A Retrograde Trafficking Inhibitor of Ricin and Shiga-Like Toxins Inhibits Infection of Cells by Human and Monkey Polyomaviruses
ABSTRACT Polyomaviruses are ubiquitous pathogens that cause severe disease in immunocompromised individuals. JC polyomavirus (JCPyV) is the causative agent of the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML), whereas BK polyomavirus (BKPyV) causes polyomavirus-induced...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2013-12-01
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| Series: | mBio |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.00729-13 |
| _version_ | 1818893292717211648 |
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| author | Christian D. S. Nelson Dan W. Carney Aaron Derdowski Alex Lipovsky Gretchen V. Gee Bethany O’Hara Paul Williard Daniel DiMaio Jason K. Sello Walter J. Atwood |
| author_facet | Christian D. S. Nelson Dan W. Carney Aaron Derdowski Alex Lipovsky Gretchen V. Gee Bethany O’Hara Paul Williard Daniel DiMaio Jason K. Sello Walter J. Atwood |
| author_sort | Christian D. S. Nelson |
| collection | DOAJ |
| description | ABSTRACT Polyomaviruses are ubiquitous pathogens that cause severe disease in immunocompromised individuals. JC polyomavirus (JCPyV) is the causative agent of the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML), whereas BK polyomavirus (BKPyV) causes polyomavirus-induced nephropathy and hemorrhagic cystitis. Vaccines or antiviral therapies targeting these viruses do not exist, and treatments focus on reducing the underlying causes of immunosuppression. We demonstrate that retro-2cycl, an inhibitor of ricin and Shiga-like toxins (SLTs), inhibits infection by JCPyV, BKPyV, and simian virus 40. Retro-2cycl inhibits retrograde transport of polyomaviruses to the endoplasmic reticulum, a step necessary for productive infection. Retro-2cycl likely inhibits polyomaviruses in a way similar to its ricin and SLT inhibition, suggesting an overlap in the cellular host factors used by bacterial toxins and polyomaviruses. This work establishes retro-2cycl as a potential antiviral therapy that broadly inhibits polyomaviruses and possibly other pathogens that use retrograde trafficking. IMPORTANCE The human polyomaviruses JC polyomavirus (JCPyV) and BK polyomavirus (BKPyV) cause rare but severe diseases in individuals with reduced immune function. During immunosuppression, JCPyV disseminates from the kidney to the central nervous system and destroys oligodendrocytes, resulting in the fatal disease progressive multifocal leukoencephalopathy. Kidney transplant recipients are at increased risk of BKPyV-induced nephropathy, which results in kidney necrosis and loss of the transplanted organ. There are currently no effective therapies for JCPyV and BKPyV. We show that a small molecule named retro-2cycl protects cells from infection with JCPyV and BKPyV by inhibiting intracellular viral transport. Retro-2cycl treatment reduces viral spreading in already established infections and may therefore be able to control infection in affected patients. Further optimization of retro-2cycl may result in the development of an effective antiviral therapy directed toward pathogens that use retrograde trafficking to infect their hosts. |
| first_indexed | 2024-12-19T18:10:17Z |
| format | Article |
| id | doaj.art-20244ec9a75f4271800339dd3e7b07da |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-19T18:10:17Z |
| publishDate | 2013-12-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-20244ec9a75f4271800339dd3e7b07da2022-12-21T20:11:20ZengAmerican Society for MicrobiologymBio2150-75112013-12-014610.1128/mBio.00729-13A Retrograde Trafficking Inhibitor of Ricin and Shiga-Like Toxins Inhibits Infection of Cells by Human and Monkey PolyomavirusesChristian D. S. Nelson0Dan W. Carney1Aaron Derdowski2Alex Lipovsky3Gretchen V. Gee4Bethany O’Hara5Paul Williard6Daniel DiMaio7Jason K. Sello8Walter J. Atwood9Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USADepartment of Chemistry, Brown University, Providence, Rhode Island, USADepartment of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USADepartment of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USADepartment of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USADepartment of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USADepartment of Chemistry, Brown University, Providence, Rhode Island, USADepartment of Genetics, Yale School of Medicine, New Haven, Connecticut, USADepartment of Chemistry, Brown University, Providence, Rhode Island, USADepartment of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USAABSTRACT Polyomaviruses are ubiquitous pathogens that cause severe disease in immunocompromised individuals. JC polyomavirus (JCPyV) is the causative agent of the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML), whereas BK polyomavirus (BKPyV) causes polyomavirus-induced nephropathy and hemorrhagic cystitis. Vaccines or antiviral therapies targeting these viruses do not exist, and treatments focus on reducing the underlying causes of immunosuppression. We demonstrate that retro-2cycl, an inhibitor of ricin and Shiga-like toxins (SLTs), inhibits infection by JCPyV, BKPyV, and simian virus 40. Retro-2cycl inhibits retrograde transport of polyomaviruses to the endoplasmic reticulum, a step necessary for productive infection. Retro-2cycl likely inhibits polyomaviruses in a way similar to its ricin and SLT inhibition, suggesting an overlap in the cellular host factors used by bacterial toxins and polyomaviruses. This work establishes retro-2cycl as a potential antiviral therapy that broadly inhibits polyomaviruses and possibly other pathogens that use retrograde trafficking. IMPORTANCE The human polyomaviruses JC polyomavirus (JCPyV) and BK polyomavirus (BKPyV) cause rare but severe diseases in individuals with reduced immune function. During immunosuppression, JCPyV disseminates from the kidney to the central nervous system and destroys oligodendrocytes, resulting in the fatal disease progressive multifocal leukoencephalopathy. Kidney transplant recipients are at increased risk of BKPyV-induced nephropathy, which results in kidney necrosis and loss of the transplanted organ. There are currently no effective therapies for JCPyV and BKPyV. We show that a small molecule named retro-2cycl protects cells from infection with JCPyV and BKPyV by inhibiting intracellular viral transport. Retro-2cycl treatment reduces viral spreading in already established infections and may therefore be able to control infection in affected patients. Further optimization of retro-2cycl may result in the development of an effective antiviral therapy directed toward pathogens that use retrograde trafficking to infect their hosts.https://journals.asm.org/doi/10.1128/mBio.00729-13 |
| spellingShingle | Christian D. S. Nelson Dan W. Carney Aaron Derdowski Alex Lipovsky Gretchen V. Gee Bethany O’Hara Paul Williard Daniel DiMaio Jason K. Sello Walter J. Atwood A Retrograde Trafficking Inhibitor of Ricin and Shiga-Like Toxins Inhibits Infection of Cells by Human and Monkey Polyomaviruses mBio |
| title | A Retrograde Trafficking Inhibitor of Ricin and Shiga-Like Toxins Inhibits Infection of Cells by Human and Monkey Polyomaviruses |
| title_full | A Retrograde Trafficking Inhibitor of Ricin and Shiga-Like Toxins Inhibits Infection of Cells by Human and Monkey Polyomaviruses |
| title_fullStr | A Retrograde Trafficking Inhibitor of Ricin and Shiga-Like Toxins Inhibits Infection of Cells by Human and Monkey Polyomaviruses |
| title_full_unstemmed | A Retrograde Trafficking Inhibitor of Ricin and Shiga-Like Toxins Inhibits Infection of Cells by Human and Monkey Polyomaviruses |
| title_short | A Retrograde Trafficking Inhibitor of Ricin and Shiga-Like Toxins Inhibits Infection of Cells by Human and Monkey Polyomaviruses |
| title_sort | retrograde trafficking inhibitor of ricin and shiga like toxins inhibits infection of cells by human and monkey polyomaviruses |
| url | https://journals.asm.org/doi/10.1128/mBio.00729-13 |
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