the noted gene effect(s) has shed considerable light on the pathophysiology of the infection, including host response mechanisms. J. Leukoc. Biol. 77: 000-000; 2005.