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. 2005 Aug;167(2):455-63.
doi: 10.1016/S0002-9440(10)62989-6.

Pneumonitis and multi-organ system disease in common marmosets (Callithrix jacchus) infected with the severe acute respiratory syndrome-associated coronavirus

Thomas C Greenough  1 , Angela Carville, James Coderre, Mohan Somasundaran, John L Sullivan, Katherine Luzuriaga, Keith Mansfield
Affiliations

Pneumonitis and multi-organ system disease in common marmosets (Callithrix jacchus) infected with the severe acute respiratory syndrome-associated coronavirus

Thomas C Greenough et al. Am J Pathol. 2005 Aug.

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.

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Figures

Figure 1
Figure 1
Pulmonary pathology in common marmosets inoculated with SARS-CoV. A: Multifocal interstitial pneumonitis 4 days after inoculation [inset: multinucleated syncytial cell (lung, H&E-stained section)]. B: Multifocal interstitial pneumonitis with type 2 pneumocyte hyperplasia 7 days after inoculation (inset: type 2 pneumocyte hyperplasia). C: Moderate lymphocytic bronchiolitis accompanied by loss of respiratory epithelium integrity. D: Pulmonary perivasculitis 7 days after inoculation.
Figure 2
Figure 2
Localization of SARS-CoV viral antigen by immunohistochemistry. A–C: Viral antigen within cells morphologically compatible with type 1 pneumocytes (A); mononuclear alveolar exudates (B); and multinucleated syncytial cells (C). D: Mock-infected control lung (rabbit anti-S-glycoprotein, ABC immunostain technique, DAB chromogen).
Figure 3
Figure 3
Hepatic pathology in common marmosets inoculated with SARS-CoV. A: Small aggregates of mononuclear cells within hepatic sinusoids (arrows) and multifocally defined mild lymphocytic hepatitis (higher power inset) 2 days after inoculation (H&E-stained section). B: More pronounced multifocal random lymphocytic hepatitis in four of five animals 4 days after inoculation. C: Hepatitis in five of five animals associated with death of individual hepatocytes (arrows) 7 days after inoculation. D: A second pattern superimposed on hepatic lesions in 4 of 11 animals characterized by inflammation centered on hepatic veins and accompanied by death of hepatocytes (inset, arrow). E: Increased expression of the MHC II antigen HLA-DR at sites of lymphocytic hepatitis and perivascular inflammation (inset) (HLA-DR, ABC immunostain technique, DAB chromogen). F: Foci of inflammation contained T-cell intracytoplasmic antigen (TIA-1)-positive cells compatible with cytotoxic T lymphocytes or NK cells (TIA-1, ABC immunostain technique, DAB chromogen).
Figure 4
Figure 4
Viral RNA concentrations in pulmonary tissue (animal experiment 2). Each symbol represents results from a separate lung specimen. Specimens with positive results are shown. Each animal had five separate lung specimens.
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