Genomewide Association Analysis of Respiratory Syncytial Virus Infection in Mice

Abstract

Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection in infants, with about half being infected in their first year of life. Yet only 2 to 3% of infants are hospitalized for RSV infection, suggesting that individual susceptibility contributes to disease severity. Previously, we determined that AKR/J (susceptible) mice developed high lung RSV titers and showed delayed weight recovery, whereas C57BL/6J (resistant) mice demonstrated low lung RSV titers and rapid weight recovery. In addition, we have reported that gene-targeted mice lacking the cystic fibrosis transmembrane conductance regulator (Cftr; ATP-binding cassette subfamily C, member 7) are susceptible to RSV infection. For this report, recombinant backcross and F2 progeny derived from C57BL/6J and AKR/J mice were infected with RSV, their lung titers were measured, and quantitative trait locus (QTL) analysis was performed. A major QTL, designated Rsvs1, was identified on proximal mouse chromosome 6 in both recombinant populations. Microarray analysis comparing lung transcripts of the parental strains during infection identified several candidate genes that mapped to the Rsvs1 interval, including Cftr. These findings add to our understanding of individual RSV susceptibility and strongly support a modifier role for CFTR in RSV infection, a significant cause of respiratory morbidity in infants with cystic fibrosis.A major cause of lower respiratory tract infection during infancy and childhood, respiratory syncytial virus (RSV) produces annual epidemics in which Ͼ50% of infants are infected during their first RSV season, and nearly all children are infected by 2 to 3 years of age (25,32). Approximately 2 to 3% of infected infants and an increasing number of elderly patients develop significant morbidity and mortality from RSV infection (4,54,59,62). Although the mechanism is unclear, early, severe RSV infection is a risk factor for recurrent wheezing and asthma (42, 45). In infants, RSV can cause bronchiolitis, leading to severe respiratory illness requiring hospitalization (ϳ120,000 cases/year in the United States) (4, 54, 59). Severe RSV infections are more likely to occur in patients that are immunocompromised or in infants born prematurely. Outside of these high-risk groups, it is not clear why only a small percentage of children develop severe illness.While almost every child becomes infected with RSV, the gene-environment interactions that predispose children to develop severe RSV infection are unknown. Previous studies of children have suggested several candidate genes associated with severe RSV infection, including polymorphisms in surfactant-associated proteins A and D (34, 36, 49) and several cytokines (21,23,26,27,50). However, these genetic differences explain only a part of the variable response to RSV infection, making it difficult to assess the specific role(s) of these genes in disease severity. Severity of RSV infection is likely to be a complex trait and involves differences that control the initial infect...

Multigenic Control and Sex Bias in Host Susceptibility to Spore-Induced Pulmonary Anthrax in Mice

“…However, the four SNPs that define the chromosome 11 QTL peak in our study map about 7 Mbp proximal to Nalp1b, suggesting one or more possible new candidate genes. The QTL on chromosome 6 coincides with the confidence interval of the recently reported Rsvs1 locus (59). This QTL controls the differential susceptibility to respiratory syncytial virus infection, as identified in C57BL/6J and AKR/J mice by measuring lung viral titers (CFU) at 4 days postinoculation.…”

Genetic Susceptibility to the Delayed Sequelae of Neonatal Respiratory Syncytial Virus Infection Is MHC Dependent

“…In fact, analysis of mouse genetic models has generated novel approaches for treatment of narcotic drug addiction (20) and for prevention of acetaminophen-induced liver toxicity (21). Differences in response to RSV have been observed among inbred mouse strains, including differences in viral load (22)(23)(24) postinfection, and in eosinophilic responses after vaccination with the RSV glycoprotein (25,26). Therefore, we examined the effect of neonatal RSV infection on the outcome after reinfection in 10 inbred strains of mice.…”

Investigation of Syntropic Gene Polimorfisms of Multifactorial Diseases

“…The damages in gen IL17 on mice was provided smaller susceptibility to lung damage provoked by a virus infection. In addition, defective mice was recorded reduced levels of neutrophils in the lung (Stark et al, 2002., Stark et al, 2010.…”