Intranasal Treatment with Poly(I.C) Protects Aged Mice from Lethal Respiratory Virus Infections

In the 2002-2003 severe acute respiratory syndrome coronavirus (SARS-CoV) epidemic, no patients under 24 years of age died, while mortality was greater than 50% in those over 65 years. Greater than 90% of all deaths from influenza A virus (IAV) occur in the elderly (>65 years of age). To address this age-related susceptibility to SARS-CoV and IAV, we infected C57BL/6 (B6) mice with mouse-adapted SARS-CoV (MA15) or IAV (PR8), both of which cause severe disease in aged mice. Intranasal pretreatment of aged mice with poly(I.C) (a TLR3 agonist) and, to a lesser extent, CpG, R848, or lipopolysaccharide (TLR9, TLR7/8, or TLR4 agonists), provided a high level of protection [90% to 100% survival rate after poly(I.C) treatment] against lethal MA15 or IAV challenge and reduced pathological changes and virus loads in the lungs at early times after infection. Poly(I.C) pretreatment upregulated beta interferon (IFN-beta), IFN-gamma, IL-1 beta, and tumor necrosis factor (TNF) gene expression in the lungs. Intranasal pretreatment with IFN-beta or IFN-gamma but not IL-1 beta or TNF also protected aged mice, consistent with the notion that poly(I.C) pretreatment functioned, at least in part, by inducing IFN-beta and IFN-gamma. We also identified a potential cellular target for poly(I.C) by showing that treatment inhibited virus replication in primary human airway epithelial cells. These results suggest that intranasal poly(I.C) should be evaluated as a prophylactic agent in aged individuals at high risk for contracting SARS-CoV or IAV infections.