Science Bite (3 minute oral presentation with PPT in live session and poster) - Students and ECRs only 14th Lorne Infection and Immunity 2024

Understanding the AhR and innate immunity axis in RNA virus infection (#35)

Xavier B Montin 1 2 , Timothy P Allen 2 , Emily N Kirby 1 2 , Murray Whitelaw 2 , Michael R Beard 1 2
  1. Research Centre for Infectious Diseases, University of Adelaide, Adelaide, SA, Australia
  2. School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia

Interferon (IFN) signalling is a crucial part of the host response to viral infection, comprising rapid, non-specific and potently antiviral responses via the expression of interferon stimulated genes (ISGs). The antiviral effects of these ISGs are robust enough that nearly all pathogenic viruses impede IFN responses in some manner. While many of the main signalling pathways mediating IFN have been described, there is little characterisation of interactions between IFN signalling and other cellular pathways which may impact innate immune responses. Recently implicated in IFN modulation is the Aryl Hydrocarbon Receptor (AhR), a ligand-activated transcription factor primarily involved in toxicological responses and neuronal development, which was shown to be spontaneously activated upon infection with Zika virus (ZIKV) (1) and some coronaviruses (2). We have demonstrated that AhR activation is triggered by a multitude of RNA virus infections in different cell types, including ZIKV, the Kunjin strain of West Nile Virus (WNVKUN), Dengue Virus (DENV) and human coronavirus 229E, and have shown via RNA sequencing and qPCR that IFN responses and the expression of a variety of antiviral ISGs are significantly enhanced in an AhR knockout context, as well as increases in the replication of RNA viruses ZIKV and WNV when functional AhR is not present. This demonstrates the potential for an AhR-IFN signalling axis that is exploited by RNA viruses to enhance their replication. Ongoing experiments aim to use CRISPR knockout and activation techniques to elucidate the mechanism behind virus-mediated AhR activation, with preliminary results indicating the involvement of cytosolic sensors such as RIG-I. In addition, we aim to investigate the mechanism of the inhibitory effect AhR itself exerts on innate immune responses. Our study demonstrates that AhR is a novel proviral host factor for a variety of RNA viruses, and this work may thus represent potential therapeutic angles for a multitude of RNA virus infections of which there is a scarcity of available treatment, such as ZIKV, via targeting the AhR.

  1. 1. Giovannoni et al., “AHR Is a Zika Virus Host Factor and a Candidate Target for Antiviral Therapy.” 2020, Nature Neuroscience
  2. 2. Giovannoni et al., “AHR Signaling Is Induced by Infection with Coronaviruses.” 2021, Nature Communications