Bacterial pneumonia is an important clinical problem and host defense mechanisms against pneumonia are not fully understood. Preliminary data from our laboratory using a murine model of Klebsiella pneumoniae infection has shown that bacterial deposition in the lung results in the release of the T-cell derived cytokines IL-17A and IL-17F, both of which can mediate neutrophil recruitment into the lung. Moreover, we have shown that signaling through the IL-17 receptor is critical for optimal granulocyte-colony stimulating factor (G-CSF) and both Gro-alpha and macrophage inflammatory protein 2 (MIP-2) production in the lung which are critical for granulopoeisis and neutrophil chemotaxis respectively in this model. Furthermore, preliminary data using both in vitro bone marrow derived dendritic cells (DC) and T-cell co-cultures as well as in our experimental model of pneumoniae in vivo has demonstrated that host release of these lymphocyte-derived IL-17 family members is dependent on recognition of the organism by Toll-like receptor 4 (presumably on both alveolar macrophages and lung dendritic cells) and the subsequent production of IL-23 (a novel heterodimeric cytokine composed of a unique p19 subunit and the p40 subunit of IL-12) by these cell populations which signal to T-cell to produce IL-17. This data allows us to propose an experimental hypothesis that both TLR4 and IL-23 are required for the production of IL-17A and IL-17F in the lung and that IL-17R signaling by lung parenchymal cells is critical for host defense against Klebsiella pneumoniae. We will test this hypothesis with the following Specific Aims: 1. Our hypothesis predicts that TLR4 on lung DCs and alveolar macrophages is critical for pulmonary production of IL-23 and IL-17 in response to experimental K. pneumoniae infection. 2. Our hypothesis predicts that IL-23 is required for the production of IL-17A and IL-17F, G-CSF and optimal CXC chemokine production and subsequent neutrophil recruitment in response to experimental K. pneumoniae infection. 3. Our hypothesis predicts that IL-17R signaling by lung parenchymal cells is required for production of G-CSF and optimal CXC chemokine production and subsequent neutrophil recruitment in response to experimental K. pneumoniae infection.
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