Infant baboons infected with respiratory syncytial virus develop clinical and pathological changes that parallel those of human infants

Abstract

infection of the lower respiratory tract is the leading cause of respiratory failure among infants in the United States of America and annually results in Ͼ300,000 deaths worldwide. Despite the importance of RSV, there is no licensed vaccine, and no specific form of therapy. This is largely due to the absence of an appropriate animal model for the evaluation of vaccines and therapeutic agents. We inoculated anesthetized infant (4 wk) baboons (Papio anubis) with a human strain of RSV intranasally or intratracheally. Baboons were monitored daily for clinical changes. Anesthetized baboons were intubated at various intervals, and bronchoalveolar lavage (BAL) was performed for viral culture and determination of leukocyte counts. Sham-infected baboons served as controls. Necropsies were performed on infected baboons on days 1, 3, 5, 8, or 13 after inoculation, with pathological analysis and immunohistochemical staining of lung tissues to detect RSV antigen. Infected baboons developed tachypnea and reduced oxygenation peaking from 4 to 8 days after infection and persisting for Ն14 days. Virus was recoverable in BAL fluid up to 8 days following infection. Necropsy revealed intense interstitial pneumonia, sloughing of the bronchiolar epithelium, and obstruction of the bronchiolar lumen with inflammatory cells and sloughed epithelial cells. RSV antigen was identified in bronchiolar and alveolar epithelium. We conclude that RSV-infected infant baboons develop clinical and pathological changes that parallel those observed in human infants with RSV infection. The infant baboon represents a muchneeded model for studying the pathogenesis of RSV infection and evaluating antivirals and vaccines. interstitial pneumonia; bronchiolitis; baboon model; animal models; respiratory syncytial virus vaccine RESPIRATORY SYNCYTIAL VIRUS (RSV) is the most important respiratory pathogen of early life. RSV infection, in the form of interstitial pneumonia and bronchiolitis, annually results in Ͼ120,000 hospitalizations in the United States of America and Ͼ300,000 deaths worldwide (21, 24). RSV lower respiratory tract infection (LRTI) in infancy also may predispose to the development of childhood asthma (33). Despite the considerable impact of RSV infection, there is no approved vaccine and no effective specific form of therapy. The lack of an appropriate animal model has resulted in an incomplete understanding of the pathophysiology of the disease and an inability to evaluate the safety and efficacy of vaccines and pharmacological agents. An animal model developing clinical and pathological manifestations similar to those of human infants with RSV infection would provide a significant step toward overcoming these problems. To reflect human disease, an appropriate animal model should develop tachypnea, reduced oxygenation, and interstitial and peribronchiolar inflammation with obstruction of the bronchiolar lumen by invading leukocytes and exfoliated epithelial cells following infection. These manifestations should be most prominent in an infant...

Animal models of respiratory syncytial virus infection

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“…Progress in understanding the pathogenesis of RSV and host response using in vivo experiments in small animal models have not always translated to humans (Mestas and Hughes 2004). This coupled with the physiological differences between adult and pediatric populations (Papin et al 2013) and the ethical and technical difficulty of studying infants and children are major obstacles to advancing our understanding of RSV pathogenesis, and the mechanisms through which RSV contributes to recurrent wheezing and asthma development.…”

Animal models of bronchopulmonary dysplasia. The preterm baboon models

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