Genetic analysis of resistance to infections in mice: A/J meets C57BL/6J.

Susceptibility to infectious diseases has long been known to have a genetic component in human populations. This genetic effect is often complex and difficult to study as it is further modified by environmental factors including the disease-causing pathogen itself. The laboratory mouse has proved a useful alternative to implement a genetic approach to study host defenses against infections. Our laboratory has used genetic analysis and positional cloning to characterize single and multi-gene effects regulating inter-strain differences in the susceptibility of A/J and C57BL/6J mice to infection with several bacterial and parasitic pathogens. This has led to the identification of several proteins including Nrampl (Slc11a1), Birc1e, Icsbp, C5a, and others that play critical roles in the antimicrobial defenses of macrophages against intracellular pathogens. The use of AcB/BcA recombinant congenic strains has further facilitated the characterization of single gene effects in complex traits such as susceptibility to malaria. The genetic identification of erythrocyte pyruvate kinase (Pklr) and myeloid pantetheinase enzymes (Vnn1/3) as key regulators of blood-stage parasitemia has suggested that cellular redox potential may be a key biochemical determinant of Plasmodium parasite replication. Expanding these types of studies to additional inbred strains and to emerging stocks of mutagenized mice will undoubtedly continue to unravel the molecular basis of host defense against infections.