A ratio of group mean organ weight to group mean body weight (mean organ wt/mean body wt) was calculated for all those groups
A ratio of group mean organ weight to group mean body weight (mean organ wt/mean body wt) was calculated for all those groups. particularly mice (Hogan et al., 2004, Roberts et al., 2005a, Wentworth et al., 2004, Yang et al., 2004) and hamsters (Roberts et al., 2006, Roberts et al., 2005b), can provide experimental systems for the study of infectivity, immunity and pathogenesis, while serving as a very useful tools for screening of vaccines and antiviral drugs. However, their power in the study of the clinical progression of disease is limited by the inherent differences between small mammals and humans in anatomical structure, respiratory physiology and manifestation of clinical HGFR disease. Furthermore, FDA approval of vaccines and therapeutics for the treatment of emerging diseases such as SARS requires demonstration of efficacy in at least two animal modelsa rodent and a nonrodent. The nonhuman primate has been used as a model for studies of clinical progression and evaluation of treatments for SARS-CoV contamination and disease pathogenesis. However, there has been animal-to-animal variability in the level of viral replication in the lung tissues from SARS-CoV infected African green monkeys (McAuliffe et al., 2004), cynomolgus macaques (Haagmans and Osterhaus, 2006, Kuiken et al., 2003b, Lawler et al., 2006, Osterhaus et al., 2004) and rhesus macaques (Qin et al., 2005, Rowe et al., 2004, Tang et al., 2005, Zhou et al., 2005). Reported symptoms in SARS-CoV infected cynomolgus macaques (Haagmans and Osterhaus, 2006, Kuiken et al., 2003b, Lawler et al., 2006, Rowe et al., 2004) or rhesus macaque (Li c-FMS inhibitor et al., 2005, Qin et al., 2005) included lethargy, skin rash, respiratory distress, interstitial pneumonia, and diffuse alveoli damage. Although nonhuman primate models mimic contamination and disease symptoms seen in humans, they are very expensive and require special housing and husbandry practices not available in most BSL3 facilities. One alternative nonrodent model is the domestic ferret, Ferrets have not been commonly used as animal models; therefore, and the literature sources about them are limited. However, these animals have shown great promise in reproducing human correlates of disease for influenza. Preliminary studies showed that this domestic ferret presents disease symptoms and pathology comparable c-FMS inhibitor to that observed with SARS-CoV infected humans (Martina et al., 2003). When both cats and ferrets infected with SARS-CoV via the intratracheal route using high-virus titer (up to 106?TCID50 U/mL), the cats showed no clinical symptoms except shedding computer virus, whereas the ferrets showed classical symptoms of SARS, including death in some cases, in addition to shedding computer virus (Martina et al., 2003). These studies suggested that this ferret could be developed into a model for preclinical evaluation of efficacy for SARS-CoV therapeutics. The c-FMS inhibitor overall objective of our efforts was to develop and characterize the ferret model for permissive SARS-CoV contamination and disease following intensive optimization of the dosing and various endpoints. Herein, we report the validation of the model in an contamination and challenge over 58?days. The study validated standard health indicator endpoints that allow comparisons to clinical manifestation of SARS-CoV in human patients. These included: clinical findings, heat, mean body weight, hematology and clinical chemistry parameters, gross pathology and histopathology, and virological and immunological assessments. This model will c-FMS inhibitor provide insight into understanding many of the underlying features of SARS disease in humans and promote the evaluation of promising therapeutics and vaccines. Results Study design Ferrets were divided randomly c-FMS inhibitor into four groups, mock-infected, SARS-CoV infected, mock-challenged, and SARS-CoV challenged (Table 1 ). The dose of SARS-CoV chosen for these studies was based upon several smaller studies in ferrets with different challenge doses ranging from 103 to 107 TCID50/mL (Fig. 1 ). In general, the lower dose of computer virus produced more reproducible results. The lower dose of computer virus showed less variation in the level of viral contamination in the lung. Specifically, the higher dose, 107 TCID50/mL, showed minimal contamination of the ferret nasal turbinates (NT) and variability in the lung. The 103 TCID50/mL dose provided the highest contamination and reproducibility in NT and lung tissues (Fig. 1). Table 1.