Matrix Metalloproteinase-9 Mediates RSV Infection in Vitro and in Vivo.
Respiratory Syncytial Virus (RSV) is an important human pathogen associated with substantial morbidity and mortality. The present study tested the hypothesis that RSV infection would increase matrix metalloproteinase (MMP)-9 expression, and that MMP-9 inhibition would decrease RSV replication both in vitro and in vivo. RSV A2 infection of human bronchial epithelial cells increased MMP-9 mRNA and protein release. Cells transfected with siRNA against MMP-9 following RSV infection had lower viral titers. In RSV infected wild-type (WT) mice, MMP-9, airway resistance and viral load peaked at day 2 post infection, and remained elevated on days 4 and 7. RSV infected MMP-9 knockout (KO) mice had decreased lung inflammation. On days 2 and 4 post inoculation, the RSV burden was lower in the MMP-9 KO mice compared to WT controls. In conclusion, our studies demonstrate that RSV infection is a potent stimulus of MMP-9 expression both in vitro and in vivo. Reduction of MMP-9 (via siRNA knockdown, and in MMP-9 KO mice) resulted in decreased viral replication. Our findings suggest MMP-9 is a potential therapeutic target for RSV disease.
Departments of Pediatrics, University of Alabama at Birmingham, PPS 102, 1600 5th Ave South, Birmingham, AL 35233, USA. mkong@peds.uab.edu.
Michele Y F
MY
Kong
Departments of Pediatrics, University of Alabama at Birmingham, PPS 102, 1600 5th Ave South, Birmingham, AL 35233, USA. rwhitley@peds.uab.edu.
Richard J
RJ
Whitley
Departments of Pediatrics, University of Alabama at Birmingham, PPS 102, 1600 5th Ave South, Birmingham, AL 35233, USA. npeng@peds.uab.edu.
Ning
N
Peng
Departments of Medicine, University of Alabama at Birmingham, PPS 102, 1600 5th Ave South, Birmingham, AL 35233, USA. roster@uabmc.edu.
Robert
R
Oster
Departments of Genetics, University of Alabama at Birmingham, PPS 102, 1600 5th Ave South, Birmingham, AL 35233, USA. trs@uab.edu.
Trenton R
TR
Schoeb
Center for Global Health, Colorado School of Public Health, 13199 E Montview Blvd, Suite 310,A090 Aurora, CO 80045, USA. wsull@me.com.
Wayne
W
Sullender
Departments of Pediatrics, University of Alabama at Birmingham, PPS 102, 1600 5th Ave South, Birmingham, AL 35233, USA. nambalavanan@peds.uab.edu.
Namasivayam
N
Ambalavanan
Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. john.clancy@cchmc.org.
John Paul
JP
Clancy
Departments of Medicine, University of Alabama at Birmingham, PPS 102, 1600 5th Ave South, Birmingham, AL 35233, USA. agaggar1@uab.edu.
Amit
A
Gaggar
Departments of Medicine, University of Alabama at Birmingham, PPS 102, 1600 5th Ave South, Birmingham, AL 35233, USA. blalock@uab.edu.
J Edwin
JE
Blalock
D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000821:virology; D020868:Gene Silencing; D054884:Host-Pathogen Interactions; D006801:Humans; D008168:Lung / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000378:metabolism; D012136:Respiratory Syncytial Viruses / Q000502:physiology*; D019562:Viral Load
D034741:RNA, Small Interfering; D020780:Matrix Metalloproteinase 9
cell; matrix metalloproteinase; murine model; respiratory syncytial virus