Positive Selection of a Serine Residue in Bat IRF3 Confers Enhanced Antiviral Protection.

Katharina S. Schulz,Karen Mossman,Xi Zhang,Alyssa Yip,Brian Golding,Arinjay Banerjee,Lin-Fa Wang,Aaron T. Irving,Dawn Bowdish

doi:10.1016/j.isci.2020.100958

Katharina S. Schulz, Karen Mossman + Show 7 more

Open Access

https://doi.org/10.1016/j.isci.2020.100958

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Abstract

SummaryCompared with other mammals, bats harbor more zoonotic viruses per species and do not demonstrate signs of disease on infection with these viruses. To counteract infections with viruses, bats have evolved enhanced mechanisms to limit virus replication and immunopathology. However, molecular and cellular drivers of antiviral responses in bats largely remain an enigma. In this study, we demonstrate that a serine residue in IRF3 is positively selected for in multiple bat species. IRF3 is a central regulator of innate antiviral responses in mammals. Replacing the serine residue in bat IRF3 with the human leucine residue decreased antiviral protection in bat cells, whereas the addition of this serine residue in human IRF3 significantly enhanced antiviral protection in human cells. Our study provides genetic and functional evidence for enhanced IRF3-mediated antiviral responses in bats and adds support to speculations that bats have positively selected for multiple adaptations in their antiviral immune responses.

Highlights

IntroductionBats are reservoirs of several emerging RNA viruses, such as filoviruses (ebolavirus and Marburg virus), paramyxoviruses (Nipah and Hendra viruses), and coronaviruses (severe acute respiratory syndrome [SARS] and Middle East respiratory syndrome [Middle-East respiratory syndrome (MERS)] coronaviruses [CoVs]) that cause serious and often fatal disease in humans and agricultural animals (Anthony et al, 2017; Forbes et al, 2019; Ge et al, 2013; Swanepoel et al, 2007; Yang et al, 2019)
Bats are reservoirs of several emerging RNA viruses, such as filoviruses, paramyxoviruses (Nipah and Hendra viruses), and coronaviruses that cause serious and often fatal disease in humans and agricultural animals (Anthony et al, 2017; Forbes et al, 2019; Ge et al, 2013; Swanepoel et al, 2007; Yang et al, 2019)
Our study provides genetic and functional evidence for enhanced IRF3-mediated antiviral responses in bats and adds support to speculations that bats have positively selected for multiple adaptations in their antiviral immune responses

Summary

Introduction

Bats are reservoirs of several emerging RNA viruses, such as filoviruses (ebolavirus and Marburg virus), paramyxoviruses (Nipah and Hendra viruses), and coronaviruses (severe acute respiratory syndrome [SARS] and Middle East respiratory syndrome [MERS] coronaviruses [CoVs]) that cause serious and often fatal disease in humans and agricultural animals (Anthony et al, 2017; Forbes et al, 2019; Ge et al, 2013; Swanepoel et al, 2007; Yang et al, 2019). Bats that are naturally or experimentally infected with these viruses do not demonstrate overt signs of disease (Munster et al, 2016; Hayman, 2016) These observations have led to studies that have explored innate and intrinsic antiviral immune responses in this intriguing mammalian order and the unique ability of bats to control virus infection-induced immunopathology (Pavlovich et al, 2018; Schountz et al, 2017). In addition to identifying conserved features of the mammalian innate immune system in bats, recent studies have discovered novel adaptations in bat antiviral responses (Banerjee et al, 2020) These adaptations include constitutive expression of interferon alpha (IFNa) (Zhou et al, 2016), wider tissue distribution of interferon regulatory factor 7 (IRF7) (Zhou et al, 2014), stricter regulation of pro-inflammatory processes (Banerjee et al, 2017; Ahn et al, 2019), and atypical expression of interferon-stimulated genes (ISGs) (de La Cruz-Rivera et al, 2018; Holzer et al, 2019). Most antiviral and innate immune signaling studies in bat cells have used surrogate virus (poly I:C, a synthetic double-stranded RNA molecule) and virus infections to stimulate downstream expression of IFNs and ISGs; the evolution and function of critical transcription factors, such as IRFs, and associated downstream antiviral signaling events remain an enigma

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