Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Ebolavirus Species-Specific Interferon Antagonism Mediated by VP24

Version 1 : Received: 14 April 2023 / Approved: 17 April 2023 / Online: 17 April 2023 (03:54:31 CEST)

A peer-reviewed article of this Preprint also exists.

Ramanathan, P.; Tigabu, B.; Santos, R.I.; Ilinykh, P.A.; Kuzmina, N.; Vogel, O.A.; Thakur, N.; Ahmed, H.; Wu, C.; Amarasinghe, G.K.; Basler, C.F.; Bukreyev, A. Ebolavirus Species-Specific Interferon Antagonism Mediated by VP24. Viruses 2023, 15, 1075. Ramanathan, P.; Tigabu, B.; Santos, R.I.; Ilinykh, P.A.; Kuzmina, N.; Vogel, O.A.; Thakur, N.; Ahmed, H.; Wu, C.; Amarasinghe, G.K.; Basler, C.F.; Bukreyev, A. Ebolavirus Species-Specific Interferon Antagonism Mediated by VP24. Viruses 2023, 15, 1075.

Abstract

Members of the Ebolavirus genus demonstrate a marked differences in pathogenicity in humans with Ebola (EBOV) being the most pathogenic, Bundibugyo (BDBV) less pathogenic and Reston (RESTV) causing no severe disease in humans. The VP24 protein encoded by members of the Ebolavirus genus blocks type I interferon (IFN-I) signaling through interaction with host karyopherin alpha nuclear transporters, potentially contributing to virulence. Previously we demonstrated that BDBV VP24 (bVP24) binds with lower affinities to karyopherin alpha proteins relative to EBOV VP24 (eVP24), and this correlated with reduced inhibition of IFN-I signaling. We hypothesized that modification of eVP24-karyopherin alpha interface to make it similar to bVP24 would attenuate the ability to antagonize IFN-I response. We generated a panel of recombinant EBOVs containing single or combinations of point mutations in the eVP24-karyopherin alpha interface. Most of the viruses appeared to be attenuated in both IFN-I-competent 769-P and IFN-I-deficient Vero-E6 cells in the presence of IFNs. However, the R140A mutant grew at reduced levels even in the absence of IFNs in both cell lines, as well as in U3A STAT1 knockout cells. Both the R140A mutation and its combination with the N135A mutation caused almost complete inhibition of genome replication and transcription suggesting the role of these mutations in an IFN-I-independent attenuation. Additionally, we found that unlike eVP24, bVP24 does not inhibit interferon lambda 1 (IFN-λ1), which potentially explains the lower pathogenicity of BDBV relative to EBOV. Thus, the VP24 residues binding karyopherin alpha affect ebolavirus pathogenicity by IFN-I-dependent and independent mechanisms.

Keywords

Ebola virus; VP24; immune evasion; STAT1

Subject

Biology and Life Sciences, Virology

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our Diversity statement.

Leave a public comment
Send a private comment to the author(s)
* All users must log in before leaving a comment
Views 0
Downloads 0
Comments 0
Metrics 0


×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.