| 1. |
- Axberg Pålsson, Sandra, et al.
(author)
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Single-Stranded Oligonucleotide-Mediated Inhibition of Respiratory Syncytial Virus Infection
- 2020
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In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 11
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Journal article (peer-reviewed)abstract
- Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in young children. Currently, there is no RSV vaccine or universally accessible antiviral treatment available. Addressing the urgent need for new antiviral agents, we have investigated the capacity of a non-coding single-stranded oligonucleotide (ssON) to inhibit RSV infection. By utilizing a GFP-expressing RSV, we demonstrate that the ssON significantly reduced the proportion of RSV infected A549 cells (lung epithelial cells). Furthermore, we show that ssON's antiviral activity was length dependent and that both RNA and DNA of this class of oligonucleotides have antiviral activity. We reveal that ssON inhibited RSV infection by competing with the virus for binding to the cellular receptor nucleolin in vitro. Additionally, using a recombinant RSV that expresses luciferase we show that ssON effectively blocked RSV infection in mice. Treatment with ssON in vivo resulted in the upregulation of RSV-induced interferon stimulated genes (ISGs) such as Stat1, Stat2, Cxcl10, and Ccl2. This study highlights the possibility of using oligonucleotides as therapeutic agents against RSV infection. We demonstrate that the mechanism of action of ssON is the inhibition of viral entry in vitro, likely through the binding of the receptor, nucleolin and that ssON treatment against RSV infection in vivo additionally results in the upregulation of ISGs.
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| 2. |
- Bergenstråhle, Joseph, et al.
(author)
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Spatial transcriptomic profiling of RespiratorySyncytial Virus (RSV) infection
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Other publication (other academic/artistic)abstract
- Despite the fact that the human Respiratory Syncytial Virus (RSV) was first discoveredback in 1956, it remains one of the leading causes of morbidity and mortality inyoung children. Transcriptome-wide spatially resolved transcriptomics is a technologyunder rapid development that introduces a new modality for exploratory examinationof cellular behavior. With this modality, we examine how RSV infection changes thelocal cellular environment in the lung by infecting mice with RSV and comparing itto control samples four days after infection. We find viral presence in all compartmentsof the tissue, well-defined induced tertiary lymphoid tissue within some of thesamples, compartmentalized infiltration of innate immune cells, as well as functionalenrichment of airway epithelial repair pathways.
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| 3. |
- Groß, Rüdiger, et al.
(author)
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Macromolecular Viral Entry Inhibitors as Broad-Spectrum First-Line Antivirals with Activity against SARS-CoV-2
- 2022
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In: Advanced Science. - : Wiley. - 2198-3844. ; 9:20
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Journal article (peer-reviewed)abstract
- Inhibitors of viral cell entry based on poly(styrene sulfonate) and its core–shell nanoformulations based on gold nanoparticles are investigated against a panel of viruses, including clinical isolates of SARS-CoV-2. Macromolecular inhibitors are shown to exhibit the highly sought-after broad-spectrum antiviral activity, which covers most analyzed enveloped viruses and all of the variants of concern for SARS-CoV-2 tested. The inhibitory activity is quantified in vitro in appropriate cell culture models and for respiratory viral pathogens (respiratory syncytial virus and SARS-CoV-2) in mice. Results of this study comprise a significant step along the translational path of macromolecular inhibitors of virus cell entry, specifically against enveloped respiratory viruses.
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| 4. |
- Whitehead, Jack D., et al.
(author)
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Structure of the N-RNA/P interface indicates mode of L/P recruitment to the nucleocapsid of human metapneumovirus
- 2023
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Journal article (peer-reviewed)abstract
- Human metapneumovirus (HMPV) is a major cause of respiratory illness in young children. The HMPV polymerase (L) binds an obligate cofactor, the phosphoprotein (P). During replication and transcription, the L/P complex traverses the viral RNA genome, which is encapsidated within nucleoproteins (N). An essential interaction between N and a C-terminal region of P tethers the L/P polymerase to the template. This N-P interaction is also involved in the formation of cytoplasmic viral factories in infected cells, called inclusion bodies. To define how the polymerase component P recognizes N-encapsidated RNA (N-RNA) we employed cryogenic electron microscopy (cryo-EM) and molecular dynamics simulations, coupled to activity assays and imaging of inclusion bodies in cells. We report a 2.9 Å resolution structure of a triple-complex between multimeric N, bound to both RNA and the C-terminal region of P. Furthermore, we also present cryo-EM structures of assembled N in different oligomeric states, highlighting the plasticity of N. Combined with our functional assays, these structural data delineate in molecular detail how P attaches to N-RNA whilst retaining substantial conformational dynamics. Moreover, the N-RNA-P triple complex structure provides a molecular blueprint for the design of therapeutics to potentially disrupt the attachment of L/P to its template.
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