The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection

Abstract

Baculovirus inhibitor of apoptosis repeat-containing 1 (Birc1) proteins have homology to several germline-encoded receptors of the innate immune system. However, their function in immune surveillance is not clear. Here we describe a Birc1e-dependent signaling pathway that restricted replication of the intracellular pathogen Legionella pneumophila in mouse macrophages. Translocation of bacterial products into host-cell cytosol was essential for Birc1e-mediated control of bacterial replication. Caspase-1 was required for Birc1e-dependent antibacterial responses ex vivo in macrophages and in a mouse model of Legionnaires' disease. The interleukin 1β converting enzyme–protease-activating factor was necessary for L. pneumophila growth restriction, but interleukin 1β was not required. These results establish Birc1e as a nucleotide-binding oligomerization–leucine-rich repeat protein involved in the detection and control of intracellular L. pneumophila.

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Figure 1: Birc1e-mediated caspase-1-dependent cell death of HEK293 cells.
Figure 2: Dot-Icm–dependent Birc1e response in HEK293 cells.
Figure 3: Impaired L. pneumophila–induced caspase-1 activation in A/J macrophages.
Figure 4: Birc1e regulation of L. pneumophila–induced activation in macrophages.
Figure 5: Birc1e activation is independent of L. pneumophila replication and trafficking.
Figure 6: Caspase-1 dependency of L. pneumophila growth restriction in macrophages.
Figure 7: Adapter proteins involved in Birc1e-mediated restriction of L. pneumophila growth.

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Acknowledgements

We thank K. Archer, S. Shin and J. Galán for discussions and advice. Supported by the National Institutes of Health (AI48770 and AI41699 to C.R.R., AI062017 to R.E.V., and AI049987 to W.F.D.), the Pew Latin American Fellows program (D.S.Z.), the Crohn's and Colitis Foundation of America (K.S.K.), the Eli and Edythe L. Broad Foundation (K.S.K.) and the Howard Hughes Medical Institute (R.A.F. and W.F.D.).

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Correspondence to Craig R Roy.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Caspase-1-dependency of L. pneumophila growth restriction. (PDF 29 kb)

Supplementary Fig. 2

Co-immunoprecipitation of Ipaf and Birc1e. (PDF 26 kb)

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Zamboni, D., Kobayashi, K., Kohlsdorf, T. et al. The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nat Immunol 7, 318–325 (2006). https://doi.org/10.1038/ni1305

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