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Characterization of chicken Mda5 activity: regulation of IFN-β in the absence of RIG-I functionality
Adam J Karpala1, Cameron Stewart, Jim McKay
1Commonwealth Scientific and Industrial Research Organisation, Livestock Industries, Australian Animal Health Laboratory, Victoria 3220, Australia. adam.karpala@csiro.au
Abstract:
In mammals, Mda5 and RIG-I are members of the evolutionary conserved RIG-like helicase family that play critical roles in the outcome of RNA virus infections. Resolving influenza infection in mammals has been shown to require RIG-I; however, the apparent absence of a RIG-I homolog in chickens raises intriguing questions regarding how this species deals with influenza virus infection. Although chickens are able to resolve certain strains of influenza, they are highly susceptible to others, such as highly pathogenic avian influenza H5N1. Understanding RIG-like helicases in the chicken is of critical importance, especially for developing new therapeutics that may use these systems. With this in mind, we investigated the RIG-like helicase Mda5 in the chicken. We have identified a chicken Mda5 homolog (ChMda5) and assessed its functional activities that relate to antiviral responses. Like mammalian Mda5, ChMda5 expression is upregulated in response to dsRNA stimulation and following IFN activation of cells. Furthermore, RNA interference-mediated knockdown of ChMda5 showed that ChMda5 plays an important role in the IFN response of chicken cells to dsRNA. Intriguingly, although ChMda5 levels are highly upregulated during influenza infection, knockdown of ChMda5 expression does not appear to impact influenza proliferation. Collectively, although Mda5 is functionally active in the chicken, the absence of an apparent RIG-I-like function may contribute to the chicken's susceptibility to highly pathogenic influenza.
Insights
Chicken Mda5 (ChMda5) is functionally active in antiviral responses to dsRNA, but its role in influenza infection is limited. The absence of RIG-I may explain chickens' susceptibility to severe influenza strains.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- RIG-I-like helicases (RLHs) like Mda5 and RIG-I are crucial for mammalian RNA virus infection outcomes.
- Chickens lack a RIG-I homolog, yet can resolve some influenza strains, posing questions about their antiviral mechanisms.
- Highly pathogenic avian influenza (HPAI) poses a significant threat to poultry, necessitating research into chicken antiviral immunity.
Purpose of the Study:
- To identify and characterize the chicken Mda5 homolog (ChMda5) and its role in antiviral immunity.
- To investigate the functional activity of ChMda5 in response to double-stranded RNA (dsRNA) and interferon (IFN) activation.
- To determine the impact of ChMda5 on influenza virus proliferation in chickens.
Main Methods:
- Identification of a chicken Mda5 homolog (ChMda5).
- Assessment of ChMda5 expression following dsRNA stimulation and IFN activation.
- RNA interference (RNAi)-mediated knockdown of ChMda5 to evaluate its role in antiviral responses and influenza proliferation.
Main Results:
- Chicken Mda5 (ChMda5) was identified and found to be upregulated by dsRNA and IFN.
- ChMda5 knockdown demonstrated its importance in the chicken IFN response to dsRNA.
- Despite upregulation during influenza infection, ChMda5 knockdown did not affect influenza proliferation.
Conclusions:
- ChMda5 is a functionally active RLH in chickens, contributing to dsRNA-mediated antiviral immunity.
- The lack of a functional RIG-I homolog, alongside active Mda5, may underlie chickens' differential susceptibility to influenza strains.
- Understanding ChMda5 and the absence of RIG-I is critical for developing novel therapeutics against avian influenza.
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