Patients with familial surfactant protein-C (SP-C) deficiency develop a progressive interstitial lung disease (ILD) with considerable morbidity, mortality and no effective therapy. Respiratory exacerbation in SP-C deficient patients has been associated with viral infections including Respiratory Syncytial Virus (RSV) indicating that viral infection is a contributing factor to disease. This application is based upon preliminary data demonstrating a novel role for SP-C in innate protection of the lung from viral infection. SP-C deficient mice (Sftpc -/-) have been generated in order to determine the role of SP-C in pulmonary homeostasis. Sftpc -/- mice develop an ILD like disease and are highly susceptible to RSV lung infection with decreased viral clearance and robust and sustained pulmonary inflammation. The increased severity of RSV infection in the Sftpc -/- mice and the impact of viral infection in SP-C deficient patients indicate that SP-C is a significant component of the innate immune system of the lung. A role for SP-C in innate defense is supported by preliminary data showing that SP-C inhibits signaling through toll-like receptor 3 (TLR3). This application will determine the role of SP-C in protecting the lung from RSV and will test the central hypothesis that SP-C reduces RSV infectivity and RSV induced inflammation.
In aim1 mechanisms will be identified whereby SP-C reduces viral titers. Experiments will determine if SP-C impedes viral uptake, alters phagocytosis or binds to RSV proteins that mediate attachment and cell entry.
In aim2 mechanisms will be defined whereby SP-C reduces RSV induced inflammation. Experiments will test whether SP-C modulates TLR3 activity by regulating TLR3 association and internalization or by regulating intracellular TLR3 signaling events. The site of SP-C and TLR3 interaction and structural motifs on SP-C that regulate TLR3 function will be determined using site specific mutagenesis of SP-C.
Aim3 will identify the pulmonary responses to RSV regulated by SP-C. SP-C will be conditionally expressed in the lungs of Sftpc -/- mice and exogenous SP-C will be delivered to Sftpc -/- mice during infection to establish parameters for correction of RSV induced injury. The proposed studies will identify mechanisms whereby SP-C protects the lung from RSV injury. Data from the translational experiments of aim 3 will be useful in designing therapy for exacerbations in SP-C deficient patients.

Public Health Relevance

Pulmonary surfactant lines the surface of the lung, is essential for normal lung function and protects the lung from infection. People that do not produce normal amounts of the surfactant protein C (SP-C) develop lung disease and are more susceptible to infection by the virus Respiratory Syncytial Virus (RSV). In this application, we propose to determine how SP-C protects the lung against RSV infection and reduces inflammation. We will also determine the conditions where SP-C replacement in the lung will reduce the inflammation and injury from RSV infections. These studies should be useful in designing therapies for treatment of RSV infection in patients that have SP-C deficiency.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL050046-18
Application #
8304331
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Lin, Sara
Project Start
1994-01-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
18
Fiscal Year
2012
Total Cost
$371,250
Indirect Cost
$123,750
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Conkright, J J; Bridges, J P; Na, C L et al. (2001) Secretion of surfactant protein C, an integral membrane protein, requires the N-terminal propeptide. J Biol Chem 276:14658-64