Bacterial pneumonia is an important clinical problem and host defense mechanisms against pneumonia are not fully understood. Data from the prior funding period using a murine model of Klebsiella pneumonia 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, we have shown that IL-22, a product of Th17 cells as well as NK cells is induced in the lung in this model and is critical for mucosal host defense and containment of bacteria within the lung in part by regulating the production of anti-microbial proteins in the lung. Moreover we demonstrated that TRL4 and IL-23 are critical in regulating IL-17 and IL-22 production. Preliminary data strongly implicate that the lung epithelium represent critical target cells of T-cell derived IL-17 and IL-22 and that G-CSF and anti-microbial genes represent critical effectors of these cytokines. These data allow us to propose an experimental hypothesis that IL-23 regulates IL-17 and IL- 22 production in lung T-cells and these cytokines regulate both G-CSF and antimicrobial proteins in lung epithelial cells to achieve mucosal immunity in the lung. We will test this hypothesis with the following Specific Aims:
Specific Aim 1. Determine the role of IL-23 and IL-1R signaling in regulating IL-17 and IL- 22 in lung T cells in response to K. pneumoniae and S. aureus.
Specific Aim 2. Determine the role of CXCR2 signaling and the antimicrobial protein lipocalin-2 as effector molecules downstream from IL-17 and IL-22.
Specific Aim 3. Determine the role of IL-17+ cell homing to the bone marrow in regulating granulopoeisis in response to K. pneumoniae infection. The series of proposed experiments should greatly increase our knowledge on how the IL-23-IL-17 axis coordinates G-CSF, IL-22, CXC chemokine production, and PMN recruitment into the lung. It is hoped that this knowledge will improve therapy for patients with bacterial pneumonia.
Bacterial pneumonia is an important clinical problem and host defense mechanisms against pneumonia are not fully understood. We have identified a novel T-cell population that plays a critical role in defense against pneumonia. This application will explore how these cells are generated and how they control host defense in the lung.
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