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-β), IFN-γ, IL-1β, and tumor necrosis factor (TNF) gene expression in the lungs. Intranasal pretreatment with IFN-β or IFN-γ but not IL-1β or TNF also protected aged mice, consistent with the notion that poly(I·C) pretreatment functioned, at least in part, by inducing IFN-β and IFN-γ. 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.
Departments of Microbiology, University of Iowa, Iowa City, Iowa, USA. jincun-zhao@uiowa.edu
Jincun
J
Zhao
Christine
C
Wohlford-Lenane
Jingxian
J
Zhao
Erica
E
Fleming
Thomas E
TE
Lane
Paul B
PB
McCray
Stanley
S
Perlman
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000281:Administration, Intranasal; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D009980:Influenza A virus / Q000472:pathogenicity; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008168:Lung / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D009976:Orthomyxoviridae Infections / Q000401:mortality / Q000517:prevention & control*; D011070:Poly I-C / Q000008:administration & dosage*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000472:pathogenicity; D045169:Severe Acute Respiratory Syndrome / Q000401:mortality / Q000517:prevention & control*; D016019:Survival Analysis; D019562:Viral Load
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D016207:Cytokines; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D011070:Poly I-C