Current Animal Models for Understanding the Pathology Caused by the Respiratory Syncytial Virus (original) (raw)
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Viruses, 2016
Human respiratory syncytial virus (HRSV) is an important cause of severe respiratory tract disease in immunocompromised patients. Animal models are indispensable for evaluating novel intervention strategies in this complex patient population. To complement existing models in rodents and non-human primates, we have evaluated the potential benefits of an HRSV infection model in ferrets (Mustela putorius furo). Nine-to 12-month-old HRSV-seronegative immunocompetent or immunocompromised ferrets were infected with a low-passage wild-type strain of HRSV subgroup A (10 5 TCID 50) administered by intra-tracheal or intra-nasal inoculation. Immune suppression was achieved by bi-daily oral administration of tacrolimus, mycophenolate mofetil, and prednisolone. Throat and nose swabs were collected daily and animals were euthanized four, seven, or 21 days post-infection (DPI). Virus loads were determined by quantitative virus culture and qPCR. We observed efficient HRSV replication in both the upper and lower respiratory tract. In immunocompromised ferrets, virus loads reached higher levels and showed delayed clearance as compared to those in immunocompetent animals. Histopathological evaluation of animals euthanized 4 DPI demonstrated that the virus replicated in the respiratory epithelial cells of the trachea, bronchi, and bronchioles. These animal models can contribute to an assessment of the efficacy and safety of novel HRSV intervention strategies.
A rhesus monkey model of respiratory syncytial virus infection
Journal of Medical Primatology, 2002
Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract disease in infants and young children worldwide. To date, there is no single animal model that adequately reproduces all human disease states. Here, we have developed a model of experimental infection with human RSV in infant Rhesus macaques. Infected animals demonstrated mild clinical disease including increased respiratory rates, fever and adventitious lung sounds. While more severe disease was not observed, preliminary virological and histopathological findings are promising. It is anticipated that with further optimization, this model will provide a useful system with which to study disease due to RSV infection and evaluate candidate vaccines.
Growth of Respiratory Syncytial Virus in Primary Epithelial Cells from the Human Respiratory Tract
Journal of Virology, 2005
Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract disease in infants and children. To study RSV replication, we have developed an in vitro model of human nasopharyngeal mucosa, human airway epithelium (HAE). RSV grows to moderate titers in HAE, though they are significantly lower than those in a continuous epithelial cell line, HEp-2. In HAE, RSV spreads over time to form focal collections of infected cells causing minimal cytopathic effect. Unlike HEp-2 cells, in which wild-type and live-attenuated vaccine candidate viruses grow equally well, the vaccine candidates exhibit growth in HAE that parallels their level of attenuation in children.
Primary respiratory syncytial virus infection in mice
Journal of medical …, 1988
A mouse model of respiratory syncytial virus (RSV) infection is described. A high-titered, large-volume inoculum results in replication of RSV to a high titer in lungs of BALBic mice. Mice older than 15 weeks of age are more susceptible to RSV infection. Titers up to 106.9 plaque-forming units (pfu)/gram lung can be attained in 32-week-old mice. Older mice experience a clinical illness manifested by ruffled fur, reduced activity, and weight loss. Lung histology of older mice infected with RSV shows bronchiolitis and increased number of lymphocytes and macrophages in alveolar spaces compared with that of mice less than 8 weeks old. This model will serve as the basis for investigating immunodeterminants of recovery and protection from RSV infection.
Respiratory Syncytial Virus Affects Pulmonary Function in BALB/c Mice
The Journal of Infectious Diseases, 1998
BALB/c mice inoculated intranasally with respiratory syncytial virus (RSV) were studied in a whole-body plethysmograph to determine if signs of respiratory illness similar to those observed in human infants could be detected. Also, responsiveness to methacholine was assessed. RSV-infected mice showed significantly higher respiratory rates than did controls (409.2 vs. 305.2 breaths/min, P õ .0001). Significantly increased airway responsiveness to methacholine was noted, infected mice responding to a 100-fold lower dose than controls (P Å .003). Together, these data provide the first objective evidence of respiratory illness in the mouse model of RSV infection, which enhances the value of this model for evaluating effects of vaccines, antivirals, and other drugs acting on respiratory tract disease caused by RSV. cin B, and 5% (vol/vol) fetal calf serum. Cells and media were Respiratory syncytial virus (RSV) is the most important viral harvested when 80%-90% cytopathic effect was observed, sonipathogen causing respiratory tract disease in infants and young cated for 2 min with a high-output sonicator (Sonic 2000; Braun children [1-5]. Despite the clear importance of RSV in both Instruments, Burlingame, CA), and centrifuged for 10 min at 500 acute and chronic respiratory diseases of childhood, the underg. The supernatant was divided into small aliquots and quickly
Chinchilla and Murine Models of Upper Respiratory Tract Infections with Respiratory Syncytial Virus
Journal of Virology, 2005
following intranasal challenge; however, the chinchilla proved to be more permissive than the mouse. The chinchilla model will likely be extremely useful to test the role of RSV in bacterial OM and the efficacy of RSV vaccine candidates designed to provide mucosal and cytotoxic T-lymphocyte immunity. Ultimately, we hope to investigate the relative ability of these candidates to potentially protect against viral predisposal to bacterial OM.
Host Components Contributing to Respiratory Syncytial Virus Pathogenesis
Frontiers in Immunology
Respiratory syncytial virus (RSV) is the most prevalent viral etiological agent of acute respiratory tract infection. Although RSV affects people of all ages, the disease is more severe in infants and causes significant morbidity and hospitalization in young children and in the elderly. Host factors, including an immature immune system in infants, low lymphocyte levels in patients under 5 years old, and low levels of RSV-specific neutralizing antibodies in the blood of adults over 65 years of age, can explain the high susceptibility to RSV infection in these populations. Other host factors that correlate with severe RSV disease include high concentrations of proinflammatory cytokines such as interleukins (IL)-6, IL-8, tumor necrosis factor (TNF)-α, and thymic stromal lymphopoitein (TSLP), which are produced in the respiratory tract of RSV-infected individuals, accompanied by a strong neutrophil response. In addition, data from studies of RSV infections in humans and in animal models revealed that this virus suppresses adaptive immune responses that could eliminate it from the respiratory tract. Here, we examine host factors that contribute to RSV pathogenesis based on an exhaustive review of in vitro infection in humans and in animal models to provide insights into the design of vaccines and therapeutic tools that could prevent diseases caused by RSV.
A lamb model for human respiratory syncytial virus infection
Pediatric Pulmonology, 1993
Respiratory syncytial virus (RSV) is the most important cause of bronchiolitis and pneumonia in young children. The development of an animal model of RSV disease serves to better understanding the pathophysiology of airway disease from RSV infection in infants and children. Groups of six lambs were inoculated intratracheally (IT) or intranasally (IN) with a human strain of RSV (H-RSV). For controls 8 lambs received IT virus-free cell lysate. Tachypnea and fever were observed significantly more often following IT than following IN inoculation of H-RSV or IT placebo (for tachypnea: 20 of 69 days, 5 of 63 days, and 3 of 89 days, respectively, P < 0.001 ; for fever: 6 of 69 days, 0 of 63 days, and 1 of 89 days, respectively, P < 0.02). Nasal fluid production was significantly more frequent in both IT (1 4 of 69 days) and IN (1 5 of 63 days) groups than in the placebo group (2 of 87 days, P < 0.001). Postvaccination geometric mean titers (GMT, arithmetic transformation of log 2) of RSV-specific neutralizing antibody were significantly increased in the IT H-RSV group compared with postplacebo GMTs at 1 week (72 vs. 6.7, P < 0.03). By the second week postinoculation both H-RSV-infected groups had comparable levels of RSV-specific neutralizing antibody titers and had significantly greater GMTs for the second through to the fourth week than the placebo group (144, 128, and 4.8, respectively P < 0.0008). Bacterial isolates of the upper airway were comparable among the three groups. Histopathology at day 28 postinoculation was unremarkable for the three study groups. The development of overt clinical illness in lambs inoculated with H-RSV suggests that the H-RSV lamb model may be used to delineate the pathogenesis of lung injury of H-RSV infection.