27 Severe SARS coronavirus infection in aged macaques is associated with reduced expression of anti-inflammatory type-1 interferons

Advanced age is an independent correlate for adverse outcome of many viral infections, including severe acute respiratory syndrome virus (SARS-CoV) infection that causes respiratory disease in humans. To study the pathogenesis of SARS-CoV in relation to age, six aged (10–18 years old) and four young adult (3–5 years old) cynomolgus macaques were infected with SARS-CoV HKU39849. Aged macaques were more prone to develop severe SARS-CoV-associated clinical symptoms and gross pathology than young adult macaques. Histopathological analysis revealed diffuse alveolar damage in the lungs with pulmonary edema, desquamation of epithelial cells, hyaline membrane formation, and infiltration of inflammatory cells. Comprehensive genomic analysis of the host response indicates that aged macaques have a more zealous response to virus infection than young adult macaques, with a significant increase in the differential expression of genes associated with influx and activation of immune cells whereas the expression of type-1 interferons was reduced. Therapeutic administration of pegylated interferon alpha in aged macques on the other hand, inhibited gross pathology and expression of pathogenic pathways, including IL-8 levels. Because viral replication in the lungs was similar between the different groups, the intrinsic host response seems to regulate the severity of SARS-CoV induced acute lung injury. We conclude that anti-inflammatory actions of type-1 interferons may determine the outcome of virus induced acute lung injury.