A Mouse-Adapted SARS-Coronavirus Causes Disease and Mortality in BALB/c Mice

Abstract

No single animal model for severe acute respiratory syndrome (SARS) reproduces all aspects of the human disease. Young inbred mice support SARS-coronavirus (SARS-CoV) replication in the respiratory tract and are available in sufficient numbers for statistical evaluation. They are relatively inexpensive and easily accessible, but their use in SARS research is limited because they do not develop illness following infection. Older (12- to 14-mo-old) BALB/c mice develop clinical illness and pneumonitis, but they can be hard to procure, and immune senescence complicates pathogenesis studies. We adapted the SARS-CoV (Urbani strain) by serial passage in the respiratory tract of young BALB/c mice. Fifteen passages resulted in a virus (MA15) that is lethal for mice following intranasal inoculation. Lethality is preceded by rapid and high titer viral replication in lungs, viremia, and dissemination of virus to extrapulmonary sites accompanied by lymphopenia, neutrophilia, and pathological changes in the lungs. Abundant viral antigen is extensively distributed in bronchial epithelial cells and alveolar pneumocytes, and necrotic cellular debris is present in airways and alveoli, with only mild and focal pneumonitis. These observations suggest that mice infected with MA15 die from an overwhelming viral infection with extensive, virally mediated destruction of pneumocytes and ciliated epithelial cells. The MA15 virus has six coding mutations associated with adaptation and increased virulence; when introduced into a recombinant SARS-CoV, these mutations result in a highly virulent and lethal virus (rMA15), duplicating the phenotype of the biologically derived MA15 virus. Intranasal inoculation with MA15 reproduces many aspects of disease seen in severe human cases of SARS. The availability of the MA15 virus will enhance the use of the mouse model for SARS because infection with MA15 causes morbidity, mortality, and pulmonary pathology. This virus will be of value as a stringent challenge in evaluation of the efficacy of vaccines and antivirals.

Studies of Severe Acute Respiratory Syndrome Coronavirus Pathology in Human Cases and Animal Models

“…Several groups have recently developed rodent-adapted strains of SARS-CoV that cause mild to fatal acute respiratory disease. 43,53 These inexpensive and relatively reproducible animal models have potential for their use in testing vaccines and antiviral agents for the treatment of SARS.…”

Synthetic Reconstruction of Zoonotic and Early Human Severe Acute Respiratory Syndrome Coronavirus Isolates That Produce Fatal Disease in Aged Mice

“…As none of these models recapitulate the complex pathogenic phenotype noted during the SARS-CoV epidemic in humans, animal models that are more robust are needed to evaluate the efficacy of SARS-CoV vaccines and therapeutics, especially in the more vulnerable elderly populations. The recent adaptation of the Urbani isolate to mice by serial passage of the virus in the respiratory tract of young BALB/c mice resulted in a virus that is lethal in young BALB/c mice after intranasal inoculation and that showed extensive pathological changes (44). Histopathologic changes after inoculation with this mouse-adapted virus included damage to bronchiolar and alveolar epithelial cells but not the alveolar edema and damage to hyaline membranes that were reported for many SARSCoV-infected patients (12,18,44).…”

“…The recent adaptation of the Urbani isolate to mice by serial passage of the virus in the respiratory tract of young BALB/c mice resulted in a virus that is lethal in young BALB/c mice after intranasal inoculation and that showed extensive pathological changes (44). Histopathologic changes after inoculation with this mouse-adapted virus included damage to bronchiolar and alveolar epithelial cells but not the alveolar edema and damage to hyaline membranes that were reported for many SARSCoV-infected patients (12,18,44). During passage the virus did, however, acquire six coding mutations, including one in the S glycoprotein, all of which were necessary for the lethal phenotype (44).…”

Rat respiratory coronavirus infection: replication in airway and alveolar epithelial cells and the innate immune response

“…A number of animal models exist for the investigation of SARS-CoV, including systems that use mice, guinea pigs, ferrets, cats and rats (Nagata et al, 2007;Roberts et al, 2007;Subbarao & Roberts, 2006; van den Brand et al, 2008). However, no animal models are available for the other, less pathogenic human CoVs 229E, OC43, NL63 and HKU1.…”

“…After the discovery of SARS-CoV, two additional human CoVs were identified, NL63 and HKU1 (van der Hoek et al, 2004;Woo et al, 2005). On a global basis, the human CoVs 229E, OC43, HKU1 and NL63 are estimated to cause approximately 10 % of all hospitalizations of children for respiratory tract infections (Gerna et al, 2007;Vabret et al, 2008).A number of animal models exist for the investigation of SARS-CoV, including systems that use mice, guinea pigs, ferrets, cats and rats (Nagata et al, 2007;Roberts et al, 2007;Subbarao & Roberts, 2006; van den Brand et al, 2008). However, no animal models are available for the other, less pathogenic human CoVs 229E, OC43, NL63 and HKU1.…”