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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
3R37HL079142-09S1
Application #
8639177
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Eu, Jerry Pc
Project Start
2004-12-13
Project End
2014-12-31
Budget Start
2013-04-01
Budget End
2014-12-31
Support Year
9
Fiscal Year
2013
Total Cost
$64,421
Indirect Cost
$22,178
Name
University of Pittsburgh
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
McAleer, Jeremy P; Nguyen, Nikki L H; Chen, Kong et al. (2016) Pulmonary Th17 Antifungal Immunity Is Regulated by the Gut Microbiome. J Immunol 197:97-107
Chen, Kong; Eddens, Taylor; Trevejo-Nunez, Giraldina et al. (2016) IL-17 Receptor Signaling in the Lung Epithelium Is Required for Mucosal Chemokine Gradients and Pulmonary Host Defense against K.√ā¬†pneumoniae. Cell Host Microbe 20:596-605
Chen, Kong; Campfield, Brian T; Wenzel, Sally E et al. (2016) Antiinflammatory effects of bromodomain and extraterminal domain inhibition in cystic fibrosis lung inflammation. JCI Insight 1:
Zheng, Mingquan; Horne, William; McAleer, Jeremy P et al. (2016) Therapeutic Role of Interleukin 22 in Experimental Intra-abdominal Klebsiella pneumoniae Infection in Mice. Infect Immun 84:782-9
Way, Emily E; Trevejo-Nunez, Giraldina; Kane, Lawrence P et al. (2016) Dose-Dependent Suppression of Cytokine production from T cells by a Novel Phosphoinositide 3-Kinase Delta Inhibitor. Sci Rep 6:30384
Conti, Heather R; Bruno, Vincent M; Childs, Erin E et al. (2016) IL-17 Receptor Signaling in Oral Epithelial Cells Is Critical for Protection against Oropharyngeal Candidiasis. Cell Host Microbe 20:606-617
Kumar, Pawan; Monin, Leticia; Castillo, Patricia et al. (2016) Intestinal Interleukin-17 Receptor Signaling Mediates Reciprocal Control of the Gut Microbiota and Autoimmune Inflammation. Immunity 44:659-71
Trevejo-Nunez, Giraldina; Elsegeiny, Waleed; Conboy, Parker et al. (2016) Critical Role of IL-22/IL22-RA1 Signaling in Pneumococcal Pneumonia. J Immunol 197:1877-83
Kolls, Jay K; Szabo, Gyongyi (2015) The genetics of hepatitis C virus underlie its ability to escape humoral immunity. J Clin Invest 125:97-8
McAllister, Florencia; Kolls, Jay K (2015) Th17 cytokines in non-melanoma skin cancer. Eur J Immunol 45:692-4

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