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Filovirus VP24 Proteins Differentially Regulate RIG-I and MDA5-Dependent Type I and III Interferon Promoter

Felix B He1, Hira Khan1, Moona Huttunen1

  • 1Institute of Biomedicine/Virology, University of Turku, Turku, Finland.

Frontiers in Immunology
|January 24, 2022
PubMed

Insights

Filovirus VP24 proteins inhibit innate immunity by interfering with interferon signaling. However, Mengla and Bombali virus VP24s do not inhibit, suggesting varied immune evasion strategies within the filovirus family.

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • Filoviruses, including Ebola and Marburg, are highly pathogenic, causing significant global health threats.
  • Research has historically focused on specific filoviruses, leaving others less studied.
  • Filoviruses possess mechanisms to suppress the host's innate immune response, particularly interferon pathways, involving viral proteins like VP24.

Purpose of the Study:

  • To systematically analyze the innate immune inhibitory capabilities of VP24 proteins from nine filovirus species.
  • To investigate the interference of filovirus VP24 proteins with retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated antigen 5 (MDA5) mediated interferon signaling.
  • To determine the interaction of VP24 proteins with importin α5, crucial for nuclear import of STAT complexes.

Main Methods:

  • Assessed VP24 protein localization in cellular compartments (cytoplasm and nucleus).
  • Evaluated the inhibition of RIG-I and MDA5 induced IFN-β and IFN-λ1 promoter activation by VP24 proteins.
  • Analyzed the binding affinity of VP24 proteins to importin α5.

Main Results:

  • VP24 proteins from Zaire, Sudan, Lloviu, Taï Forest, Reston, Marburg, and Bundibugyo viruses inhibited RIG-I and MDA5 stimulated interferon promoter activation.
  • Inhibition by most VP24 proteins occurred downstream of IRF3 phosphorylation, suggesting nuclear action.
  • VP24 proteins from Mengla and Bombali viruses did not inhibit interferon promoter activation.
  • Six ebolavirus VP24s and Lloviu VP24 bound tightly to importin α5, while Marburg and Mengla VP24s showed weak binding.

Conclusions:

  • Filovirus VP24 proteins exhibit varied abilities to inhibit innate immune responses, with most suppressing interferon pathways.
  • The VP24 proteins of Mengla and Bombali viruses appear to lack this specific interferon inhibitory function.
  • Differential binding to importin α5 suggests distinct mechanisms for nuclear transport and potential roles in filovirus pathogenesis.
Keywords:
MDA5 pathwayRIG-I pathwayVP24ebolavirusfilovirusinnate immunitytype I interferontype III interferon

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