A Kaposi's Sarcoma-Associated Herpesvirus Infection Mechanism Is Independent of Integrins α3β1, αVβ3, and αVβ5

TerBush, Allison Alwan; Hafkamp, Florianne; Lee, Hee Jun; Coscoy, Laurent

doi:10.1128/jvi.00803-18

Cited by 27 publications

(24 citation statements)

References 72 publications

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“…cellular receptor EphA2 for KSHV entry into various adherent target cells (2)(3)(4)(5). While the KSHV gH/gL complex exhibits the highest avidity for EphA2, it can also interact with other members of the Eph family of receptor tyrosine kinases (Ephs), similar to the gH/gL complex of the related rhesus monkey rhadinovirus (RRV) (6).…”

mentioning

confidence: 99%

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

Großkopf

Schlagowski

Hörnich

et al. 2019

J Virol

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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.IMPORTANCEInfection 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.

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mentioning

confidence: 99%

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

Großkopf

Schlagowski

Hörnich

et al. 2019

J Virol

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“…However, redundant functions among the receptors involved may hinder this approach. For example, although integrins such as ␣3␤1, ␣V␤3, or ␣V␤5 are presumed to play a crucial role in KSHV infection (13), they were recently proven to be dispensable for epithelial cell infection (60), suggesting that they may not be ideal targets in a clinical setting. Similarly, a recent study identified conserved residues in the N-terminal domain of gH that mediate EphA2 binding (63).…”

Section: Discussionmentioning

confidence: 99%

Kaposi Sarcoma-Associated Herpesvirus Glycoprotein H Is Indispensable for Infection of Epithelial, Endothelial, and Fibroblast Cell Types

Muniraju

Mutsvunguma

Foley

et al. 2019

J Virol

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Kaposi sarcoma-associated herpesvirus (KSHV) is an emerging pathogen and is the causative infectious agent of Kaposi sarcoma and two malignancies of B cell origin. To date, there is no licensed KSHV vaccine. Development of an effective vaccine against KSHV continues to be limited by a poor understanding of how the virus initiates acute primary infection in vivo in diverse human cell types. The role of glycoprotein H (gH) in herpesvirus entry mechanisms remains largely unresolved. To characterize the requirement for KSHV gH in the viral life cycle and in determination of cell tropism, we generated and characterized a mutant KSHV in which expression of gH was abrogated. Using a bacterial artificial chromosome containing a complete recombinant KSHV genome and recombinant DNA technology, we inserted stop codons into the gH coding region. We used electron microscopy to reveal that the gH-null mutant virus assembled and exited from cells normally, compared to wild-type virus. Using purified virions, we assessed infectivity of the gH-null mutant in diverse mammalian cell types in vitro. Unlike wild-type virus or a gH-containing revertant, the gH-null mutant was unable to infect any of the epithelial, endothelial, or fibroblast cell types tested. However, its ability to infect B cells was equivocal and remains to be investigated in vivo due to generally poor infectivity in vitro. Together, these results suggest that gH is critical for KSHV infection of highly permissive cell types, including epithelial, endothelial, and fibroblast cells. IMPORTANCE All homologues of herpesvirus gH studied to date have been implicated in playing an essential role in viral infection of diverse permissive cell types. However, the role of gH in the mechanism of KSHV infection remains largely unresolved. In this study, we generated a gH-null mutant KSHV and provided evidence that deficiency of gH expression did not affect viral particle assembly or egress. Using the gH-null mutant, we showed that gH was indispensable for KSHV infection of epithelial, endothelial, and fibroblast cells in vitro. This suggests that gH is an important target for the development of a KSHV prophylactic vaccine to prevent initial viral infection.

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“…The epithelial cell-tropism complex gH/gL binds to the ligand-binding domain of EphA2 similar to KSHV (Chen et al, 2018. Interestingly, EBV enters epithelial cells by direct fusion with the plasma membrane, whereas KSHV enters its host cells via an endocytosis pathway involving gH/gL-binding to EphA2, A4 or A5 (Chen et al, 2018, Miller and Hutt-Fletcher, 1992, Chakraborty et al, 2012a, Hahn et al, 2012, Chandran, 2010, Chen et al, 2019, TerBush et al, 2018. EBV gH/gL acts as tropism switch by either interacting with gp42 that facilitates B cell receptor binding or directly binding to the epithelial cell receptor EphA2 (Borza and Hutt-Fletcher, 2002, Matsuura et al, 2010, Möhl et al, 2016.…”

Section: Ebv-driven Entry and Fusionmentioning

confidence: 99%

“…Previous studies demonstrated that several integrins such as αVβ3, αVβ5 and α3β1 are important for infection of human epithelial and endothelial cells as well as esophageal fibroblasts (Akula et al, 2002, Chandran, 2010, Damania and Cesarman, 2013. More recent studies suggest that KSHV infection of epithelial cells is independent of αν-and β1-family integrin expression (TerBush et al, 2018), but requires HSPGs and either EphA2, EphA4, or EphA5 (Chakraborty et al, 2012a, Chandran, 2010, Chen et al, 2019, Damania and Cesarman, 2013, Hahn et al, 2012, TerBush et al, 2018. Interestingly, EphA7 has recently been found to be a receptor required for KSHV entry into B cells (Grosskopf et al, 2019).…”

Section: Kshv-driven Entry and Fusionmentioning

confidence: 99%

Gammaherpesvirus entry and fusion: A tale how two human pathogenic viruses enter their host cells

Möhl

Chen

Longnecker

2019

Advances in Virus Research

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The prototypical human γ-herpesviruses Epstein-Barr virus (EBV) and Kaposi Sarcomaassociated herpesvirus (KSHV) are involved in the development of malignancies. Like all herpesviruses, they share the establishment of latency, the typical architecture, and the conserved fusion machinery to initiate infection. The fusion machinery reflects virus-specific adaptations due to the requirements of the respective herpesvirus. For example, EBV evolved a tropism switch involving either the B-or epithelial cell-tropism complexes to activate fusion driven by gB. Most of the EBV entry proteins and their cellular receptors have been crystallized providing molecular details of the initial steps of infection. For KSHV, a variety of entry and binding receptors has also been reported but the mechanism how receptor binding activates gB-driven fusion is not as well understood as that for EBV. However, the downstream signaling pathways that promote the early steps of KSHV entry are well described. This review summarizes the current knowledge of the key players involved in EBV and KSHV entry and the cell-type specific mechanisms that allow infection of a wide variety of cell types.

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A Kaposi's Sarcoma-Associated Herpesvirus Infection Mechanism Is Independent of Integrins α3β1, αVβ3, and αVβ5

Cited by 27 publications

References 72 publications

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

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

Kaposi Sarcoma-Associated Herpesvirus Glycoprotein H Is Indispensable for Infection of Epithelial, Endothelial, and Fibroblast Cell Types

Gammaherpesvirus entry and fusion: A tale how two human pathogenic viruses enter their host cells

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