Pneumonitis and Multi-Organ System Disease in Common Marmosets (Callithrix jacchus) Infected with the Severe Acute Respiratory Syndrome-Associated Coronavirus

Abstract

Severe acute respiratory syndrome (SARS) is a significant emerging infectious disease. Humans infected with the etiological agent, SARS-associated coronavirus (SARS-CoV), primarily present with pneumonitis but may also develop hepatic, gastrointestinal, and renal pathology. We inoculated common marmosets (Callithrix jacchus) with the objective of developing a small nonhuman primate model of SARS. Two groups of C. jacchus were inoculated intratracheally with cell culture supernatant containing SARS-CoV. In a time course pathogenesis study, animals were evaluated at 2, 4, and 7 days after infection for morphological changes and evidence of viral replication. All animals developed a multifocal mononuclear cell interstitial pneumonitis, accompanied by multinucleated syncytial cells, edema, and bronchiolitis in most animals. Viral antigen localized primarily to infected alveolar macrophages and type-1 pneumocytes by immunohistochemistry. Viral RNA was detected in all animals from pulmonary tissue extracts obtained at necropsy. Viral RNA was also detected in tracheobronchial lymph node and myocardium, together with inflammatory changes, in some animals. Hepatic inflammation was observed in most animals, predominantly as a multifocal lymphocytic hepatitis accompanied by necrosis of individual hepatocytes. These findings identify the common marmoset as a promising nonhuman primate to study SARS-CoV pathogenesis.

The Immunobiology of SARS

“…Moreover, the disease in NHP models appears self-limiting and different from the human disease (148). The common marmoset model seems promising and should be evaluated further (149).…”

Pathology of Experimental SARS Coronavirus Infection in Cats and Ferrets

“…Before infection, they were examined clinically and determined to be healthy by a registered veterinarian and were placed in negative-pressurized glove boxes. Four cats and 4 ferrets were inoculated intratracheally in 1-5 seconds under ketamine anesthesia with 10 6 TCID 50 of SARS-CoV. The animals were checked daily for clinical signs.…”

“…20 The distribution of ACE2 in human tissues corresponds largely to the cell types in which SARS-CoV replication has been observed: in addition to type II pneumocytes and bronchial epithelial cells, ACE2 expression has been observed in type I pneumocytes and endothelial cells as well as smooth muscle cells of blood vessels, but not alveolar macrophages. 15,37 Since the appearance of SARS, several animal models have been developed for SARS-CoV infection in humans: SARS-CoV infection in macaques, 6 marmosets, 10 mice, 8,31 golden Syrian hamsters, 32 rats, 24 cats, and ferrets. 22 Subbarao and Roberts 35 reviewed the advantages and disadvantages of the above animal models.…”

An immunosuppressed Syrian golden hamster model for SARS-CoV infection

“…Animal models described to date include several inbred mouse strains, hamsters, civet cats, ferrets, cats, or nonhuman primates (Fouchier et al, 2003; Glass et al, 2004; Greenough et al, 2005; Hogan et al, 2004; Lawler et al, 2006; Martina et al, 2003; McAuliffe et al, 2004; Qin et al, 2005; Roberts et al, 2005a; 2005b; 2007; Rowe et al, 2004a; Subbarao et al, 2004; ter Meulen et al, 2004; Wu et al, 2005). The timecourse of virus replication in these small animal models is significantly more rapid than that observed in human infections (Roberts et al, 2008) and no model fully reproduces the clinical illness or the pathology observed in humans.…”