The alphavirus determinants of intercellular long extension formation
ABSTRACT The alphavirus chikungunya virus (CHIKV) is a serious human pathogen that can cause large-scale epidemics characterized by fever and joint pain and often resulting in chronic arthritis. Infection by alphaviruses including CHIKV and the closely related Semliki Forest virus (SFV) can induce t...
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American Society for Microbiology
2025-02-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.01986-24 |
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| author | Caroline K. Martin Judy J. Wan Peiqi Yin Thomas E. Morrison William B. Messer Vanessa Rivera-Amill Jonathan R. Lai Nina Grau Félix A. Rey Thérèse Couderc Marc Lecuit Margaret Kielian |
| author_facet | Caroline K. Martin Judy J. Wan Peiqi Yin Thomas E. Morrison William B. Messer Vanessa Rivera-Amill Jonathan R. Lai Nina Grau Félix A. Rey Thérèse Couderc Marc Lecuit Margaret Kielian |
| author_sort | Caroline K. Martin |
| collection | DOAJ |
| description | ABSTRACT The alphavirus chikungunya virus (CHIKV) is a serious human pathogen that can cause large-scale epidemics characterized by fever and joint pain and often resulting in chronic arthritis. Infection by alphaviruses including CHIKV and the closely related Semliki Forest virus (SFV) can induce the formation of filopodia-like intercellular long extensions (ILEs). ILEs emanate from an infected cell, stably attach to a neighboring cell, and mediate cell-to-cell viral transmission that is resistant to neutralizing antibodies. However, our mechanistic understanding of ILE formation is limited, and the potential contribution of ILEs to CHIKV virulence or human CHIKV infection is unknown. Here, we used well-characterized virus mutants and monoclonal antibodies with known epitopes to dissect the virus requirements for ILE formation. Our results showed that both the viral E2 and E1 envelope proteins were required for ILE formation, while viral proteins 6K and transframe, and cytoplasmic nucleocapsid formation were dispensable. A subset of CHIKV monoclonal antibodies reduced ILE formation by masking specific regions particularly on the E2 A domain. Studies of the viral proteins from different CHIKV strains showed that ILE formation is conserved across the four major CHIKV lineages. Sera from convalescent human CHIKV patients inhibited ILE formation in cell culture, providing the first evidence for ILE inhibitory antibody production during human CHIKV infections.IMPORTANCEChikungunya virus (CHIKV) infections can cause severe fever and long-lasting joint pain in humans. CHIKV is disseminated by mosquitoes and is now found world-wide, including in the Americas, Asia, and Africa. In cultured cells, CHIKV can induce the formation of long intercellular extensions that can transmit virus to another cell. However, our understanding of the formation of extensions and their importance in human CHIKV infection is limited. We here identified viral protein requirements for extension formation. We demonstrated that specific monoclonal antibodies against the virus envelope proteins or sera from human CHIKV patients can inhibit extension formation. Our data highlight the importance of evaluation of extension formation in the context of human CHIKV infection. |
| format | Article |
| id | doaj-art-6b6e810dd2bd4bda8c1f87241a0f86f9 |
| institution | Kabale University |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj-art-6b6e810dd2bd4bda8c1f87241a0f86f92025-02-05T14:00:48ZengAmerican Society for MicrobiologymBio2150-75112025-02-0116210.1128/mbio.01986-24The alphavirus determinants of intercellular long extension formationCaroline K. Martin0Judy J. Wan1Peiqi Yin2Thomas E. Morrison3William B. Messer4Vanessa Rivera-Amill5Jonathan R. Lai6Nina Grau7Félix A. Rey8Thérèse Couderc9Marc Lecuit10Margaret Kielian11Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USADepartment of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USADepartment of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USADepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USADepartment of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, Oregon, USAPonce Health Sciences University/Ponce Research Institute, Ponce, Puerto RicoDepartment of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USAInstitut Pasteur, Université Paris Cité, CNRS UMR 3569, Unité de Virologie Structurale, Paris, FranceInstitut Pasteur, Université Paris Cité, CNRS UMR 3569, Unité de Virologie Structurale, Paris, FranceInstitut Pasteur, Université Paris Cité, Inserm U1117, Biology of Infection Unit, Paris, FranceInstitut Pasteur, Université Paris Cité, Inserm U1117, Biology of Infection Unit, Paris, FranceDepartment of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USAABSTRACT The alphavirus chikungunya virus (CHIKV) is a serious human pathogen that can cause large-scale epidemics characterized by fever and joint pain and often resulting in chronic arthritis. Infection by alphaviruses including CHIKV and the closely related Semliki Forest virus (SFV) can induce the formation of filopodia-like intercellular long extensions (ILEs). ILEs emanate from an infected cell, stably attach to a neighboring cell, and mediate cell-to-cell viral transmission that is resistant to neutralizing antibodies. However, our mechanistic understanding of ILE formation is limited, and the potential contribution of ILEs to CHIKV virulence or human CHIKV infection is unknown. Here, we used well-characterized virus mutants and monoclonal antibodies with known epitopes to dissect the virus requirements for ILE formation. Our results showed that both the viral E2 and E1 envelope proteins were required for ILE formation, while viral proteins 6K and transframe, and cytoplasmic nucleocapsid formation were dispensable. A subset of CHIKV monoclonal antibodies reduced ILE formation by masking specific regions particularly on the E2 A domain. Studies of the viral proteins from different CHIKV strains showed that ILE formation is conserved across the four major CHIKV lineages. Sera from convalescent human CHIKV patients inhibited ILE formation in cell culture, providing the first evidence for ILE inhibitory antibody production during human CHIKV infections.IMPORTANCEChikungunya virus (CHIKV) infections can cause severe fever and long-lasting joint pain in humans. CHIKV is disseminated by mosquitoes and is now found world-wide, including in the Americas, Asia, and Africa. In cultured cells, CHIKV can induce the formation of long intercellular extensions that can transmit virus to another cell. However, our understanding of the formation of extensions and their importance in human CHIKV infection is limited. We here identified viral protein requirements for extension formation. We demonstrated that specific monoclonal antibodies against the virus envelope proteins or sera from human CHIKV patients can inhibit extension formation. Our data highlight the importance of evaluation of extension formation in the context of human CHIKV infection.https://journals.asm.org/doi/10.1128/mbio.01986-24alphaviruschikungunyaintercellular transmissionvirus buddingvirus exit |
| spellingShingle | Caroline K. Martin Judy J. Wan Peiqi Yin Thomas E. Morrison William B. Messer Vanessa Rivera-Amill Jonathan R. Lai Nina Grau Félix A. Rey Thérèse Couderc Marc Lecuit Margaret Kielian The alphavirus determinants of intercellular long extension formation mBio alphavirus chikungunya intercellular transmission virus budding virus exit |
| title | The alphavirus determinants of intercellular long extension formation |
| title_full | The alphavirus determinants of intercellular long extension formation |
| title_fullStr | The alphavirus determinants of intercellular long extension formation |
| title_full_unstemmed | The alphavirus determinants of intercellular long extension formation |
| title_short | The alphavirus determinants of intercellular long extension formation |
| title_sort | alphavirus determinants of intercellular long extension formation |
| topic | alphavirus chikungunya intercellular transmission virus budding virus exit |
| url | https://journals.asm.org/doi/10.1128/mbio.01986-24 |
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