Ebolavirus Species-Specific Interferon Antagonism Mediated by VP24
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) is not known to cause a disease in humans. The VP24 protein encoded by members of the Ebolavirus genus blocks...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-04-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/15/5/1075 |
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| author | Palaniappan Ramanathan Bersabeh Tigabu Rodrigo I. Santos Philipp A. Ilinykh Natalia Kuzmina Olivia A. Vogel Naveen Thakur Hamza Ahmed Chao Wu Gaya K. Amarasinghe Christopher F. Basler Alexander Bukreyev |
| author_facet | Palaniappan Ramanathan Bersabeh Tigabu Rodrigo I. Santos Philipp A. Ilinykh Natalia Kuzmina Olivia A. Vogel Naveen Thakur Hamza Ahmed Chao Wu Gaya K. Amarasinghe Christopher F. Basler Alexander Bukreyev |
| author_sort | Palaniappan Ramanathan |
| collection | DOAJ |
| description | 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) is not known to cause a 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 a reduced inhibition in 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 greatly reduced the amounts of viral genomic RNA and mRNA suggesting that these mutations attenuate the virus in an IFN-I-independent attenuation. Additionally, we found that unlike eVP24, bVP24 does not inhibit interferon lambda 1 (IFN-λ1), interferon beta (IFN-β), and ISG15, which potentially explains the lower pathogenicity of BDBV relative to EBOV. Thus, the VP24 residues binding karyopherin alpha attenuates the virus by IFN-I-dependent and independent mechanisms. |
| first_indexed | 2024-03-11T03:14:35Z |
| format | Article |
| id | doaj.art-9daf9e18ecfc4868816c4867f5e79888 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-11T03:14:35Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-9daf9e18ecfc4868816c4867f5e798882023-11-18T03:38:37ZengMDPI AGViruses1999-49152023-04-01155107510.3390/v15051075Ebolavirus Species-Specific Interferon Antagonism Mediated by VP24Palaniappan Ramanathan0Bersabeh Tigabu1Rodrigo I. Santos2Philipp A. Ilinykh3Natalia Kuzmina4Olivia A. Vogel5Naveen Thakur6Hamza Ahmed7Chao Wu8Gaya K. Amarasinghe9Christopher F. Basler10Alexander Bukreyev11Department of Pathology, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USADepartment of Pathology, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USADepartment of Pathology, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USADepartment of Pathology, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USADepartment of Pathology, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USADepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USADepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USADepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USADepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADepartment of Pathology, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USAMembers 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) is not known to cause a 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 a reduced inhibition in 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 greatly reduced the amounts of viral genomic RNA and mRNA suggesting that these mutations attenuate the virus in an IFN-I-independent attenuation. Additionally, we found that unlike eVP24, bVP24 does not inhibit interferon lambda 1 (IFN-λ1), interferon beta (IFN-β), and ISG15, which potentially explains the lower pathogenicity of BDBV relative to EBOV. Thus, the VP24 residues binding karyopherin alpha attenuates the virus by IFN-I-dependent and independent mechanisms.https://www.mdpi.com/1999-4915/15/5/1075EbolavirusVP24immune evasionSTAT1 |
| spellingShingle | Palaniappan Ramanathan Bersabeh Tigabu Rodrigo I. Santos Philipp A. Ilinykh Natalia Kuzmina Olivia A. Vogel Naveen Thakur Hamza Ahmed Chao Wu Gaya K. Amarasinghe Christopher F. Basler Alexander Bukreyev Ebolavirus Species-Specific Interferon Antagonism Mediated by VP24 Viruses Ebolavirus VP24 immune evasion STAT1 |
| title | Ebolavirus Species-Specific Interferon Antagonism Mediated by VP24 |
| title_full | Ebolavirus Species-Specific Interferon Antagonism Mediated by VP24 |
| title_fullStr | Ebolavirus Species-Specific Interferon Antagonism Mediated by VP24 |
| title_full_unstemmed | Ebolavirus Species-Specific Interferon Antagonism Mediated by VP24 |
| title_short | Ebolavirus Species-Specific Interferon Antagonism Mediated by VP24 |
| title_sort | ebolavirus species specific interferon antagonism mediated by vp24 |
| topic | Ebolavirus VP24 immune evasion STAT1 |
| url | https://www.mdpi.com/1999-4915/15/5/1075 |
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