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Infection and Immunity, May 2009, p. 1981-1991, Vol. 77, No. 5
0019-9567/09/$08.00+0     doi:10.1128/IAI.01382-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Asc and Ipaf Inflammasomes Direct Distinct Pathways for Caspase-1 Activation in Response to Legionella pneumophila{triangledown}

Christopher L. Case, Sunny Shin, and Craig R. Roy*

Section of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut 06536

Received 12 November 2008/ Returned for modification 23 December 2008/ Accepted 12 February 2009

Caspase-1 activation is a key feature of the innate immune response of macrophages elicited by pathogens and a variety of toxins. Here, we determined the requirement for different adapter proteins involved in regulating host processes mediated by caspase-1 after macrophage infection by Legionella pneumophila. The adapter protein Asc was found to be important for caspase-1 activation during L. pneumophila infection. Activation of caspase-1 through Asc did not require the flagellin-sensing pathway involving the host nucleotide-binding domain and leucine-rich repeat-containing protein Ipaf (NLRC4). Asc-dependent caspase-1 activation was inhibited by high extracellular potassium levels, whereas Ipaf-dependent activation was unaffected by potassium treatment. Activation of caspase-1 in macrophages occurred independently of Nalp3 and proteasome activity, suggesting that a previously uncharacterized mechanism for caspase-1 activation through Asc may be triggered by L. pneumophila. Rapid pore formation and pyroptosis induced by L. pneumophila required caspase-1, Ipaf, and bacterial flagellin but occurred independently of Asc. Equivalent levels of active interleukin-18 (IL-18) were detected in the lungs of mice infected with a flagellin-deficient strain of L. pneumophila and Asc-deficient mice infected with wild-type L. pneumophila. Active IL-18 was undetectable in the lungs of Asc-deficient mice infected with an L. pneumophila flagellin mutant, indicating independent roles for Ipaf and Asc in caspase-1-mediated processing and release of IL-18 in vivo. Ipaf-dependent activation of caspase-1 restricted bacterial replication in vivo, whereas Asc was dispensable for restriction of L. pneumophila replication in mice. Thus, L. pneumophila-mediated caspase-1 activation involves the coordinate activities of inflammasomes differentially regulated by Ipaf and Asc.

* Corresponding author. Mailing address: Section of Microbial Pathogenesis, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, CT 06536. Phone: (203) 737-2408. Fax: (203) 703-2630. E-mail: craig.roy{at}yale.edu

{triangledown} Published ahead of print on 23 February 2009.

Editor: J. B. Bliska

Infection and Immunity, May 2009, p. 1981-1991, Vol. 77, No. 5
0019-9567/09/$08.00+0     doi:10.1128/IAI.01382-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Fortier, A., Doiron, K., Saleh, M., Grinstein, S., Gros, P. (2009). Restriction of Legionella pneumophila Replication in Macrophages Requires Concerted Action of the Transcriptional Regulators Irf1 and Irf8 and Nod-Like Receptors Naip5 and Nlrc4. Infect. Immun. 77: 4794-4805 [Abstract] [Full Text]  


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