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
Monica High,
Hye-Youn Cho,
Jacqui Marzec,
Tim Wiltshire,
Kirsten C. Verhein,
Mauricio T. Caballero,
Patricio L. Acosta,
Jonathan Ciencewicki,
Zackary R. McCaw,
Lester Kobzik,
Laura Miller-DeGraff,
Wes Gladwell,
David B. Peden,
M. Elina Serra,
Min Shi,
Clarice Weinberg,
Oscar Suzuki,
Xuting Wang,
Douglas A. Bell,
Fernando P. Polack,
Steven R. Kleeberger
Affiliations
Monica High
Immunity, Inflammation, and Diseases Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
Hye-Youn Cho
Immunity, Inflammation, and Diseases Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
Jacqui Marzec
Immunity, Inflammation, and Diseases Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
Tim Wiltshire
Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA
Kirsten C. Verhein
Immunity, Inflammation, and Diseases Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
Mauricio T. Caballero
Fundación INFANT, Buenos Aires, Argentina
Patricio L. Acosta
Fundación INFANT, Buenos Aires, Argentina
Jonathan Ciencewicki
Immunity, Inflammation, and Diseases Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
Zackary R. McCaw
Immunity, Inflammation, and Diseases Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
Lester Kobzik
Department of Environmental Health, Harvard University School of Public Health, Boston, MA, USA
Laura Miller-DeGraff
Immunity, Inflammation, and Diseases Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
Wes Gladwell
Immunity, Inflammation, and Diseases Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
David B. Peden
Center for Environmental Medicine, Asthma and Lung Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
M. Elina Serra
Fundación INFANT, Buenos Aires, Argentina
Min Shi
Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
Clarice Weinberg
Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
Oscar Suzuki
Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA
Xuting Wang
Genome Integrity & Structural Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
Douglas A. Bell
Genome Integrity & Structural Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
Fernando P. Polack
Fundación INFANT, Buenos Aires, Argentina
Steven R. Kleeberger
Immunity, Inflammation, and Diseases Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
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 5 days post-infection and they were used in genome-wide association (GWA) studies to identify quantitative trait loci (QTL) and susceptibility gene candidates. Findings: 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. Interpretation: 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).
