While it is hypothesized that Sever Acute Respiratory Syndrome (SARS) in humans is caused by a disproportional immune response illustrated by inappropriate induction of inflammatory cytokines, the exact nature of the host response to SARS coronavirus (CoV) infection causing severe pathology that includes diffuse alveolar damage (DAD) and acute respiratory distress syndrome (ARDS) has not been fully revealed. In order to further understand early events after SARS-CoV infection contributing to SARS mediated pathology, we studied SARS pathogenesis in different animal models. A range of techniques to establish parameters such as viral loads, virus tropism and the severity of pathology were employed to analyze SARS-CoV infection in macaques, mice and ferrets. Additionally, functional genomics was used to explore the host response at gene expression level in these animal models. Combining these observations allowed us to further elucidate the pathogenesis of SARS. In this thesis we show that, although SARS-CoV replicates efficiently to high titers in the lungs of macaques, ferrets and mice, characteristics of the host response to SARS-CoV infection are different in each animal model. The differential activation of host responses in these different animal models resulted in multiple SARS phenotypes, dependent on host factors such as age, species and strain differences. In macaques and mice strong host responses are driven by uninfected cells, while in ferrets SARS-CoV infected cells may dominate the observed pathogenesis. The fact that SARS-CoV leads to a range of host dependent phenotypes has implications for development of SARS treatments and the use of SARS animal models.

SARS, coronavirus, genomics, host response, pathogenesis
A.D.M.E. Osterhaus (Albert)
Erasmus MC: University Medical Center Rotterdam
EU, Greiner Bio-one, National Instititute of Health, ViroClinics Biosciences B.V.
Erasmus MC: University Medical Center Rotterdam

de Lang, A. (2012, January 5). SARS Pathogenesis: Host Factors. Erasmus MC: University Medical Center Rotterdam. Retrieved from http://hdl.handle.net/1765/30799