Abstract
As the only flying mammal, bats harbor a number of emerging and re-emerging viruses, many of which cause severe diseases in humans and other mammals yet result in no clinical symptoms in bats. As the master regulator of the interferon (IFN)-dependent immune response, IFN regulatory factor 7 (IRF7) plays a central role in innate antiviral immunity. To explore the role of bat IRF7 in the regulation of the IFN response, we performed sequence and functional analysis of IRF7 from the pteropid bat, Pteropus alecto. Our results demonstrate that bat IRF7 retains the ability to bind to MyD88 and activate the IFN response despite unique changes in the MyD88 binding domain. We also demonstrate that bat IRF7 has a unique expression pattern across both immune and non-immune related tissues and is inducible by double-strand RNA. The broad tissue distribution of IRF7 may provide bats with an enhanced ability to rapidly activate the IFN response in a wider range of tissues compared to other mammals. The importance of IRF7 in antiviral activity against the bat reovirus, Pulau virus was confirmed by siRNA knockdown of IRF7 in bat cells resulting in enhanced viral replication. Our results highlight the importance of IRF7 in innate antiviral immunity in bats.
Highlights
Bats have been implicated in the spillover of many deadly viruses including rabies, henipaviruses (Hendra and Nipah), ebola virus, and the coronaviruses (CoV): severe acute respiratory syndrome (SARS-CoV) and the recently emerged Middle Eastern respiratory syndrome virus (MERS-CoV), all of which impose a significant threat to human health [1,2,3,4,5,6]
Characterization of P. alecto IFN regulatory factor 7 (IRF7) To explore possible differences in the bat antiviral immune system which may influence the association between bats and viruses, IFN regulatory factor (IRF) family members were chosen as primary targets due to their importance in IFN induction and signaling [10]
To determine whether the relatively low sequence conservation of the bat IRF7 gene compared to human and mouse affects the functional activity of bat IRF7, this gene was chosen for further functional analysis
Summary
Bats have been implicated in the spillover of many deadly viruses including rabies, henipaviruses (Hendra and Nipah), ebola virus, and the coronaviruses (CoV): severe acute respiratory syndrome (SARS-CoV) and the recently emerged Middle Eastern respiratory syndrome virus (MERS-CoV), all of which impose a significant threat to human health [1,2,3,4,5,6]. Identifying the mechanisms responsible for controlling viral replication in bats has profound implications for the development of therapeutic strategies targeting viral infections in humans and other species. Due to the importance of IFNs in controlling viral replication, the regulation of the IFN response has been extensively studied in humans and other mammals. Only IRF1, IRF3, IRF5 and IRF7 have been implicated as positive regulators of type I IFN transcription, and only IRF3 and IRF7 are designated as antiviral IRFs [10,11] Since their first discovery within the biological context of EpsteinBarr virus latency, IRF7 was identified as the master regulator of the type I IFN-dependent immune response, and perhaps that of type III IFN as well [12,13,14]
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