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* Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine and
Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI 48109;
Coley Pharmaceutical Group, Wellesley, MA 02481; and
Department of Host Defense, Research Institute for Microbial Defenses, Osaka University, Osaka, Japan
In this study, experiments were performed to determine the contribution of TLR9 to the generation of protective innate immunity against virulent bacterial pathogens of the lung. In initial studies, we found that the intratracheal administration of Klebsiella pneumoniae in wild-type (WT) BALB/c mice resulted in the rapid accumulation of dendritic cells (DC) expressing TLR9. As compared with WT mice, animals deficient in TLR9 (TLR9–/–) displayed significantly increased mortality that was associated with a >50-fold increase in lung CFU and a >400-fold increase in K. pneumoniae CFU in blood and spleen, respectively. Intrapulmonary bacterial challenge in TLR9–/– mice resulted in reduced lung DC accumulation and maturation as well as impaired activation of lung macrophages, NK cells, and 
and 
T cells. Mice deficient in TLR9 failed to generate an effective Th1 cytokine response following bacterial administration. The adoptive transfer of bone marrow-derived DC from syngeneic WT but not TLR9–/– mice administered intratracheally reconstituted antibacterial immunity in TLR9–/– mice. Collectively, our findings indicate that TLR9 is required for effective innate immune responses against Gram-negative bacterial pathogens and that approaches to maximize TLR9-mediated DC responses may serve as a means to augment antibacterial immunity in 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 Address correspondence and reprint requests to Dr. Theodore J. Standiford, University of Michigan Medical Center, Division of Pulmonary and Critical Care Medicine, 109 Zina Pitcher Place, 4062 Biomedical Science Research Building, Ann Arbor, MI 48109-2200. E-mail address: tstandif{at}umich.edu
2 Abbreviations used in this paper: AM, alveolar macrophage; DC, dendritic cell; iNOS, inducible NO synthase; IP-10, IFN-inducible protein 10; i.t., intratracheal; ODN, oligodeoxynucleotide; WT, wild type.
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