Elsevier

Biologicals

Volume 37, Issue 3, June 2009, Pages 152-159
Biologicals

The cotton rat model of respiratory viral infections

https://doi.org/10.1016/j.biologicals.2009.02.017Get rights and content

Abstract

Development of successful vaccines against human infectious diseases depends on using appropriate animal models for testing vaccine efficacy and safety. For some viral infections the task is further complicated by the frequently changing genetic make-up of the virus, as in the case of influenza, or by the existence of the little-understood phenomenon of vaccine-enhanced disease, as in the case of respiratory syncytial virus (RSV). The cotton rat Sigmodon hispidus has been used for years as an excellent small animal model of the RSV vaccine-enhanced disease. Recently, using cotton rats, we have demonstrated that vaccination against another paramyxovirus, human metapneumovirus (hMPV), can also lead to vaccine-enhanced disease. In addition to the study of paramyxoviruses, S. hispidus presents important advantages for the study of orthomyxoviruses such as influenza. The cotton rat is susceptible to infection with unadapted human influenza strains, and heterosubtypic immunity to influenza can be evoked in S. hispidus. The mechanisms of influenza, RSV, and hMPV pathogenesis and immunity can now be investigated in the cotton rat with the development of species-specific reagents for this animal model.

Introduction

The cotton rat Sigmodon hispidus is a small rodent susceptible to a surprisingly large variety of human pathogens (for review see [1]). This model is best known, however, for its use in research related to respiratory viruses. Permissiveness of cotton rats to infection with human respiratory syncytial virus (RSV) surpasses that of mice by more than 100-fold. Predictive quality of this model is so high that the only available prophylactic treatment for severe RSV disease (antibodies RespiGam and Synagis) advanced to clinical trials based on the results of efficacy and safety studies in cotton rats, bypassing the need for testing in primates. The cotton rat model also accurately predicted the dose of the drug currently being used in human infants. The application of cotton rats to biomedical research has been limited until recently because of the lack of species-specific reagents to study mechanisms of disease pathogenesis and immunity in this model. The situation has changed in the past decade with our endeavor to develop cotton rat-specific reagents. Over 200 cotton rat genes encoding cytokines, chemokines, cell surface markers and regulatory molecules have been cloned and reagents to many of these were derived through a collaboration with R&D Systems, Inc. (Table 1). Molecular level analysis reveals important features of the model that makes S. hispidus stand out in comparison to other small animal models. For example, the cotton rat carries functional set of Mx genes encoding antiviral proteins Mx1 and Mx2 [2]. Human Mx protein is a crucial component of innate antiviral defense system which, together with the adaptive immune mechanisms, facilitates clearance of viral infections. In contrast, most common laboratory strains of mice lack functional Mx system, and murine antiviral defense relies mostly on adaptive immune mechanisms. This often results in prolonged replication of viruses in murine models compared to what is seen in humans, ferrets and cotton rats.

Although having achieved its reputation in the past primarily as a RSV model, the cotton rat turns out to be a superior model of other respiratory viral diseases as well. For example, the model of recently discovered human metapneumovirus (hMP) was recently established in the cotton rat [3]. Available data indicates that the model will be useful for not only elucidating mechanisms of hMPV pathogenesis, but also for developing a safe vaccine against hMPV disease [4]. Moreover, S. hispidus appears to be a uniquely suitable small animal model for research on influenza pathogenesis and immunity. Unlike mice, cotton rats can be infected with unadapted influenza virus strains and dynamics of viral replication in the cotton rat model resemble those reported in humans. This review will focus on recent advances in the field of respiratory virus research in the cotton rat model and will cover issues related to RSV, hMPV and influenza viruses' pathogenesis and immunity.

Section snippets

Human respiratory syncytial virus (hRSV) infection in the cotton rat model

Respiratory syncytial virus (RSV) is the major cause of severe respiratory infections in infants and young children. It is also a serious health threat in the immunocompromized and the elderly. The quest for a successful RSV vaccine, spanning over four decades, has been hampered by the lack of understanding of RSV pathogenesis and by the failed trials in the 1960's of a formalin-inactivated RSV (FI-RSV) vaccine. Rather than providing protection, immunization with FI-RSV led to a more severe,

Human metapneumovirus (hPMV) infection in the cotton rat model

hMPV is a newly-described member of the paramyxovirus family, closely related in sequence to RSV. Since its original discovery in 2001 in young Dutch children with acute respiratory tract infections, worldwide distribution of hMPV has been described and many features of hMPV-caused disease were found to resemble the disease caused by RSV. Similar to RSV, hMPV infects virtually all children by the age of 5 and can re-infect humans repeatedly throughout life. Like RSV, hMPV causes more severe

Influenza infection in the cotton rat model

A number of animal models has been developed for influenza infection, but each one is plagued with problems. Primates get infected with influenza when inoculated intranasally or intracheally, but their limited availability, expense, and outbred nature limits primates' use in influenza research. Ferrets present a promising small animal model of influenza infection, as these animals are susceptible to infection with unadapted influenza strains and upon infection exhibit fever, lethargy, and

Conclusions

The cotton rat is a small animal model that was originally selected for respiratory viral research not because of the availability of reagents and tools, but because of its ability to faithfully reproduce human infectious diseases and to accurately predict efficacy and safety of vaccines and therapeutics. S. hispidus model has undergone significant transformation in recent years with the development of species-specific reagents. From a model amenable only to basic virology, serology, and

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