Abstract

A complex immune system protects the mucosal surfaces of the respiratory tract from the constant exposure to pathogenic microorganisms and environmental allergens. The collectin proteins (collagen-like lectins) are components of this multifaceted system. Two of the 6-member collectin family, surfactant protein A (SP-A) and surfactant protein D (SP-D), are present in the lining fluids of the respiratory tract, in good position to provide immunological surveillance against both microbes and allergens. The long-term objectives behind this proposal are to determine the mechanisms of collectin action in pulmonary host defense and the relative importance of the collectins in maintaining human health. To best focus on specific mechanisms a single model organism, influenza virus (IAV), will be studied in several transgenic mouse models of altered collectin expression. The hypothesis to be tested in this proposal is that SP-A and SP-D limit lung injury from IAV infection by distinct and complementary mechanisms, specifically SP-D acts primarily as a direct viral neutralizing molecule blocking infection of the epithelium while SP-a reduces the viral load primarily by enhancing macrophage phagocytosis. The proposal also tests the idea that the collectins present IAV to the cells of the adaptive immune response and modify the cellular and humoral response to infection. These hypotheses will be tested by four specific aims.
Aim 1 : To determine the respective role of SP-A and SP-D during strain specific IAV infection in vivo.
Aim 2 : To characterize the effects of SP-A and SP-D on the response of macrophages to IAV.
Aim 3 : To determine if SP-A or SP-D influences the humoral and cellular immune response to IAV infection.
Aim 4 : To characterize the critical functional domains of the collectins in mediating the mouse response to influenza virus. Although our studies are focused on a specific organism, we expect the mechanisms underlying collectin-IAV-host interactions will pertain more generally to the action of collectins in respiratory immune responses.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058047-08
Application #
6753615
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Denholm, Elizabeth M
Project Start
1997-07-01
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2006-06-30
Support Year
8
Fiscal Year
2004
Total Cost
$271,725
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Pediatrics
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Mun, James J; Tam, Connie; Kowbel, David et al. (2009) Clearance of Pseudomonas aeruginosa from a healthy ocular surface involves surfactant protein D and is compromised by bacterial elastase in a murine null-infection model. Infect Immun 77:2392-8
Ni, Minjian; Tam, Connie; Verma, Amrisha et al. (2008) Expression of surfactant protein D in human corneal epithelial cells is upregulated by Pseudomonas aeruginosa. FEMS Immunol Med Microbiol 54:177-84
Vigerust, David J; Ulett, Kimberly B; Boyd, Kelli L et al. (2007) N-linked glycosylation attenuates H3N2 influenza viruses. J Virol 81:8593-600
Giannoni, Eric; Sawa, Teiji; Allen, Lennell et al. (2006) Surfactant proteins A and D enhance pulmonary clearance of Pseudomonas aeruginosa. Am J Respir Cell Mol Biol 34:704-10
Casey, John; Kaplan, Jennifer; Atochina-Vasserman, Elena N et al. (2005) Alveolar surfactant protein D content modulates bleomycin-induced lung injury. Am J Respir Crit Care Med 172:869-77
Jung, Anja; Allen, Lennell; Nyengaard, Jens R et al. (2005) Design-based stereological analysis of the lung parenchymal architecture and alveolar type II cells in surfactant protein A and D double deficient mice. Anat Rec A Discov Mol Cell Evol Biol 286:885-90
Palaniyar, Nades; Clark, Howard; Nadesalingam, Jeya et al. (2005) Innate immune collectin surfactant protein D enhances the clearance of DNA by macrophages and minimizes anti-DNA antibody generation. J Immunol 174:7352-8
Atochina, Elena N; Beck, James M; Preston, Angela M et al. (2004) Enhanced lung injury and delayed clearance of Pneumocystis carinii in surfactant protein A-deficient mice: attenuation of cytokine responses and reactive oxygen-nitrogen species. Infect Immun 72:6002-11
Atochina, Elena N; Gow, Andrew J; Beck, James M et al. (2004) Delayed clearance of pneumocystis carinii infection, increased inflammation, and altered nitric oxide metabolism in lungs of surfactant protein-D knockout mice. J Infect Dis 189:1528-39
Hawgood, Samuel; Brown, Cynthia; Edmondson, Jess et al. (2004) Pulmonary collectins modulate strain-specific influenza a virus infection and host responses. J Virol 78:8565-72

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