Submitted on December 29, 2008
Revised on March 13, 2009
Accepted on March 16, 2009
Surfactant Protein C Deficient Mice are Susceptible to Respiratory Syncytial Virus Infection
Stephan W Glasser1*, Teah L Witt2, Albert P. Senft2, John E. Baatz3, Dusti Folger1, Melissa D Maxfield1, Henry T Akinbi1, Danforth A. Newton3, Daniel R Prows1, and Thomas R Korfhagen1
1 Cincinnati Children's Hospital Medical Center
2 Lovelace Respiratory Research Institute
3 Medical University of South Carolina
* To whom correspondence should be addressed. E-mail: steve.glasser{at}cchmc.org.
Patients with mutations in the pulmonary surfactant protein C (SP-C) gene develop interstitial lung disease (ILD) and pulmonary exacerbations associated with viral infections including respiratory syncytial virus (RSV). Pulmonary infection with RSV caused more severe interstitial thickening, airspace consolidation and goblet cell hyperplasia in SP-C deficient (Sftpc-/-) mice compared to SP-C replete mice. The RSV induced pathology resolved more slowly in Sftpc-/- mice with lung inflammation persistent up to 30 days post-infection. Polymorphonuclear leukocyte and macrophage counts were increased in the broncho-alveolar lavage fluid (BALF) of Sftpc-/- mice. Viral titers and viral F and G protein mRNA were significantly increased in both Sftpc-/- and heterozygous Sftpc+/- mice compared to controls. Expression of toll-like receptor 3 (TLR3) mRNA was increased in the lungs of Sftpc-/- mice relative to Sftpc+/+ mice before and after RSV infection. Consistent with the increased TLR3 expression, BAL inflammatory cells were increased in the Sftpc-/- mice after exposure to a TLR3 specific ligand, poly (I-C). Preparations of purified SP-C and synthetic phospholipids blocked poly (I-C) induced TLR3 signaling in vitro. SP-C deficiency increases the severity of RSV induced pulmonary inflammation through regulation of TLR3 signaling.
