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Altered Inflammatory Responses in TLR5-Deficient Mice Infected with Legionella pneumophila¹

Thomas R. Hawn^2,*, William R. Berrington^*, Ian A. Smith^*, Satoshi Uematsu, Shizuo Akira, Alan Aderem, Kelly D. Smith^* and Shawn J. Skerrett^*

^* University of Washington School of Medicine, Seattle, WA 98195; Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; and Institute for Systems Biology, Seattle, WA 98103

Legionella pneumophila (Lp), an important cause of morbidity and mortality from pneumonia, infects alveolar macrophages (AMs) and is recognized by several TLRs as well as Birc1e (NAIP5) and IL-1 converting enzyme-protease activating factor. We examined the role of TLR5 during the murine response to aerosolized Lp infection. At 4 h after infection, Tlr5^–/– mice had lower numbers of polymorphonuclear neutrophils (PMNs) in their broncho-alveolar lavage fluid in comparison to wild-type (WT) mice. At 24 and 72 h, the PMN recruitment was similar. WT mice infected with a flagellin-deficient strain (LpFlaA–) also showed an impaired early PMN response at 4 h compared with those infected with the WT strain. There was no consistent difference in bacterial counts at any of the time points when comparing the Tlr5^–/– and WT mice. However, at 6 days after infection, the Tlr5^–/– mice had increased leukocytic infiltrates in the alveolar and peribronchial interstitial spaces that were consistent with organizing pneumonia. We also examined the role of TLR5 during macrophage infection. In contrast to bone marrow-derived macrophages, AMs secreted TNF- after stimulation with purified flagellin. In addition, WT, but not Tlr5^–/–, AMs produced TNF- after stimulation with Lp. Live LpFlaA– did not induce TNF- secretion in AM. These results suggested that AMs recognize Lp flagellin and that a majority of the Lp-induced TNF- response is TLR5-mediated. Thus, TLR5 mediates recognition of Lp in AMs and performs a distinct role during the in vivo pulmonary immune response through regulation of early PMN recruitment and subsequent later development of pneumonia.

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 R01 AI061464 (to T.R.H.), R01 AI052286 (to A.A.), and R01 HL54972 (to S.J.S.).

² Address correspondence and reprint requests to Dr. Thomas R. Hawn, Box 356523, Department of Medicine, University of Washington School of Medicine, 1959 NE Pacific Street, Seattle WA 98195. E-mail address: thawn{at}u.washington.edu

³ Abbreviations used in this paper: NLR, Nod-like receptors; IPAF, IL-1 converting enzyme-protease activating factor; FliC, Flagellin C from S. typhimukium; WT, wild type; BCYE, buffered charcoal yeast extract; Lp, Legionella pneumophila; BAL, bronchoalveolar lavage; BMDM, bone marrow-derived macrophage; AM, alveolar macrophage; FlaA, Flagellin A from L. pneumophila.

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