Severe acute respiratory syndrome (SARS) is a highly contagious respiratory disease caused by a novelhuman coronavirus (CoV), designated SARS-CoV. Although there have been no new reported field casessince 2003, this virus continues to exist in the nature, posing a threat for its return. To date, effectivetherapeutic measures against SARS are not available, thus making the development of effective antiviraltherapy and vaccines imperative. The main objective of this application is to establish effective antiviraltherapy against future SARS outbreaks. Animal models are critical for preclinical evaluation of the safety,immunogenicity, and efficacy of candidate antiviral drugs and vaccines. To establish an economical animalmodel for SARS-CoV infection, we generated transgenic mouse lineages expressing human angiotensinconverting enzyme 2 (hACE2), a functional receptor of SARS-CoV. Importantly, these hACE2 transgeniclineages were highly susceptible to SARS-CoV infection, showing consistent clinical manifestations anddeath, making them superior to existing models described for SARS (i.e., nonhuman primates, ferrets,hamsters, and mice). Among several transgenic lineages, the AC70 lineage is the best characterized withregard to the infectivity and tissue of SARS-CoV, clinical manifestations, histopathology, inflammatoryresponses, and mortality, in response to infection. To accomplish this objective, I propose in this applicationto evaluate the therapeutic efficacy of some antiviral agents, including interferons (i.e., IFN-a and IFN-y),ribavirin, and immune plasma, in this innovative and highly sensitive transgenic mouse model. Theseantiviral agents are selected, because they were used empirically in treating SARS patients, resulting inanecdotal benefits during the explosive outbreak in 2002-2003. Their anti-SARS efficacy alone or incombination will be carefully assessed in a highly randomized and controlled fashion in these transgenicmice, using clinical, virological, pathological, and inflammatory changes, along with the mortality as criteria. Ifapplicable, I will extend this project to include new lead compounds, such as protease inhibitors, compoundsthat prevent viral entry, siRNA for SARS-CoV replication, and vaccines that warrant inclusion in this study.
Four specific aims are proposed: 1) Determine the nontoxic dosages of selected antiviral agents withtherapeutic efficacy against SARS-CoV infection. 2) Determine the most optimal therapeutic treatmentregimen of individual antiviral agents. 3) Evaluate the therapeutic efficacy of immune plasma/serum againstSARS-CoV infection and 4) Investigate the therapeutic potentials of combination treatments of selectedantiviral agents. Upon completion of proposed studies, with close and productive mentor-trainee interactions,anticipate not only gaining extensive scientific knowledge and hands-on experience in antiviral testing, butalso research results identifying effective anti-SARS therapies.
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