Poster Presentation 9th Australasian Vaccines & Immunotherapeutics Development Meeting 2022

Modulation of the renin-angiotensin system to reduce immunopathology in SARS-CoV-2 and influenza A infection (#105)

Melanie Wu 1 , Keng Yih Chew 1 , Larisa Labzin 2 , Georgina McCallum 1 , Lauren Steele 1 , Jane Sinclair 1 , Haru Nomura 3 , Sanjaya Kuruppu 4 , Ian Smith 4 , Niwanthi Rajapakse 3 , Kirsty R Short 1
  1. School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD, Australia
  2. Institute for Molecular Biosciences, University of Queensland, Brisbane, QLD, Australia
  3. School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia
  4. Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia

SARS-CoV-2 and influenza virus infections are associated with pronounced pro-inflammatory responses and immunopathology.  Angiotensin-converting enzyme 2 (ACE2) and the Mas receptor (MasR) are key components of the renin-angiotensin system (RAS) and play a significant role in the protective ACE2/Ang(1-7)/MasR axis. Activation of ACE2 and/or MasR induces anti-inflammatory and anti-fibrotic responses including vasodilation, vasoprotection, and hypotension. However, no studies to date have investigated the therapeutic potential of modulating RAS to reduce the immunopathology associated with respiratory virus infection. Here, we studied how activation of ACE2 and/or MasR affects SARS-CoV-2 and influenza virus replication and virus-induced inflammatory pathways.

In infection, SARS-CoV-2 binds to and internalizes ACE2, resulting in an upregulation of pro-inflammatory pathways. Here, we show that pre-treatment with a novel ACE2 activator (peptide 2A; derived from snake venom) prevents SARS-CoV-2 infection and the associated inflammatory response in vitro. Peptide 2A treatment also reduced the pro-inflammatory response to influenza virus infection in vitro (as determined by IL-6 expression). We further demonstrate the anti-inflammatory effects of MasR agonists, Ang(1-7) and AVE0991, and MasR antagonist A779 in viral induced inflammation in vitro.

Together, these data provide the first evidence that modulating of RAS may represent a novel approach to prevent the immunopathology associated with SARS-CoV-2 and influenza virus infection.