Poster Presentation 14th Lorne Infection and Immunity 2024

Defective interfering RNA induce innate immunity and broad pan-antiviral activity (#145)

David Harrich 1 2 , Min-Hsuan Lin 1 , Dongsheng Li 1 , Bing Tang 1 , Pramilla Maniam 1 , Li Li 3 , Felicity Y Han 3 , Andreas Suhrbier 1 2 , Yaman Tayyar 4 5 , Nigel McMillan 4
  1. QIMR Berghofer, Herston, QLD, Australia
  2. Global Virus Network (GVN) Center of Excellence, Australian Infectious Disease Research Centre, Brisbane, Queensland, Australia
  3. Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Saint Lucia, Queensland, Australia
  4. Menzies Health Institute Queensland and School of Pharmacy and Medical Science, Griffith University, Gold Coast, Queensland, Australia
  5. Protenata Biotech, Molendinar, Queensland, Australia

RNA viruses such as dengue (DENV), influenza A (IAV), respiratory syncytial virus (RSV), and SARS-CoV-2 (CoV-2) pose significant challenges to health systems worldwide. These viruses have phenotypic plasticity that allows them to evade humoral immunity and small molecule antivirals, which enables endemic viruses to replicate and reinfect populations. The rapid evolution of human viruses and the potential threat from unknown viruses reinforces the need for new broadly acting antiviral medicines.

The retinoic acid-inducible gene I (RIG-I) is an essential cytosolic pattern recognition receptor (PRR) that recognises viral RNA and activates the production of interferons (IFNs) and pro-inflammatory cytokines in response to viral infections. RIG-I agonists have great potential as antivirals for treating viral pandemics.

Our project focuses on designing and applying an efficient delivery system for the novel RIG-I agonist, DI290 RNA and more recently two small RNA derived from SARS-CoV-2 infected cell culture. DI290 RNA is 290 nucleotides long and was identified through in vivo and in vitro screenings of defective interfering (DI) RNAs made by DENV. DI290 RNA is a folded double-stranded RNA that mimics infectious viral RNA genome. Our results demonstrate the efficacy of DI290 RNA in activating RIG-I-mediated type I IFN response and suggest that DI290 RNA can be used as a novel, effective RIG-I agonist that inhibits viral infections. We also studied the ability of DI290 RNA to provide pan-antiviral protection and defence against different viral infections. To achieve this, we utilised robust tissue culture and synthetic systems to produce different types of nanoparticles containing DI290 RNA and SARS-CoV2-derived RNAs. Our recent experiments show that DI290 has broad-spectrum activity, capable of inhibiting the replication of DENV, RSV, Yellow Fever virus, Zika virus and CoV2.  In vitro and in vivo studies will be presented.

Li D et al. Dengue virus-free defective interfering particles have potent and broad anti-dengue virus activity. Commun Biol. 2021;4(1):557.

Lin MH, Li D, Tang B, Li L, Suhrbier A, Harrich D. Defective Interfering Particles with Broad-Acting Antiviral Activity for Dengue, Zika, Yellow Fever, Respiratory Syncytial and SARS-CoV-2 Virus Infection. Microbiol Spectr. 2022;10(6):e0394922.