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The Nod-Like Receptor Family Member Naip5/Birc1e Restricts Legionella pneumophila Growth Independently of Caspase-1 Activation¹

Mohamed Lamkanfi^*, Amal Amer^*, Thirumala-Devi Kanneganti^*, Raúl Muñoz-Planillo^*, Grace Chen^*, Peter Vandenabeele, Anne Fortier, Philippe Gros and Gabriel Núñez^2,*

^* Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109; Department of Molecular Biomedical Research, Molecular Signalling and Cell Death Unit, Flanders Institute for Biotechnology and Ghent University, Zwijnaarde, Belgium; and Department of Biochemistry and Center for the Study of Host Resistance, McGill University, Montreal, Quebec, Canada

Similar to Ipaf and caspase-1, the Nod-like receptor protein Naip5 restricts intracellular proliferation of Legionella pneumophila, the causative agent of a severe form of pneumonia known as Legionnaires’ disease. Thus, Naip5 has been suggested to regulate Legionella replication inside macrophages through the activation of caspase-1. In this study, we show that cytosolic delivery of recombinant flagellin activated caspase-1 in A/J macrophages carrying a mutant Naip5 allele, and in C57BL/6 (B6) macrophages congenic for the mutant Naip5 allele (B6-Naip5^A/J), but not in Ipaf^–/– cells. In line with these results, A/J and B6-Naip5^A/J macrophages induced high levels of caspase-1 activation and IL-1 secretion when infected with Legionella. In addition, transgenic expression of a functional Naip5 allele in A/J macrophages did not alter Legionella-induced caspase-1 activation and IL-1 secretion. Notably, defective Naip5 signaling renders B6-Naip5^A/J macrophages permissive for Legionella proliferation despite normal caspase-1 activation. These results indicate that the restriction of intracellular Legionella replication is more complex than previously appreciated and requires both Ipaf-dependent caspase-1 activation as well as functional Naip5 signaling.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI064748 and 1AR051790 (to G.N.). T.K. was supported by National Institutes of Health Training Grant 5/T32/HL007517.

² Address correspondence and reprint requests to Dr. Gabriel Núñez, Department of Pathology, University of Michigan Medical School, 4215 Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109. E-mail address: bclx{at}umich.edu

³ Abbreviations used in this paper: NLR, Nod-like receptor; BAC, bacterial artificial chromosome; BMDM, bone marrow-derived macrophage; LCP, Legionella-containing phagosome; MOI, multiplicity of infection; SLO, streptolysin O; WT, wild type.

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