Bacterial pneumonia represents a major cause of morbidity, mortality, and health care expenditure. Protective immunity against bacterial pathogens in the lung requires the generation of both innate immunity and acquired immune responses. Cells within the lung that are critical in bridging innate and acquired immune responses include macrophages and dendritic cells, which do so by expressing co-stimulatory molecules, presenting antigen, and by expressing type 1 cytokines and chemokines required for the development of cell mediated and humoral immunity. Bacterial components and cellular receptors that initiate this process have been incompletely defined. It has been known for some time that bacterial DMA serves as a potent activator of distinct leukocyte populations, including dendritic cells. More recently, it was shown that the immunostimulatory effects of bacterial DMA are attributable to unmethylated CpG dinucleotide motifs, and CpG induced-activation of host cells occurs through the toll like-receptor TLR9. The hypothesis to be tested in this application is that TLR9 contributes to the generation of effective immunity against both extracellular and intracellular bacterial pathogens of the lung.
The Specific Aims of this proposal are as follows: 1) to determine the contribution of TLR9 to dendritic cell activation and effector cell function in response to extracellular (Klebsiella pneumoniae) and intracellular (Legionella pneumophila) bacterial pathogens in-vitro;2) to determine the time course of expression, the cellular sources, and role of TLR9 to antibacterial host in murine pneumonia due to extracellular and intracellular bacterial pathogens of the lung;3) to determine the effect of adoptive transfer of naive and antigen-pulsed DC on lung antibacterial host defense in WT and TLR9-deficient mice with bacterial pneumonia;and 4) to assess the effect of compartmentalized delivery of CpG motif-containing oligodeoxynucleotides on the generation of protective immunity in murine Klebsiella and Legionella pneumonia. The studies outlined will explore fundamental mechanisms that link innate and adaptive immunity in bacterial pneumonia and potentially identify new approaches to immunotherapy in the treatment of this disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057243-13
Application #
7781294
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Harabin, Andrea L
Project Start
1996-12-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
13
Fiscal Year
2010
Total Cost
$371,680
Indirect Cost
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
Bhan, Urvashi; Newstead, Michael J; Zeng, Xianying et al. (2013) TLR9-dependent IL-23/IL-17 is required for the generation of Stachybotrys chartarum-induced hypersensitivity pneumonitis. J Immunol 190:349-56
Kovach, Melissa A; Standiford, Theodore J (2012) The function of neutrophils in sepsis. Curr Opin Infect Dis 25:321-7
Surendran, Naveen; Hiltbold, Elizabeth M; Heid, Bettina et al. (2012) Role of TLRs in Brucella mediated murine DC activation in vitro and clearance of pulmonary infection in vivo. Vaccine 30:1502-12
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
Ballinger, Megan N; Newstead, Michael W; Zeng, Xianying et al. (2012) TLR signaling prevents hyperoxia-induced lung injury by protecting the alveolar epithelium from oxidant-mediated death. J Immunol 189:356-64
Bhan, Urvashi; Newstead, Michael J; Zeng, Xianying et al. (2011) Stachybotrys chartarum-induced hypersensitivity pneumonitis is TLR9 dependent. Am J Pathol 179:2779-87
Kovach, Melissa A; Standiford, Theodore J (2011) Toll like receptors in diseases of the lung. Int Immunopharmacol 11:1399-406
Deng, Jane C; Standiford, Theodore J (2011) Growth factors and cytokines in acute lung injury. Compr Physiol 1:81-104
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
Hubbard, Leah L N; Ballinger, Megan N; Thomas, Peedikayil E et al. (2010) A role for IL-1 receptor-associated kinase-M in prostaglandin E2-induced immunosuppression post-bone marrow transplantation. J Immunol 184:6299-308

Showing the most recent 10 out of 60 publications