Respiratory syncytial virus (RSV) infection in infancy is implicated in asthma development in later childhood. Our group previously has shown that there is a severity-dependent relationship of infant bronchiolitis on the risk and morbidity of early childhood asthma. More recently, using the cohort our group enrolled in the Tennessee Children?s Respiratory Initiative (TCRI), we found that a specific RSV genotype was associated with enhanced bronchiolitis severity in infants. In our preliminary data, we show that a previously described mutation in RSV isolates is the current predominant circulating genotype of RSV subgroup A strains. This mutation is an A to G transition in the 4th nucleotide position of the attachment glycoprotein (G) gene transcription terminator (A4G). We also identified a second mutation of RSV with 2 tandem stop codons for the G gene (2stop-A4G) and infants infected with this RSV mutation had statistically significantly increased bronchiolitis severity scores compared to infants infected with either the RSV WT genotype (A at the 4th position in the G gene) or the A4G mutation (one stop codon and G at the 4th position in the G gene). Additional preliminary data reveals that infection with 3 RSV clinical strains isolated from respiratory tracts secretions obtained from infants enrolled in INSPIRE that contained the 2stop-A4G mutation resulted in a Th2 predominant phenotype in mice. This 2stop-A4G mutation was also associated with enhanced Th2 cytokine response during acute infection in human infants in the INSPIRE birth cohort (Project 1) and increased age 4-6 year asthma risk in TCRI. We have published that we have the capability to create chimeric viruses in which we can substitute the G and F genes from individual viruses into the RSV A2 backbone and mutate specific regions of those genes using a reverse genetics approach,2-4 giving us the capability to specifically determine the contribution of 2stop-A4G on host immunity. Our overarching hypotheses for this proposal are that infection with RSV strains that contain 2stop-A4G enhance innate and adaptive Th2 immune responses, and augment subsequent allergic airway inflammation while exacerbating existing allergen- induced airway inflammation. These studies are paradigm shifting because prior to this project there has been no RSV mutation that has been identified as a risk factor for the development of asthma, and our preliminary data strongly supports that RSV 2stop-A4G may be the first described. The proposed experiments will advance the field in that they will define the mechanisms by which RSV 2stop-A4G controls both the early innate and adaptive Th2 responses. Defining the contribution of RSV 2stop-A4G to infant bronchiolitis and asthma pathogenesis highlights the clinical significance of our studies and may provide a therapeutic target for vaccines and precision medicine approaches that focus on this RSV mutation.
PROJECT 2: 2stop-A4G genotype in RSV-induced bronchiolitis and asthma We have identified respiratory syncytial virus (RSV) strains that contain a specific mutation in the attachment gene are associated with increased risk of severe infant illness and later wheezing. We have found that strains containing this same mutation are associated with severe disease in mice. In this project, we will determine the specific effect of this mutation on disease severity in mice so that we can better understand the mechanisms by which this mutation causes increased illness in humans.
Showing the most recent 10 out of 111 publications
