Inhibition of severe acute respiratory syndrome coronavirus replication in a lethal SARS-CoV BALB/c mouse model by stinging nettle lectin, Urtica dioica agglutinin.

Abstract

Urtica dioica agglutinin (UDA) is a small plant monomeric lectin, 8.7 kDa in size, with an N-acetylglucosamine specificity that inhibits viruses from Nidovirales in vitro. In the current study, we first examined the efficacy of UDA on the replication of different SARS-CoV strains in Vero 76 cells. UDA inhibited virus replication in a dose-dependent manner and reduced virus yields of the Urbani strain by 90% at 1.1 ± 0.4 μg/ml in Vero 76 cells. Then, UDA was tested for efficacy in a lethal SARS-CoV-infected BALB/c mouse model. BALB/c mice were infected with two LD50 (575 PFU) of virus for 4 h before the mice were treated intraperitoneally with UDA at 20, 10, 5 or 0 mg/kg/day for 4 days. Treatment with UDA at 5 mg/kg significantly protected the mice against a lethal infection with mouse-adapted SARS-CoV (p < 0.001), but did not significantly reduce virus lung titers. All virus-infected mice receiving UDA treatments were also significantly protected against weight loss (p < 0.001). UDA also effectively reduced lung pathology scores. At day 6 after virus exposure, all groups of mice receiving UDA had much lower lung weights than did the placebo-treated mice. Thus, our data suggest that UDA treatment of SARS infection in mice leads to a substantial therapeutic effect that protects mice against death and weight loss. Furthermore, the mode of action of UDA in vitro was further investigated using live SARS-CoV Urbani strain virus and retroviral particles pseudotyped with SARS-CoV spike (S). UDA specifically inhibited the replication of live SARS-CoV or SARS-CoV pseudotyped virus when added just before, but not after, adsorption. These data suggested that UDA likely inhibits SARS-CoV infection by targeting early stages of the replication cycle, namely, adsorption or penetration. In addition, we demonstrated that UDA neutralizes the virus infectivity, presumably by binding to the SARS-CoV spike (S) glycoprotein. Finally, the target molecule for the inhibition of virus replication was partially characterized. When UDA was exposed to N-acetylglucosamine and then UDA was added to cells just prior to adsorption, UDA did not inhibit the virus infection. These data support the conclusion that UDA might bind to N-acetylglucosamine-like residues present on the glycosylated envelope glycoproteins, thereby preventing virus attachment to cells.

• Authors: Yohichi Kumaki, Miles K Wandersee, Aaron J Smith, Yanchen Zhou, Graham Simmons, Nathan M Nelson, Kevin W Bailey, Zachary G Vest, Joseph K-K Li, Paul Kay-Sheung Chan, Donald F Smee, Dale L Barnard
• Journal: Antiviral research (Antiviral Res) Vol. 90 Issue 1 Pg. 22-32 (Apr 2011) ISSN: 1872-9096 [Electronic] Netherlands
• PMID: 21338626 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• Antiviral Agents
• Plant Lectins
• stinging nettle lectin

Topics

• Animals
• Antiviral Agents (administration & dosage)
• Body Weight
• Chlorocebus aethiops
• Disease Models, Animal
• Female
• Injections, Intramuscular
• Mice
• Mice, Inbred BALB C
• Plant Lectins (administration & dosage)
• Rodent Diseases (drug therapy, mortality, pathology, virology)
• Severe acute respiratory syndrome-related coronavirus (drug effects)
• Severe Acute Respiratory Syndrome (drug therapy, mortality, pathology, virology)
• Survival Analysis
• Vero Cells
• Virus Replication (drug effects)