Surfactant protein C-deficient mice are susceptible to respiratory syncytial virus infection.
Patients with mutations in the pulmonary surfactant protein C (SP-C) gene develop interstitial lung disease and pulmonary exacerbations associated with viral infections including respiratory syncytial virus (RSV). Pulmonary infection with RSV caused more severe interstitial thickening, air space consolidation, and goblet cell hyperplasia in SP-C-deficient (Sftpc(-/-)) mice compared with SP-C replete mice. The RSV-induced pathology resolved more slowly in Sftpc(-/-) mice with lung inflammation persistent up to 30 days postinfection. Polymorphonuclear leukocyte and macrophage counts were increased in the bronchoalveolar lavage (BAL) fluid of Sftpc(-/-) mice. Viral titers and viral F and G protein mRNA were significantly increased in both Sftpc(-/-) and heterozygous Sftpc(+/-) mice compared with 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.
Glasser
Stephan W
SW
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA. steve.glasser@cchmc.org
Witt
Teah L
TL
Senft
Albert P
AP
Baatz
John E
JE
Folger
Dusti
D
Maxfield
Melissa D
MD
Akinbi
Henry T
HT
Newton
Danforth A
DA
Prows
Daniel R
DR
Korfhagen
Thomas R
TR
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000821:virology; D002452:Cell Count; D002460:Cell Line; D037222:Collectins / Q000378:metabolism; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D015967:Gene Expression Regulation, Viral; D020397:Goblet Cells / Q000473:pathology / Q000821:virology; D006801:Humans; D006984:Hypertrophy; D008024:Ligands; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000821:virology; D051379:Mice; D011014:Pneumonia / Q000150:complications / Q000473:pathology / Q000821:virology; D037721:Pulmonary Surfactant-Associated Protein C / Q000172:deficiency* / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000378:metabolism; D018357:Respiratory Syncytial Virus Infections / Q000150:complications / Q000378:metabolism* / Q000473:pathology* / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000235:genetics; D013997:Time Factors; D051196:Toll-Like Receptor 3 / Q000378:metabolism
D037222:Collectins; D008024:Ligands; D037721:Pulmonary Surfactant-Associated Protein C; D012330:RNA, Double-Stranded; D051196:Toll-Like Receptor 3