Respiratory syncytial virus infection enhances the response to laryngeal chemostimulation and inhibits arousal from sleep in young lambs*

Abstract

To evaluate the effect of respiratory syncytial virus (RSV) infection on the response to laryngeal chemostimulation (LCS) with water, five lambs were inoculated with human RSV and three lambs were given control media at an age of 3-5 days. During RSV infection, LCS resulted in increased inhibition of minute ventilation and delayed recovery of regular breathing. Sleep further increased the response, and arousal was less likely to occur in active sleep. Two of the five infected lambs needed resuscitation after LCS when arousal was absent. Histological studies showed bronchiolitis and pneumonitis. Laryngeal tastebud morphology was unchanged at 8 days after inoculation. However, infected lambs had disrupted tastebuds 4-6 weeks after infection. Failure to arouse and to terminate reflex apnea may play a role in the pathogenesis of the sudden infant death syndrome associated with respiratory tract infection.

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

“…The RSV-infected preterm lambs showed clinical evidence of infection including elevated temperature and increased respiration rate with mild loss of appetite (milk consumption) and cough. The pyrexia and tachypnea are consistent with previous work in older neonatal lambs with hRSV or bRSV infection [16,25]. Infants with severe hRSV infection typically exhibit a lowgrade to moderate fever, croup-like cough and tachypnea with anorexia, lethargy or irritability [3].…”

“…Study of RSV infection in animal models requires comparable clinical disease, lesion development, immunity, or other features that relate to the specific aims of the experiment [10]. Animal models for study of human RSV (hRSV) pathogenesis and immune response include rats [11], mice [12], ferrets [13], guinea pigs [14], hamsters [15], lambs [16] and nonhuman primates [17]. Infection in the chimpanzee is viewed by some to be the most analogous to human disease; however, animal availability is limited, few are naive and they require specialized facilities and management, making this model impractical [18].…”

“…Late-term fetal and preterm lambs have proven valuable as pulmonary models for the study of surfactant expression and regulation [19], ventilation-induced injury [20], congenital diaphragmatic hernia [21], chorioamnionitis [22], sleep apnea [16] and persistent pulmonary hypertension of the newborn [23]. A preterm lamb model of hRSV was previously evaluated for RSV-induced sleep apnea, and infection yielded only mild clinical disease [16].…”

“…A preterm lamb model of hRSV was previously evaluated for RSV-induced sleep apnea, and infection yielded only mild clinical disease [16]. An analogous virus model is bovine RSV (bRSV), a pneumovirus that is genomically, antigenically and functionally related to hRSV and is host-adapted for ruminant infection causing significant pulmonary lesions and clinical disease [18,24,25].…”

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

“…Investigation of the mechanisms in RSV infection requires a documented animal model with comparable disease manifestations. Late-term fetal and preterm lambs have proven valuable as pulmonary models for the study of surfactant expression and regulation, ventilation-induced injury, congenital diaphragmatic hernia, chorioamnionitis, sleep apnea and persistent pulmonary hypertension in the newborn [9][10][11][12][13]. They have also been useful for study of RSV, parainfluenza virus-3 (PIV-3) infection and other infectious respiratory diseases [10,14].…”