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

Abstract

bAnimal influenza viruses (AIVs) are a major threat to human health and the source of pandemic influenza. A reliable smallmammal model to study the pathogenesis of infection and for testing vaccines and therapeutics against multiple strains of influenza virus is highly desirable. We show that cotton rats (Sigmodon hispidus) are susceptible to avian and swine influenza viruses. Cotton rats express ␣2,3-linked sialic acid (SA) and ␣2,6-linked SA residues in the trachea and ␣2,6-linked SA residues in the lung parenchyma. Prototypic avian influenza viruses (H3N2, H9N2, and H5N1) and swine-origin 2009 pandemic H1N1 viruses replicated in the nose and in the respiratory tract of cotton rats without prior adaptation and produced strong lung pathology that was characterized by early lung neutrophilia, followed by subsequent pneumonia. Consistent with other natural and animal models of influenza, only the H5N1 virus was lethal for cotton rats. More importantly, we show that the different avian and pandemic H1N1 strains tested are strong activators of the type I interferon (IFN)-inducible MX-1 gene both locally and systemically. Our data indicate that the cotton rat is a suitable small-mammal model to study the infection of animal influenza viruses and for validation of vaccines and therapeutics against these viruses.

Efficacy of the Herpes Simplex Virus 2 (HSV-2) Glycoprotein D/AS04 Vaccine against Genital HSV-2 and HSV-1 Infection and Disease in the Cotton Rat Sigmodon hispidus Model

“…To address this limitation, we evaluated the gD/AS04 vaccine in a cotton rat Sigmodon hispidus model of HSV-1 and HSV-2 genital tract disease. We selected this model because studies with other pathogens, including poliovirus, adenovirus, respiratory syncytial virus, influenza virus, measles virus, and rhinovirus indicate that the cotton rat may closely recapitulate human disease (17)(18)(19)(20). Although the vaccine induced gD-2-specific and HSV-2 neutralizing antibodies in the serum of cotton rats, it provided only partial protection against HSV-2 disease and better protected animals against HSV-1-induced genital herpes with respect to both viral replication and disease.…”

Modeling Human Respiratory Viral Infections in the Cotton Rat (Sigmodon hispidus)

“…Lectin-based staining of the trachea and minor airways of cotton rats shows strong reactivity of α 2-3-linked SA and α 2-6 linked SA. It was established that, in the trachea of cotton rats, α 2-6-linked SA receptors co-localize with ciliated cells, whereas α 2-3-linked SA receptors are more associated with mucin-producing cells [12]. In addition, the lung parenchyma of cotton rats shows a consistent staining of type I and type II pneumocytes with α 2-6-linked SA receptors, whereas α 2-3-linked SA receptors are rarely expressed [12].…”

“…It was established that, in the trachea of cotton rats, α 2-6-linked SA receptors co-localize with ciliated cells, whereas α 2-3-linked SA receptors are more associated with mucin-producing cells [12]. In addition, the lung parenchyma of cotton rats shows a consistent staining of type I and type II pneumocytes with α 2-6-linked SA receptors, whereas α 2-3-linked SA receptors are rarely expressed [12]. Thus, the presence of both α 2-3-linked and α 2-6-linked SA receptors in the airways of cotton rats most likely explains the susceptibility of these animals to infection by a wide variety of human and avian strains of influenza viruses as described below.…”

“…Recently, additional influenza strains of human and avian origin were tested [12]. Cotton rats were susceptible to infection with two different low pathogenicity strains, A/duck/Hong Kong/375/1975 (H3N2) and A/guinea fowl/Hong Kong/WF10/1999 virus (H9N2).…”

“…Mortality was a unique characteristic only evidenced during infection of cotton rats with the highly pathogenic virus isolate from a lethal human case A/Vietnam/1203/2004 (H5N1)[12]. In fact, mortality in H5N1-infected animals was seen only at high viral inoculum and correlated with the lethal outcome of this virus in humans that has been proposed to be the result of infection with a high viral dose [16].…”