A Hemidominant Naip5Allele in Mouse Strain MOLF/Ei-Derived Macrophages Restricts Legionella pneumophilaIntracellular Growth

ABSTRACTMouse-derived macrophages have the unique ability to restrict or permit Legionella pneumophilaintracellular growth. The common inbred mouse strain C57BL/6J (B6) restricts L. pneumophilagrowth, whereas macrophages derived from A/J mice allow >103-fold bacterial growth within three days. This phenotypic difference was mapped to the mouse Naip5allele. The B6 restrictive Naip5allele 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 restrict L. pneumophilagrowth, 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, the L. pneumophilagrowth restriction in MOLF/Ei macrophages was mapped to the Naip5region as well, indicating that the originally predicted change in the A/J Naip5allele may not be critical for restriction. In the product of the A/J Naip5permissive 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 of L. pneumophilaintracellular growth, and this parallels results found with human NLR variants with defects in the innate immune response.