Reduced clearance of respiratory syncytial virus infection in a preterm lamb model

Abstract

Respiratory syncytial virus (RSV) causes significant respiratory disease in children worldwide. For the study of severe RSV disease seen in preterm infants, a suitable animal model is lacking. The novel hypothesis of this study was that preterm lambs are susceptible to bovine RSV (bRSV) infection, an analogous pneumovirus with ruminant host specificity, and that there would be age-dependent differences in select RSV disease parameters. During RSV infection, preterm lambs had elevated temperatures and respiration rates with mild anorexia and cough compared to controls. Gross lesions included multifocal consolidation and atelectasis with foci of hyperinflation. Microscopic lesions included multifocal alveolar septal thickening and bronchiolitis. Immunohistochemistry localized the RSV antigen to all layers of bronchiolar epithelium from a few basal cells to numerous sloughing epithelia. A few mononuclear cells were also immunoreactive. To assess for age-dependent differences in RSV infection, neonatal lambs were infected similarly to the preterm lambs or with a high-titer viral inoculum. Using morphometry at day 7 of infection, preterm lambs had significantly more cellular immunoreactivity for RSV antigen (P <0.05) and syncytial cell formation (P <0.05) than either group of neonatal lambs. This work suggests that perinatal RSV clearance is age-dependent, which may explain the severity of RSV infection in preterm infants. The preterm lamb model is useful for assessing agedependent mechanisms of severe RSV infection. RightsWorks produced by employees of the U.S. Government as part of their official duties are not copyrighted within the U.S. The content of this document is not copyrighted. AbstractRespiratory syncytial virus (RSV) causes significant respiratory disease in children worldwide. For the study of severe RSV disease seen in preterm infants, a suitable animal model is lacking. The novel hypothesis of this study was that preterm lambs are susceptible to bovine RSV (bRSV) infection, an analogous pneumovirus with ruminant host specificity, and that there would be age-dependent differences in select RSV disease parameters. During RSV infection, preterm lambs had elevated temperatures and respiration rates with mild anorexia and cough compared to controls. Gross lesions included multifocal consolidation and atelectasis with foci of hyperinflation. Microscopic lesions included multifocal alveolar septal thickening and bronchiolitis. Immunohistochemistry localized the RSV antigen to all layers of bronchiolar epithelium from a few basal cells to numerous sloughing epithelia. A few mononuclear cells were also immunoreactive. To assess for age-dependent differences in RSV infection, neonatal lambs were infected similarly to the preterm lambs or with a high-titer viral inoculum. Using morphometry at day 7 of infection, preterm lambs had significantly more cellular immunoreactivity for RSV antigen (P <0.05) and syncytial cell formation (P <0.05) than either group of neonatal lambs. This work suggests that peri...

Expression of select immune genes (surfactant proteins A and D, sheep beta defensin 1, and toll-like receptor 4) by respiratory epithelia is developmentally regulated in the preterm neonatal lamb

“…The reduced expression of these innate immune products during development may partially explain the impaired ability to clear RSV infection and enhanced risk for respiratory infection in the preterm neonate [2,15]. Recent evidence indicates that these innate immune moieties have complex interaction patterns and synergism.…”

“…Five lambs at 115 days of gestation (80% gestation), four lambs from 130 days of gestation (90% gestation), four lambs at full-term, natural birth and four lambs 15 days old were acquired (C-section or natural birth) from date mated commercial ewes as previously described [15]. For C-section lambs (days 115 and 130), lambs were extracted from the uterus and euthanized with sodium pentobarbital.…”

“…They have also been useful for study of RSV, parainfluenza virus-3 (PIV-3) infection and other infectious respiratory diseases [10,14]. Sheep infected with ovine RSV strains have consistency with human RSV disease including increased susceptibility in newborns, lesions, and similar innate immune genes [15][16][17]. Recently, preterm lambs were shown to have reduced RSV clearance compared to full-term lambs, which is similar to age-dependent disease seen in preterm RSV infected infants [2,3,15].…”

Pretreatment with Recombinant Human Vascular Endothelial Growth Factor Reduces Virus Replication and Inflammation in a Perinatal Lamb Model of Respiratory Syncytial Virus Infection

“…During the course of infection, lambs were monitored for clinical signs including body temperature. From our previous experience with this model of RSV disease, severe lesion development and peak viral replication occur on day 5 of infection (23,25). Lambs were killed with sodium pentobarbital on day 5 of infection, and lungs were examined for gross lesions.…”

“…Lesions frequently associated with severe RSV disease include necrotizing bronchiolitis (causing atelectasis, hyperinflation, and wheezing) and pneumonia (characterized radiographically as interstitial infiltrates, alveolar filling, and consolidation) (18). Bovine RSV infection in the perinatal lamb model is a viable model for study of the RSV disease and innate immune response (20,25).…”