title: Proteins involved in extracellular matrix dynamics are associated with respiratory syncytial virus disease severity.
abstract: Severity of respiratory syncytial virus (RSV) infection ranges widely. To what extent the local immune response is involved in RSV disease pathogenesis and which markers of this response are critical in determining disease severity is still a matter of debate. The local immune response was studied in nasopharyngeal aspirates (NPAs) during RSV infection. 47 potential markers of disease severity were analysed in a screening cohort of RSV-infected infants with mild disease at home (n = 8), hospitalised infants (n = 10) and infants requiring mechanical ventilation (n = 7). Results were confirmed in a cohort of infants hospitalised for RSV infection (n = 200). Finally, genetic validation was studied in a cohort of infants hospitalised for RSV infection (n = 465) and healthy controls (n = 930). The concentration of TIMP-1 (tissue inhibitor of metalloproteinase) was higher in the NPAs of hospitalised infants compared with the NPAs of infants at home (1,199 versus 568 ng · mL(-1); p<0.0001). Similar results were found for matrix metalloproteinase (MMP)-3 (765 versus 370 pg · mL(-1); p = 0.004). MMP-3 was confirmed as a marker of disease severity in a larger cohort and MMP3 gene polymorphism rs522616 was associated with severe RSV infection (OR 0.82, p<0.05). In conclusion, extracellular matrix proteinases play an important role in the pathogenesis of RSV bronchiolitis.
authors.affiliation: Laboratory for Health Protection Research, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Schuurhof
authors.forename: Louis
authors.initials: L
authors.lastname: Bont
authors.forename: Hennie M
authors.initials: HM
authors.lastname: Hodemaekers
authors.forename: Arja
authors.initials: A
authors.lastname: de Klerk
authors.forename: Hanneke
authors.initials: H
authors.lastname: de Groot
authors.forename: Regina W
authors.initials: RW
authors.lastname: Hofland
authors.forename: Alma C
authors.initials: AC
authors.lastname: van de Pol
authors.forename: Jan L L
authors.initials: JL
authors.lastname: Kimpen
authors.forename: Riny
authors.initials: R
authors.lastname: Janssen
mesh_terms: D000208:Acute Disease; D015415:Biomarkers / Q000032:analysis; D001988:Bronchiolitis / Q000378:metabolism* / Q000821:virology; D015331:Cohort Studies; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000032:analysis / Q000235:genetics; D012121:Respiration, Artificial; D018357:Respiratory Syncytial Virus Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D018113:Respiratory Syncytial Virus, Human; D012720:Severity of Illness Index; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis
chemical_list: D015415:Biomarkers; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3