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Infection and Immunity, June 2007, p. 2903-2913, Vol. 75, No. 6
0019-9567/07/$08.00+0     doi:10.1128/IAI.00147-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Host-Dependent Trigger of Caspases and Apoptosis by Legionella pneumophila ^,

Marina Santic,^1,2 Rexford Asare,² Miljenko Doric,¹ and Yousef Abu Kwaik^2*

Department of Microbiology and Parasitology, University of Rijeka, Rijeka, Croatia,¹ Department of Microbiology and Immunology, Room 406, University of Louisville College of Medicine, 319 Abraham Flexner Way 55A, Louisville, Kentucky 40202²

Received 29 January 2007/ Returned for modification 23 March 2007/ Accepted 26 March 2007

The Dot/Icm system of Legionella pneumophila triggers activation of caspase-3 during early stages of infection of human macrophages, but apoptosis is delayed until late stages of infection. During early stages of infection of mouse macrophages, the organism triggers rapid caspase-1-mediated cytotoxicity, which is mediated by bacterial flagellin. However, it is not known whether caspase-1 is triggered by L. pneumophila in human macrophages or whether caspase-3 is activated in permissive or nonpermissive mouse macrophages. Using single-cell analyses, we show that the wild-type strain of L. pneumophila does not trigger caspase-1 activation throughout the intracellular infection of human monocyte-derived macrophages (hMDMs), even when the flagellated bacteria escape into the cytoplasm during late stages. Using single-cell analyses, we show that the Dot/Icm system of L. pneumophila triggers caspase-3 but not caspase-1 within permissive A/J mouse bone marrow-derived primary macrophages by 2 to 8 h, but apoptosis is delayed until late stages of infection. While L. pneumophila triggers a Dot/Icm-dependent activation of caspase-1 in nonpermissive BALB/c mouse-derived macrophages, caspase-3 is not activated at any stage of infection. We show that robust intrapulmonary replication of the wild-type strain of L. pneumophila in susceptible A/J mice is associated with late-stage Dot/Icm-dependent pulmonary apoptosis and alveolar inflammation. In the lungs of nonpermissive BALB/c mice, L. pneumophila does not replicate and does not trigger pulmonary apoptosis or alveolar inflammation. Thus, similar to hMDMs, L. pneumophila does not trigger caspase-1 but triggers caspase-3 activation during early and exponential replication in permissive A/J mouse-derived macrophages, and apoptosis is delayed until late stages of infection. The Dot/Icm type IV secretion system is essential for pulmonary apoptosis in the genetically susceptible A/J mice.

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* Corresponding author. Mailing address: Department of Microbiology and Immunology, Room 406, University of Louisville College of Medicine, 319 Abraham Flexner Way 55A, Louisville, KY 40202. Phone: (502) 852-4117. Fax: (502) 852-7531. E-mail: abukwaik{at}louisville.edu

Published ahead of print on 9 April 2007.

Supplemental material for this article may be found at http://iai.asm.org/.

Editor: W. A. Petri, Jr.

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Infection and Immunity, June 2007, p. 2903-2913, Vol. 75, No. 6
0019-9567/07/$08.00+0     doi:10.1128/IAI.00147-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.