SARS Coronavirus Pathogenesis and Therapeutic Treatment Design

Sheahan, Timothy P.; Baric, Ralph S.

Emerging pathogens are either new or newly recognized or those that are increasing in incidence and spread. Since the identity of emerging pathogens from animal reservoirs is difficult to predict, the development for pathogen-specific therapeutics and vaccines is problematic. The highly pathogenic SARS coronavirus (SARS-CoV) emerged from zoonotic pools in 2002 to cause a global epidemic of severe acute respiratory syndrome (SARS). Many patients with SARS-CoV experienced an exacerbated form of disease called acute respiratory distress syndrome (ARDS) requiring mechanical ventilation and supplemental oxygen and half of these patients died. Similar to other viral pathogens like influenza and West Nile Virus, the severity of SARS-CoV disease increased with age. Unfortunately, successful vaccination in the most vulnerable populations is a difficult task because of immunological deficiencies associated with aging (immune senescence). Due to the rapidity of virus emergence, technologies like synthetic biology can be harnessed to facilitate rapid recombinant virus construction for studying the novel virus biology, pathogenesis and the evaluation of therapeutic interventions. Since predicting the antigenic identity of future emergence is difficult, candidate vaccines and therapeutics should have a maximal breadth of cross-protection, and panels of antigenically divergent synthetically reconstructed viruses can be used as tools for this evaluation. We discuss how synthetic reconstruction of many animal and human SARS-CoV has provided a model to study the molecular mechanisms governing emergence and pathogenesis of viral diseases. In addition, we review the evolution, epidemiology, and pathogenesis of epidemic and zoonotic SARS-CoV with focus on the development of broadly reactive therapeutics and vaccines that protect aged populations from the zoonotic pool.