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Inhibition of respiratory syncytial virus infection with intranasal siRNA nanoparticles targeting the viral NS1 gene

Nature Medicine volume 11, pages 56–62 (2005)Cite this article

An Erratum to this article was published on 01 February 2005

Abstract

Respiratory syncytial virus (RSV) infection is one of the major causes of respiratory tract infection for which no vaccine or antiviral treatment is available. The RSV NS1 protein seems to antagonize the host interferon (IFN) response; however, its mechanism is unknown. Here, we used a plasmid-borne small interfering RNA targeting the NS1 gene (siNS1) to examine the role of NS1 in modulating RSV infection. RSV replication was reduced in A549 cells, but not IFN–deficient Vero cells, transfected with siNS1. siNS1 induced upregulated expression of IFN-β and IFN-inducible genes in A549 cells. siNS1-transfected human dendritic cells, upon RSV infection, produced elevated type-1 IFN and induced differentiation of naive CD4+ T cells to T helper type 1 (TH1) cells. Mice treated intranasally with siNS1 nanoparticles before or after infection with RSV showed substantially decreased virus titers in the lung and decreased inflammation and airway reactivity compared to controls. Thus, siNS1 nanoparticles may provide an effective inhibition of RSV infection in humans.

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Figure 1: siNS1 inhibits rgRSV infection.
Figure 2: siNS1-mediated attenuation of RSV infection involves upregulated expression of IFN-β and IFN-inducible genes in infected A549 cells.
Figure 3: Effect of siNS1 on human DCs and naive CD4+ T cells.
Figure 4: siNS1 exhibits antiviral activity in vivo.
Figure 5: Prophylactic and therapeutic potential of NG042-siNS1.

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Acknowledgements

We thank M.E. Peeples (Columbus Children's Research Institute, Ohio) for his rgRSV stock, O. Haller (Freiburg University, Germany) for his gift of MxA antibody, Saneron-Cell Therapeutics (Tampa, Florida) for the cord blood cells and Moffitt Flow Cytometry and Microarray Core for their assistance. SSM is supported by the grants from the Veterans' Affairs Merit Review Award and US National Institutes of Health #5RO1HL71101-01A2. The support from the Joy McCann Culverhouse Endowment to the Division of Allergy and Immunology, Department of Internal Medicine, College of Medicine, and the Veterans' Affairs Hospital is also gratefully acknowledged.

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Authors and Affiliations

  1. Division of Allergy and Immunology–Joy McCann Culverhouse Airway Disease Research Center, Department of Internal Medicine, University of South Florida, MDC-19-Rm 2536, 12901 Bruce B. Downs Boulevard, Tampa, 33612, Florida, USA

    Weidong Zhang, Xiaoyuan Kong, Gary Hellermann, Richard F Lockey & Shyam S Mohapatra

  2. James A. Haley Veterans Hospital, 13000 Bruce B. Downs Boulevard, Tampa, 33612, Florida, USA

    Weidong Zhang, Hong Yang, Xiaoyuan Kong, Homero San Juan-Vergara, Gary Hellermann, Richard F Lockey & Shyam S Mohapatra

  3. Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, 33612, Florida, USA

    Subhra Mohapatra

  4. TransGenex Nanobiotech Inc., UTC-II, 3650 Spectrum Boulevard, Suite 170, Tampa, 33612, Florida, USA

    Sumita Behera & Rajeswari Singam

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Correspondence to Shyam S Mohapatra.

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Weidong Zhang and Shyam S. Mohapatra have filed a patent application relating to siNS1. Shyam S. Mohapatra is a scientific founder and advisor to Transgenex Nanobiotech Inc.

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Zhang, W., Yang, H., Kong, X. et al. Inhibition of respiratory syncytial virus infection with intranasal siRNA nanoparticles targeting the viral NS1 gene. Nat Med 11, 56–62 (2005). https://doi.org/10.1038/nm1174

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