The respiratory tract, like other mucosal surfaces, is protected by a multifaceted immune system from exposure to pathogenic microorganisms, environmental particulates, and allergens. Remarkably, the normal distal respiratory epithelial surface is free of chronic inflammation, a situation that optimizes gas exchange across the alveolar membrane. The collectin proteins (collagen-like lectins) are components of the multifaceted innate response in the blood and at most mucosal surfaces of the body. Two collectins, surfactant protein A (SP-A) and surfactant protein D (SP-D), are secreted by respiratory epithelial cells into the lining fluids of the respiratory tract, in good position to modulate the immune response. In this proposal, we will focus on the role of SP-D in host defense against influenza virus and address a possibly novel role for SP-D in modulating the acquired immune response to viral infection. We will also test the hypothesis that variations in collectin quaternary structure, specifically variability in self-association of SP-D trimers into higher-order multimers, modulates the function of SP-D in defense against influenza. We further hypothesize that substitution of a threonine for a methionine at position 11 in human SP-D due to a common SNP is a genetic determinant of SP-D multimer formation. Our study design is based on the truism that structure begets function. We will first characterize the biochemical basis for SP-D multimer formation and the altered quaternary structures caused by the Met^11Thr-encoding SNP (aim 1). We will then study the role of SP-D, and its variant haplotypes, in antigen presentation and the acquired cellular response to influenza in vitro and in vivo (aims 2 and 3).

Public Health Relevance

This proposal studies a surfactant-associated protein (SP-D) involved in protecting mucosal surfaces from infection and inflammation. We will study how the structure of the protein is related to function and how common variations in the human genome affect the immuno-modulatory functions of SP-D. The results may relate to the development of new therapies including new vaccination strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL024075-34
Application #
8603257
Study Section
Special Emphasis Panel (ZHL1-PPG-S)
Project Start
Project End
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
34
Fiscal Year
2014
Total Cost
$268,298
Indirect Cost
$94,333
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Vanderbilt, Jeff N; Allen, Lennell; Gonzalez, Robert F et al. (2008) Directed expression of transgenes to alveolar type I cells in the mouse. Am J Respir Cell Mol Biol 39:253-62

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