title: Determinants of host susceptibility to murine respiratory syncytial virus (RSV) disease identify a role for the innate immunity scavenger receptor MARCO gene in human infants.
abstract: BACKGROUND
  Respiratory syncytial virus (RSV) is the global leading cause of lower respiratory tract infection in infants. Nearly 30% of all infected infants develop severe disease including bronchiolitis, but susceptibility mechanisms remain unclear.
  
  
  METHODS
  We infected a panel of 30 inbred strains of mice with RSV and measured changes in lung disease parameters 1 and 5days post-infection and they were used in genome-wide association (GWA) studies to identify quantitative trait loci (QTL) and susceptibility gene candidates.
  
  
  RESULTS
  GWA identified QTLs for RSV disease phenotypes, and the innate immunity scavenger receptor Marco was a candidate susceptibility gene; targeted deletion of Marco worsened murine RSV disease. We characterized a human MARCO promoter SNP that caused loss of gene expression, increased in vitro cellular response to RSV infection, and associated with increased risk of disease severity in two independent populations of children infected with RSV.
  
  
  CONCLUSIONS
  Translational integration of a genetic animal model and in vitro human studies identified a role for MARCO in human RSV disease severity. Because no RSV vaccines are approved for clinical use, genetic studies have implications for diagnosing individuals who are at risk for severe RSV disease, and disease prevention strategies (e.g. RSV antibodies).
authors.affiliation: Immunity, Inflammation, and Diseases Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: High
authors.affiliation: Immunity, Inflammation, and Diseases Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Hye-Youn
authors.initials: HY
authors.lastname: Cho
authors.affiliation: Immunity, Inflammation, and Diseases Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Jacqui
authors.initials: J
authors.lastname: Marzec
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Wiltshire
authors.affiliation: Immunity, Inflammation, and Diseases Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Kirsten C
authors.initials: KC
authors.lastname: Verhein
authors.affiliation: Fundación INFANT, Buenos Aires, Argentina.
authors.forename: Mauricio T
authors.initials: MT
authors.lastname: Caballero
authors.affiliation: Fundación INFANT, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Buenos Aires, Argentina.
authors.forename: Patricio L
authors.initials: PL
authors.lastname: Acosta
authors.affiliation: Immunity, Inflammation, and Diseases Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ciencewicki
authors.affiliation: Immunity, Inflammation, and Diseases Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Zackary R
authors.initials: ZR
authors.lastname: McCaw
authors.affiliation: Department of Environmental Health, Harvard University School of Public Health, Boston, MA, USA.
authors.forename: Lester
authors.initials: L
authors.lastname: Kobzik
authors.affiliation: Immunity, Inflammation, and Diseases Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Miller-DeGraff
authors.affiliation: Immunity, Inflammation, and Diseases Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Wes
authors.initials: W
authors.lastname: Gladwell
authors.affiliation: Center for Environmental Medicine, Asthma and Lung Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Peden
authors.affiliation: Fundación INFANT, Buenos Aires, Argentina.
authors.forename: M Elina
authors.initials: ME
authors.lastname: Serra
authors.affiliation: Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Shi
authors.affiliation: Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Clarice
authors.initials: C
authors.lastname: Weinberg
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Oscar
authors.initials: O
authors.lastname: Suzuki
authors.affiliation: Genome Integrity & Structural Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Xuting
authors.initials: X
authors.lastname: Wang
authors.affiliation: Genome Integrity & Structural Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Bell
authors.affiliation: Fundación INFANT, Buenos Aires, Argentina; Department of Pediatrics, Vanderbilt University, Nashville, TN, USA. Electronic address: fernando.p.polack@vanderbilt.edu.
authors.forename: Fernando P
authors.initials: FP
authors.lastname: Polack
authors.affiliation: Immunity, Inflammation, and Diseases Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Electronic address: kleeber1@niehs.nih.gov.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Kleeberger
mesh_terms: D000483:Alleles; D000818:Animals; D016022:Case-Control Studies; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D040641:Quantitative Trait Loci; D011971:Receptors, Immunologic / Q000235:genetics*; D018357:Respiratory Syncytial Virus Infections / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D017384:Sequence Deletion; D012720:Severity of Illness Index
chemical_list: C490460:MARCO protein, human; D011971:Receptors, Immunologic
keywords: Haplotype; Infectious disease; Innate immunity; Lung; Promoter; SNP; Single nucleotide polymorphism