A Genetic Model of Differential Susceptibility to Human Respiratory Syncytial Virus (RSV) Infection

FASEB J. 2014 Apr;28(4):1947-56. doi: 10.1096/fj.13-239855. Epub 2014 Jan 13.

Abstract

Respiratory syncytial virus (RSV) is the primary cause of lower respiratory tract infection during childhood and causes severe symptoms in some patients, which may cause hospitalization and death. Mechanisms for differential responses to RSV are unknown. Our objective was to develop an in vitro model of RSV infection to evaluate interindividual variation in response to RSV and identify susceptibility genes. Populations of human-derived HapMap lymphoblastoid cell lines (LCLs) were infected with RSV. Compared with controls, RSV-G mRNA expression varied from ~1- to 400-fold between LCLs. Basal expression of a number of gene transcripts, including myxovirus (influenza virus) resistance 1 (MX1), significantly correlated with RSV-G expression in HapMap LCLs. Individuals in a case-control population of RSV-infected children who were homozygous (n=94) or heterozygous (n=172) for the predicted deleterious A allele in a missense G/A SNP in MX1 had significantly greater risk for developing severe RSV disease relative to those with the major allele (n=108) (χ(2)=5.305, P=0.021; OR: 1.750, 95% CI: 1.110, 2.758, P=0.021). We conclude that genetically diverse human LCLs enable identification of susceptibility genes (e.g., MX1) for RSV disease severity in children, providing insight for disease risk.

Keywords: HapMap; MX1; bronchiolitis; gene expression; infant lung disease; lymphoblastoid cell lines.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Case-Control Studies
  • Cell Line
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Host-Pathogen Interactions
  • Humans
  • Infant
  • Lymphocytes / cytology
  • Lymphocytes / metabolism
  • Lymphocytes / virology
  • Male
  • Models, Genetic*
  • Myxovirus Resistance Proteins / genetics*
  • Polymorphism, Single Nucleotide
  • Prospective Studies
  • Respiratory Syncytial Virus Infections / genetics*
  • Respiratory Syncytial Virus Infections / pathology
  • Respiratory Syncytial Virus Infections / virology
  • Respiratory Syncytial Virus, Human / physiology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Severity of Illness Index
  • Transcriptome*

Substances

  • MX1 protein, human
  • Myxovirus Resistance Proteins