ATO (Arsenic Trioxide) Effects on Promyelocytic Leukemia Nuclear Bodies Reveals Antiviral Intervention Capacity
Abstract Human adenoviruses (HAdV) are associated with clinical symptoms such as gastroenteritis, keratoconjunctivitis, pneumonia, hepatitis, and encephalitis. In the absence of protective immunity, as in allogeneic bone marrow transplant patients, HAdV infections can become lethal. Alarmingly, vari...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-04-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.201902130 |
| _version_ | 1818837676354174976 |
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| author | Samuel Hofmann Julia Mai Sawinee Masser Peter Groitl Alexander Herrmann Thomas Sternsdorf Ruth Brack‐Werner Sabrina Schreiner |
| author_facet | Samuel Hofmann Julia Mai Sawinee Masser Peter Groitl Alexander Herrmann Thomas Sternsdorf Ruth Brack‐Werner Sabrina Schreiner |
| author_sort | Samuel Hofmann |
| collection | DOAJ |
| description | Abstract Human adenoviruses (HAdV) are associated with clinical symptoms such as gastroenteritis, keratoconjunctivitis, pneumonia, hepatitis, and encephalitis. In the absence of protective immunity, as in allogeneic bone marrow transplant patients, HAdV infections can become lethal. Alarmingly, various outbreaks of highly pathogenic, pneumotropic HAdV types have been recently reported, causing severe and lethal respiratory diseases. Effective drugs for treatment of HAdV infections are still lacking. The repurposing of drugs approved for other indications is a valuable alternative for the development of new antiviral therapies and is less risky and costly than de novo development. Arsenic trioxide (ATO) is approved for treatment of acute promyelocytic leukemia. Here, it is shown that ATO is a potent inhibitor of HAdV. ATO treatment blocks virus expression and replication by reducing the number and integrity of promyelocytic leukemia (PML) nuclear bodies, important subnuclear structures for HAdV replication. Modification of HAdV proteins with small ubiquitin‐like modifiers (SUMO) is also key to HAdV replication. ATO reduces levels of viral SUMO‐E2A protein, while increasing SUMO‐PML, suggesting that ATO interferes with SUMOylation of proteins crucial for HAdV replication. It is concluded that ATO targets cellular processes key to HAdV replication and is relevant for the development of antiviral intervention strategies. |
| first_indexed | 2024-12-19T03:26:17Z |
| format | Article |
| id | doaj.art-965de59d17624f1788412f54eaf49a86 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-12-19T03:26:17Z |
| publishDate | 2020-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-965de59d17624f1788412f54eaf49a862022-12-21T20:37:35ZengWileyAdvanced Science2198-38442020-04-0178n/an/a10.1002/advs.201902130ATO (Arsenic Trioxide) Effects on Promyelocytic Leukemia Nuclear Bodies Reveals Antiviral Intervention CapacitySamuel Hofmann0Julia Mai1Sawinee Masser2Peter Groitl3Alexander Herrmann4Thomas Sternsdorf5Ruth Brack‐Werner6Sabrina Schreiner7Institute of Virology School of Medicine Technical University of Munich 85764 Munich GermanyInstitute of Virology School of Medicine Technical University of Munich 85764 Munich GermanyInstitute of Virology School of Medicine Technical University of Munich 85764 Munich GermanyInstitute of Virology School of Medicine Technical University of Munich 85764 Munich GermanyInstitute of Virology Helmholtz Zentrum München 85764 Munich GermanyResearch Institute Children's Cancer Center Hamburg 20251 Hamburg GermanyInstitute of Virology Helmholtz Zentrum München 85764 Munich GermanyInstitute of Virology School of Medicine Technical University of Munich 85764 Munich GermanyAbstract Human adenoviruses (HAdV) are associated with clinical symptoms such as gastroenteritis, keratoconjunctivitis, pneumonia, hepatitis, and encephalitis. In the absence of protective immunity, as in allogeneic bone marrow transplant patients, HAdV infections can become lethal. Alarmingly, various outbreaks of highly pathogenic, pneumotropic HAdV types have been recently reported, causing severe and lethal respiratory diseases. Effective drugs for treatment of HAdV infections are still lacking. The repurposing of drugs approved for other indications is a valuable alternative for the development of new antiviral therapies and is less risky and costly than de novo development. Arsenic trioxide (ATO) is approved for treatment of acute promyelocytic leukemia. Here, it is shown that ATO is a potent inhibitor of HAdV. ATO treatment blocks virus expression and replication by reducing the number and integrity of promyelocytic leukemia (PML) nuclear bodies, important subnuclear structures for HAdV replication. Modification of HAdV proteins with small ubiquitin‐like modifiers (SUMO) is also key to HAdV replication. ATO reduces levels of viral SUMO‐E2A protein, while increasing SUMO‐PML, suggesting that ATO interferes with SUMOylation of proteins crucial for HAdV replication. It is concluded that ATO targets cellular processes key to HAdV replication and is relevant for the development of antiviral intervention strategies.https://doi.org/10.1002/advs.201902130antiviralsarsenichuman adenovirusespromyelocytic leukemia nuclear bodiessmall ubiquitin‐like modifiers (SUMO) |
| spellingShingle | Samuel Hofmann Julia Mai Sawinee Masser Peter Groitl Alexander Herrmann Thomas Sternsdorf Ruth Brack‐Werner Sabrina Schreiner ATO (Arsenic Trioxide) Effects on Promyelocytic Leukemia Nuclear Bodies Reveals Antiviral Intervention Capacity Advanced Science antivirals arsenic human adenoviruses promyelocytic leukemia nuclear bodies small ubiquitin‐like modifiers (SUMO) |
| title | ATO (Arsenic Trioxide) Effects on Promyelocytic Leukemia Nuclear Bodies Reveals Antiviral Intervention Capacity |
| title_full | ATO (Arsenic Trioxide) Effects on Promyelocytic Leukemia Nuclear Bodies Reveals Antiviral Intervention Capacity |
| title_fullStr | ATO (Arsenic Trioxide) Effects on Promyelocytic Leukemia Nuclear Bodies Reveals Antiviral Intervention Capacity |
| title_full_unstemmed | ATO (Arsenic Trioxide) Effects on Promyelocytic Leukemia Nuclear Bodies Reveals Antiviral Intervention Capacity |
| title_short | ATO (Arsenic Trioxide) Effects on Promyelocytic Leukemia Nuclear Bodies Reveals Antiviral Intervention Capacity |
| title_sort | ato arsenic trioxide effects on promyelocytic leukemia nuclear bodies reveals antiviral intervention capacity |
| topic | antivirals arsenic human adenoviruses promyelocytic leukemia nuclear bodies small ubiquitin‐like modifiers (SUMO) |
| url | https://doi.org/10.1002/advs.201902130 |
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