The cotton rat provides a useful small-animal model for the study of influenza virus pathogenesis

Abstract

Influenza A virus continues to cause annual epidemics. The emergence of avian viruses in the human population poses a pandemic threat, and has highlighted the need for more effective influenza vaccines and antivirals. Development of such therapeutics would be enhanced by the use of a small-animal model that is permissive for replication of human influenza virus, and for which reagents are available to dissect the host response. A model is presented of nasal and pulmonary infection in adult inbred cotton rats (Sigmodon hispidus) that does not require viral 'adaptation'. It was previously demonstrated that animals infected intranasally with 10 7 TCID 50 of a recent H3N2 influenza, A/Wuhan/359/95, have increased breathing rates. In this report it is shown that this is accompanied by weight loss and decreased temperature. Virus replication peaked within 24 h in the lung, with peak titres proportional to the infecting dose, clearing by day 3. Replication was more permissive in nasal tissues, and persisted for 6 days. Pulmonary pathology included early bronchiolar epithelial cell damage, followed by extensive alveolar and interstitial pneumonia, which persisted for nearly 3 weeks. Interleukin 1 alpha (IL1a), alpha interferon (IFN-a), IL6, tumour necrosis factor alpha (TNF-a), GROa and MIP-1b mRNA were elevated soon after infection, and expression coincided with virus replication. A biphasic response was observed for RANTES, IFN-c, IL4, IL10 and IL12-p40, with increased mRNA levels early during virus replication followed by a later increase that coincided with pulmonary inflammation. These results indicate that cotton rats will be useful for further studies of influenza pathogenesis and immunity.

Receptor Characterization and Susceptibility of Cotton Rats to Avian and 2009 Pandemic Influenza Virus Strains

“…It has been shown that viral titers in nasal and lung tissues in cotton rats infected with human influenza viruses were proportional to the infectious dose, and this model replicated many respiratory features observed in humans (16). In addition, cotton rats have also been used in evaluation of cross-protective or heterosubtypic immunity (17,18), vaccines (19), and antiviral treatments against influenza (20).…”

“…The cotton rat (Sigmodon hispidus) has been established as a model for influenza research as it is highly permissive for human influenza A and B viruses without prior adaptation (15,16). It has been shown that viral titers in nasal and lung tissues in cotton rats infected with human influenza viruses were proportional to the infectious dose, and this model replicated many respiratory features observed in humans (16).…”

“…Since the cotton rat is susceptible to infection with strains of human influenza virus without prior adaptation (16), the receptor distribution in the upper and lower respiratory tracts was analyzed. By performing lectin-based staining, the trachea and minor airways of cotton rats showed strong reactivity with Maackia amurensis agglutinin (MAA), a lectin with specificity for ␣2,3-linked SA, and Sambucus nigra agglutinin (SNA), a lectin specific for ␣2,6-linked SA (Fig.…”

Impaired Immune Response to Vaccination against Infection with Human Respiratory Syncytial Virus at Advanced Age

“…Hispid cotton rats (Sigmodon hispidus) provide a highly representative model for human infections since they are susceptible to a variety of human pathogens that do not require adaptation to infect and replicate (10)(11)(12)(13)(14). HRSV is a good example, as infection, pathology, and protection induced by candidate HRSV vaccines in cotton rats have already been explored and reflect the human situation (11,12,(15)(16)(17).…”

Pediatric Infectious Diseases: 60 Years of Contributions by Military Pediatricians

“…Additionally, he worked closely with the RSV group and helped develop multiple small animal viral models utilizing the cotton rat, S hispidus. 28 …”