Legionella pneumophila is the cause of Legionnaires' Disease and a prototypical intracellular parasite of alveolar macrophages. The pathways involved in the initial recognition of inhaled bacteria are likely to be critically important in the activation of innate defenses and the initiation of specific adaptive immunity. The signaling receptors that mediate early responses to L. pneumophila in the lower respiratory tract and the mechanisms by which this organism subverts the defensive response to infection are poorly understood. Toll-like receptors have emerged as an important family of pattern recognition molecules that can initiate cellular activation responses to a wide variety of microbial stimuli. The roles of Toll-like receptors in mediating alveolar macrophage responses to infection and in activating pulmonary anti-bacterial defenses are unknown. Virulent L. pneumophila is able to blunt the cytokine response of alveolar macrophages by unelucidated mechanisms that are dependent on the expression of specific bacterial genes. The overall goals of this proposal are to determine the recognition pathways that stimulate innate defenses to intracellular bacteria, and to explore mechanisms by which virulent organisms subvert host resistance.
The specific aims are as follows: 1. Determine the roles of Toll-like receptors (TLRs) in mediating cellular responses to L. pneumophila (Lp).
This aim will test the hypothesis that TLRs, singly or in combination, mediate the initial activation of alveolar macrophages in response to Lp, serving to defend the cell against intracellular infection. 2. Determine the roles of TLRS in pulmonary host defense against Lp in vivo.
This aim will test the hypothesis that signaling via TLRs serves to stimulate innate defenses against Lp that control early bacterial clearance and initiation of the adaptive response. 3. Define the mechanisms by which virulent L. pneumophila subverts the activation response of alveolar macrophages.
This aim will test the hypothesis that bacterial dot/icm genes direct macrophage uptake of L. pneumophila by a pathway that results in diminished cellular activation in comparison bacteria deficient in these loci.
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| Hawn, Thomas R; Smith, Kelly D; Aderem, Alan et al. (2006) Myeloid differentiation primary response gene (88)- and toll-like receptor 2-deficient mice are susceptible to infection with aerosolized Legionella pneumophila. J Infect Dis 193:1693-702 |
