Hypersensitivity pneumonitis (HP) is an inflammatory lung disease that develops following repeated exposure to inhaled particulate antigen. The epidemiology of HP remains largely unknown. HP is characterized by a vigorous Th1 (or type 1) mediated immune response and previous studies suggest that Th1 cytokines such as IL-12 and IFN-y play an important role in the pathogenesis of HP. Stachybotrys chartarum (SC) is a dimorphic fungus that has been implicated in a number of respiratory illnesses, including "sick building syndrome", asthma, and HP. In preliminary studies, we have found that inhalation of SC conidia in sensitized mice results in the development of a pulmonary hypersensitivity response. Moreover, granulmatous inflammation induced by SC is substantially reduced in mice deficient in the intracellular toll- like receptor, TLR9. Mechanisms accounting for the altered granulomatous response observed in TLR9- deficient mice have not been defined and are the focus of this studies outlined in this proposal. Based on these preliminary studies, we hypothesize that the dendritic cell (DC) is the essential antigen presenting cell that promotes Th1 responses during the development of SC-induced HP, and the promotion of granulomatous inflammation by DC is mediated by TLR9. The following Specific Aims are designed to test this hypothesis:
Aim 1) To determine the effect of SC conidia on DC effector responses in vitro, and determine if TLR9 is required for SC-mediated DC activation;
Aim 2) To determine the contribution of TLR9 to SC-induced pulmonary granulomatous inflammation in vivo;
Aim 3) To determine the contribution of TLR9-mediated DC responses in the generation of granulamatous inflammation in SC-induced HP. This proposal will serve as a natural extension of work I have performed to date investigating TLR9- mediated responses in lung antibacterial immunity. The training program outlined has been designed to provide the necessary techniques and knowledge base to successfully complete the studies outlined and the tools required to develop into a successful independent physician-scientist.

Public Health Relevance

Hypersensitivity pneumontis is a complex syndrome of varying intensity and clinical presentation affecting approximately 9% of the general population. Mechanisms underlying cause and progression of the disease are still unknown. This project will provide mechanistic insight into the role of TLR9 mediated dendritic cell responses on the generation of granulomatous inflammation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL094762-05
Application #
8403972
Study Section
Special Emphasis Panel (ZHL1-CSR-O (O1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2009-01-01
Project End
2013-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2013
Total Cost
$133,565
Indirect Cost
$9,565
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Standiford, Louis R; Standiford, Theodore J; Newstead, Michael J et al. (2012) TLR4-dependent GM-CSF protects against lung injury in Gram-negative bacterial pneumonia. Am J Physiol Lung Cell Mol Physiol 302:L447-54
Qiu, Yafeng; Zeltzer, Stuart; Zhang, Yanmei et al. (2012) Early induction of CCL7 downstream of TLR9 signaling promotes the development of robust immunity to cryptococcal infection. J Immunol 188:3940-8
Bhan, Urvashi; Newstead, Michael J; Zeng, Xianying et al. (2011) Stachybotrys chartarum-induced hypersensitivity pneumonitis is TLR9 dependent. Am J Pathol 179:2779-87
Bhan, Urvashi; Ballinger, Megan N; Zeng, Xianying et al. (2010) Cooperative interactions between TLR4 and TLR9 regulate interleukin 23 and 17 production in a murine model of gram negative bacterial pneumonia. PLoS One 5:e9896
Seki, Masafumi; Kohno, Shigeru; Newstead, Michael W et al. (2010) Critical role of IL-1 receptor-associated kinase-M in regulating chemokine-dependent deleterious inflammation in murine influenza pneumonia. J Immunol 184:1410-8
Zhang, Yanmei; Wang, Fuyuan; Bhan, Urvashi et al. (2010) TLR9 signaling is required for generation of the adaptive immune protection in Cryptococcus neoformans-infected lungs. Am J Pathol 177:754-65
Lyn-Kew, Kenneth; Rich, Eric; Zeng, Xianying et al. (2010) IRAK-M regulates chromatin remodeling in lung macrophages during experimental sepsis. PLoS One 5:e11145