IAI Accepts, published online ahead of print on 3 November 2008

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Infect. Immun. doi:10.1128/IAI.01011-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

A hemidominant Naip5 allele in MOLF/Ei-derived macrophages restricts L. pneumophila intracellular growth

Vicki P. Losick, Kristin Stephan, Irina I. Smirnova, Ralph R. Isberg^*, and Alexander Poltorak

Howard Hughes Medical Institute, and Department of Molecular Biology and Microbiology, and Department of Pathology, Tufts University School of Medicine, 150 Harrison Ave., Boston, MA 02111

^* To whom correspondence should be addressed. Email: ralph.isberg{at}tufts.edu.

Mouse derived macrophages have the unique ability to restrict or permit Legionella pneumophila intracellular growth. The common inbred mouse strain C57BL/6J (B6) restricts L. pneumophila growth whereas macrophages derived from A/J mice allow more than 10³ fold bacterial growth within three days. This phenotypic difference was mapped to the mouse Naip5 allele. The B6 restrictive Naip5 allele is dominant and six amino acid changes were predicted to control permissiveness. By using the wild-derived mouse strain MOLF/Ei we found that MOLF-derived macrophages also restrict L. pneumophlia growth yet the Naip5 protein is identical to A/J Naip5 at the six amino acid signature. The MOLF restrictive trait was not dominant over A/J, unlike B6-derived macrophages. In spite of this phenotypic difference, the L. pneumophila growth restriction in MOLF macrophages mapped to the Naip5 region as well, indicating that the originally predicted amino acids changes in A/J Naip5 allele may not be critical for restriction. In the A/J Naip5 permissive allele there are four unique amino acids 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. pneumophila intracellular growth, paralleling results found in human NLR variants with defects in the innate immune response.

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