Surfactant-associated protein D (SP-D) plays diverse roles in host defense, innate immunity, and pulmonary homeostasis - including responses to viral challenge. SP-D can specifically neutralize a variety of respiratory viruses, enhance the clearance of apoptotic cells, and modulate the proliferation and function of immune effector cells. Using the murine model of paramyxovirus-induced chronic airway remodeling, we recently observed marked increases in the production of SP-D by the airway epithelium, both at early and late time points following challenge. Notably, areas of SP-D overexpression co-distributed with areas of goblet cell metaplasia. Previous studies have shown that late airway remodeling includes a genetic backgrounddependent epithelial response primarily mediated by decreased apoptosis of airway epithelial cells, and associated with alterations in mucin expression. The latter is mediated in large part by IL-13 via the IL-4/IL- 13 receptor, a pathway that also contributes to the regulation of SP-D expression. Interactions of SP-D with viral pathogens are largely determined by interactions with the trimeric C-terminal, carbohydrate recognition domain (CRD). We hypothesize that recognition of viral envelope proteins involves multiple sites of interaction between the SP-D lectin domain and specific high mannose glycans, that airway SP-D can modulate epithelial responses to virus, and that CRD-dependent interactions with secreted host molecules can modify SP-D activity. Accordingly, we propose four specific aims: 1. to examine the expression of SP-D by the bronchiolar epithelium, both in normal mice and in the context of challenge with RNA viruses; 2. to further define mechanisms of SP-D recognition of viral glycans by SP-D and the effects of viral interactions on the epithelial response to virus; to further characterize the specific interactions of SP-D with apoptotic epithelial cells and examine potential anti-apoptotic effects of the lung collectins; and to characterize the interactions of SP-D with endogenous ligands that are expressed in the distal airways. To achieve these aims, we will combine state of the art cell culture and murine models with array-based glycomic analysis, functional assays, and crystallographic correlation. The proposed studies will increase our understanding of the contributions of SP-D to anti-viral host defense and the regulation of pulmonary homeostasis at the level of the distal airways, and yield important new and mechanistic information relating to SP-D function at the atomic and molecular level. This is highly relevant to a wide variety of human infectious and/or immune mediated airways diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL029594-30
Application #
8378770
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
30
Fiscal Year
2012
Total Cost
$237,310
Indirect Cost
$59,579
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Byers, Derek E; Wu, Kangyun; Dang-Vu, Geoffrey et al. (2018) Triggering Receptor Expressed on Myeloid Cells-2 Expression Tracks With M2-Like Macrophage Activity and Disease Severity in COPD. Chest 153:77-86
Wu, Kangyun; Byers, Derek E; Jin, Xiaohua et al. (2015) TREM-2 promotes macrophage survival and lung disease after respiratory viral infection. J Exp Med 212:681-97
Gharib, Sina A; Edelman, Jeffery D; Ge, Lingyin et al. (2015) Acute cellular rejection elicits distinct microRNA signatures in airway epithelium of lung transplant patients. Transplant Direct 1:
Pan, Jie-Hong; Adair-Kirk, Tracy L; Patel, Anand C et al. (2014) Myb permits multilineage airway epithelial cell differentiation. Stem Cells 32:3245-56
Rohani, Maryam G; Pilcher, Brian K; Chen, Peter et al. (2014) Cdc42 inhibits ERK-mediated collagenase-1 (MMP-1) expression in collagen-activated human keratinocytes. J Invest Dermatol 134:1230-1237
Holtzman, Michael J; Byers, Derek E; Alexander-Brett, Jennifer et al. (2014) The role of airway epithelial cells and innate immune cells in chronic respiratory disease. Nat Rev Immunol 14:686-98
Holtzman, Michael J; Byers, Derek E; Brett, Jennifer-Alexander et al. (2014) Linking acute infection to chronic lung disease. The role of IL-33-expressing epithelial progenitor cells. Ann Am Thorac Soc 11 Suppl 5:S287-91
Gu, Xiaoling; Karp, Philip H; Brody, Steven L et al. (2014) Chemosensory functions for pulmonary neuroendocrine cells. Am J Respir Cell Mol Biol 50:637-46
Byers, Derek E; Alexander-Brett, Jennifer; Patel, Anand C et al. (2013) Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease. J Clin Invest 123:3967-82
Chen, Peter; Edelman, Jeffrey D; Gharib, Sina A (2013) Comparative evaluation of miRNA expression between in vitro and in vivo airway epithelium demonstrates widespread differences. Am J Pathol 183:1405-1410

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