Hahn, Alexander S.

[["dc.bibliographiccitation.firstpage","e1008979"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","PLOS Pathogens"],["dc.bibliographiccitation.volume","17"],["dc.contributor.author","Großkopf, Anna K."],["dc.contributor.author","Schlagowski, Sarah"],["dc.contributor.author","Fricke, Thomas"],["dc.contributor.author","Ensser, Armin"],["dc.contributor.author","Desrosiers, Ronald C."],["dc.contributor.author","Hahn, Alexander S."],["dc.contributor.editor","Zheng, Zhi-Ming"],["dc.date.accessioned","2022-10-06T13:26:22Z"],["dc.date.available","2022-10-06T13:26:22Z"],["dc.date.issued","2021"],["dc.description.abstract","The rhesus monkey rhadinovirus (RRV), a γ2-herpesvirus of rhesus macaques, shares many biological features with the human pathogenic Kaposi’s sarcoma-associated herpesvirus (KSHV). Both viruses, as well as the more distantly related Epstein-Barr virus, engage cellular receptors from the Eph family of receptor tyrosine kinases (Ephs). However, the importance of the Eph interaction for RRV entry varies between cell types suggesting the existence of Eph-independent entry pathways. We therefore aimed to identify additional cellular receptors for RRV by affinity enrichment and mass spectrometry. We identified an additional receptor family, the Plexin domain containing proteins 1 and 2 (Plxdc1/2) that bind the RRV gH/gL glycoprotein complex. Preincubation of RRV with soluble Plxdc2 decoy receptor reduced infection by ~60%, while overexpression of Plxdc1 and 2 dramatically enhanced RRV susceptibility and cell-cell fusion of otherwise marginally permissive Raji cells. While the Plxdc2 interaction is conserved between two RRV strains, 26–95 and 17577, Plxdc1 specifically interacts with RRV 26–95 gH. The Plxdc interaction is mediated by a short motif at the N-terminus of RRV gH that is partially conserved between isolate 26–95 and isolate 17577, but absent in KSHV gH. Mutation of this motif abrogated the interaction with Plxdc1/2 and reduced RRV infection in a cell type-specific manner. Taken together, our findings characterize Plxdc1/2 as novel interaction partners and entry receptors for RRV and support the concept of the N-terminal domain of the gammaherpesviral gH/gL complex as a multifunctional receptor-binding domain. Further, Plxdc1/2 usage defines an important biological difference between KSHV and RRV."],["dc.description.sponsorship"," Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659"],["dc.description.sponsorship"," Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659"],["dc.description.sponsorship"," Wilhelm Sander-Stiftung http://dx.doi.org/10.13039/100008672"],["dc.description.sponsorship","Interdisciplinary Center for Clinical Research Erlangen"],["dc.description.sponsorship"," Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659"],["dc.description.sponsorship"," National Institutes of Health http://dx.doi.org/10.13039/100000002"],["dc.description.sponsorship"," Foundation for the National Institutes of Health http://dx.doi.org/10.13039/100000009"],["dc.identifier.doi","10.1371/journal.ppat.1008979"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/115069"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-602"],["dc.relation.eissn","1553-7374"],["dc.relation.orgunit","Deutsches Primatenzentrum"],["dc.rights.uri","http://creativecommons.org/licenses/by/4.0/"],["dc.title","Plxdc family members are novel receptors for the rhesus monkey rhadinovirus (RRV)"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e1006912"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","PLoS Pathogens"],["dc.bibliographiccitation.volume","14"],["dc.contributor.author","Großkopf, Anna K."],["dc.contributor.author","Ensser, Armin"],["dc.contributor.author","Neipel, Frank"],["dc.contributor.author","Jungnickl, Doris"],["dc.contributor.author","Schlagowski, Sarah"],["dc.contributor.author","Desrosiers, Ronald C."],["dc.contributor.author","Hahn, Alexander S."],["dc.contributor.editor","Hutt-Fletcher, Lindsey"],["dc.date.accessioned","2022-10-06T13:26:22Z"],["dc.date.available","2022-10-06T13:26:22Z"],["dc.date.issued","2018"],["dc.description.sponsorship"," Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659"],["dc.description.sponsorship","Interdisciplinary Center for Clinical Research Erlangen (IZKF)"],["dc.description.sponsorship"," Wilhelm Sander-Stiftung http://dx.doi.org/10.13039/100008672"],["dc.description.sponsorship"," Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659"],["dc.description.sponsorship","Interdisciplinary Center for Clinical Research Erlangen (IZKF)"],["dc.description.sponsorship"," Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659"],["dc.description.sponsorship"," Deutsches Primatenzentrum http://dx.doi.org/10.13039/501100004938"],["dc.description.sponsorship"," National Institutes of Health http://dx.doi.org/10.13039/100000002"],["dc.identifier.doi","10.1371/journal.ppat.1006912"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/115068"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-602"],["dc.relation.eissn","1553-7374"],["dc.relation.orgunit","Deutsches Primatenzentrum"],["dc.rights.uri","http://creativecommons.org/licenses/by/4.0/"],["dc.title","A conserved Eph family receptor-binding motif on the gH/gL complex of Kaposi’s sarcoma-associated herpesvirus and rhesus monkey rhadinovirus"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e00064-19"],["dc.bibliographiccitation.issue","15"],["dc.bibliographiccitation.journal","Journal of Virology"],["dc.bibliographiccitation.volume","93"],["dc.contributor.author","Großkopf, Anna K."],["dc.contributor.author","Schlagowski, Sarah"],["dc.contributor.author","Hörnich, Bojan F."],["dc.contributor.author","Fricke, Thomas"],["dc.contributor.author","Desrosiers, Ronald C."],["dc.contributor.author","Hahn, Alexander S."],["dc.contributor.editor","Jung, Jae U."],["dc.date.accessioned","2022-10-06T13:25:31Z"],["dc.date.available","2022-10-06T13:25:31Z"],["dc.date.issued","2019"],["dc.description.abstract","Infection of B cells is relevant for two KSHV-associated malignancies, the plasmablastic variant of multicentric Castleman’s disease and PEL. Therefore, elucidating the process of B cell infection is important for the understanding of KSHV pathogenesis. While the high-affinity receptor for the gH/gL glycoprotein complex, EphA2, has been shown to function as an entry receptor for various types of adherent cells, the gH/gL complex can also interact with other Eph receptor tyrosine kinases with lower avidity. We analyzed the Eph interactions required for infection of BJAB cells, a model for B cell infection by KSHV. We identified EphA7 as the principal Eph receptor for infection of BJAB cells by KSHV and the related rhesus monkey rhadinovirus. While two analyzed PEL cell lines exhibited high EphA2 and low EphA7 expression, a third PEL cell line, BCBL-1, showed high EphA7 and low EphA2 expression, indicating a possible relevance for KSHV pathology."],["dc.description.abstract","ABSTRACT\n Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi’s sarcoma and is associated with two B cell malignancies, primary effusion lymphoma (PEL) and the plasmablastic variant of multicentric Castleman’s disease. On several adherent cell types, EphA2 functions as a cellular receptor for the gH/gL glycoprotein complex of KSHV. KSHV gH/gL also has previously been found to interact weakly with other members of the Eph family of receptor tyrosine kinases (Ephs), and other A-type Ephs have been shown to be able to compensate for the absence of EphA2 using overexpression systems. However, whether these interactions are of functional consequence at endogenous protein levels has remained unclear so far. Here, we demonstrate for the first time that endogenously expressed EphA7 in BJAB B cells is critical for the cell-to-cell transmission of KSHV from producer iSLK cells to BJAB target cells. The BJAB lymphoblastoid cell line often serves as a model for B cell infection and expresses only low levels of all Eph family receptors other than EphA7. Endogenous EphA7 could be precipitated from the cellular lysate of BJAB cells using recombinant gH/gL, and knockout of EphA7 significantly reduced transmission of KSHV into BJAB target cells. Knockout of EphA5, the second most expressed A-type Eph in BJAB cells, had a similar, although less pronounced, effect on KSHV infection. Receptor function of EphA7 was conserved for cell-free infection by the related rhesus monkey rhadinovirus (RRV), which is relatively even more dependent on EphA7 for infection of BJAB cells.\n \n IMPORTANCE\n Infection of B cells is relevant for two KSHV-associated malignancies, the plasmablastic variant of multicentric Castleman’s disease and PEL. Therefore, elucidating the process of B cell infection is important for the understanding of KSHV pathogenesis. While the high-affinity receptor for the gH/gL glycoprotein complex, EphA2, has been shown to function as an entry receptor for various types of adherent cells, the gH/gL complex can also interact with other Eph receptor tyrosine kinases with lower avidity. We analyzed the Eph interactions required for infection of BJAB cells, a model for B cell infection by KSHV. We identified EphA7 as the principal Eph receptor for infection of BJAB cells by KSHV and the related rhesus monkey rhadinovirus. While two analyzed PEL cell lines exhibited high EphA2 and low EphA7 expression, a third PEL cell line, BCBL-1, showed high EphA7 and low EphA2 expression, indicating a possible relevance for KSHV pathology."],["dc.description.sponsorship"," HHS | National Institutes of Health https://doi.org/10.13039/100000002"],["dc.description.sponsorship"," Deutsche Forschungsgemeinschaft https://doi.org/10.13039/501100001659"],["dc.identifier.doi","10.1128/JVI.00064-19"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/114859"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-602"],["dc.relation.eissn","1098-5514"],["dc.relation.issn","0022-538X"],["dc.relation.orgunit","Deutsches Primatenzentrum"],["dc.rights.uri","https://journals.asm.org/non-commercial-tdm-license"],["dc.title","EphA7 Functions as Receptor on BJAB Cells for Cell-to-Cell Transmission of the Kaposi's Sarcoma-Associated Herpesvirus and for Cell-Free Infection by the Related Rhesus Monkey Rhadinovirus"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]