Ferrets as a Novel Animal Model for Studying Human Respiratory Syncytial Virus Infections in Immunocompetent and Immunocompromised Hosts.

Koert Stittelaar,Erhard Van Der Vries,Edwin Veldhuis Kroeze,Pieter Fraaij,Albert Osterhaus,Albert Osterhaus,Albert Osterhaus,Albert Osterhaus,Erhard Van Der Vries,Jeroen Van Kampen,Jeroen Van Kampen,Erhard Van Der Vries,Rik De Swart,Rik De Swart,Geert Van Amerongen,Leon De Waal,Pieter Fraaij,Carel Van Baalen

doi:10.3390/v8060168

Abstract

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 (105 TCID50) 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.

Highlights

Human respiratory syncytial virus (HRSV) is a member of the family Paramyxoviridae, genusPneumovirus
Since these studies were performed by IN inoculation with a laboratory-adapted HRSV strain, we set out to assess whether IT inoculation of adult immunocompetent ferrets with a low-passage wild-type HRSV strain would result in productive virus replication in the Lower respiratory tract (LRT)
In the present study we have demonstrated that ferrets are susceptible to infection with a low-passage wild-type HRSV subgroup A strain

Summary

Introduction

Human respiratory syncytial virus (HRSV) is a member of the family Paramyxoviridae, genusPneumovirus. Young infants with a history of premature birth and those with congenital heart or lung disease have an increased risk of developing severe disease upon primary HRSV infection [2]. Another high-risk group of severe HRSV disease is found at the other extreme of age—the frail elderly—with. A third high-risk group of severe HRSV disease is formed of individuals who are immunocompromised, either iatrogenically upon e.g., cell or organ transplantation or cancer treatment, or through inherited or acquired immunodeficiency [4,5,6]. Lower respiratory tract (LRT) infections with HRSV have especially been associated with high morbidity and mortality in allogenic hematopoietic cell transplant recipients [5,13]. Therapeutic options are currently restricted to administration of ribavirin and/or intravenous immunoglobulin (IVIG) [15,16], several antiviral compounds are currently in clinical development [2,17]

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