A Hemidominant Naip5 Allele in Mouse Strain MOLF/Ei-Derived Macrophages Restricts Legionella pneumophila Intracellular Growth

Mouse-derived macrophages have the unique ability to restrict or permitLegionella pneumophila intracellular growth. The common inbred mouse strain C57BL/6J (B6) restrictsL. pneumophila growth, whereas macrophages derived from A/J mice allow >103 -fold bacterial growth within three days. This phenotypic difference was mapped to the mouseNaip5 allele. The B6 restrictiveNaip5 allele is dominant, and six amino acid changes in its product were predicted to control permissiveness. By using the wild-derived mouse strain MOLF/Ei, we found that MOLF/Ei-derived macrophages also restrictL. pneumophila growth, yet the Naip5 protein is identical to the A/J Naip5 at the six-amino-acid signature. The MOLF/Ei restrictive trait, unlike that of B6-derived macrophages, was not dominant over the A/J trait. In spite of this phenotypic difference, theL. pneumophila growth restriction in MOLF/Ei macrophages was mapped to theNaip5 region as well, indicating that the originally predicted change in the A/JNaip5 allele may not be critical for restriction. In the product of the A/JNaip5 permissive allele, there are four unique amino acid changes that map to a NACHT-like domain. Similar misregulating mutations have been identified in the NACHT domains of Nod-like receptor (NLR) proteins. Therefore, one of these mutations may be critical for restriction ofL. pneumophila intracellular growth, and this parallels results found with human NLR variants with defects in the innate immune response.