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:10.1101/270108

Cited by 9 publications

(6 citation statements)

References 74 publications

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“…EphA4 is widely expressed in different tissues and cell types (3). Using RNA-seq analysis we 244 found that EphA4 is expressed in B cells, fibroblasts, epithelial cells, and endothelial cells ( an integrin-independent route of KSHV infection and also suggests that multiple Eph receptors 253 besides EphA2 can promote and regulate infection, consistent with our findings (11). 254…”

supporting

confidence: 81%

Ephrin receptor A4 (EphA4) is a new Kaposi’s sarcoma-associated herpesvirus virus entry receptor

Chen¹,

Zhang²,

Schaller³

et al. 2019

Preprint

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20Kaposi's sarcoma-associated herpesvirus (KSHV) is a human -herpesvirus associated with the 21 development of Kaposi's sarcoma (KS). KSHV target cells include endothelial cells, B cells, 22 monocytes, epithelial cells, dendritic cells, macrophages, and fibroblasts. KSHV entry into target 23 cells is a complex multistep process and is initiated by the binding and interaction of viral envelope 24 glycoproteins with the cellular receptors. In our current studies, we have found that EphA4 promotes 25 KSHV gH/gL-mediated fusion and infection better than EphA2 in HEK293T cells indicating that 26EphA4 is a new KSHV entry receptor. To confirm that epithelial cells express EphA2 and EphA4, we 27 analyzed the expression of EphA2 and EphA4 in epithelial cells, endothelial cells, B cells, 28 monocytes, fibroblasts using RNA-seq data analysis of existing data sets. We found these cell types 29 broadly express both EphA2 and EphA4 with the exception of monocytes and B cells. To confirm 30EphA4 is important for KSHV fusion and infection, we generated EphA2 and EphA4 single and 31 double knockout cells. We found that both EphA2 and EphA4 play a role in KSHV fusion and 32 infection, since EphA2/EphA4 double knockout cells had the greatest decrease in fusion activity and 33 infection compared to single knockout cells. Fusion and infection of KSHV was rescued in the 34 EphA2/EphA4 double knock cells upon overexpression of EphA2 and/or EphA4. EphA2 binds to 35 both EBV and KSHV gH/gL; however, EphA4 binds only to KSHV gH/gL. Taken together, our 36 results identify EphA4 as a new entry receptor for KSHV. 37 38 Importance. The overall entry mechanism for herpesviruses is not completely known including 39 that for the human -herpesviruses Kaposi's sarcoma-associated herpesvirus (KSHV) and 40Epstein-Barr virus (EBV). To fully understand the herpesvirus entry process, functional receptors 41 need to be identified. In our current study, we found that EphA4 can also function for a KSHV 42 3 entry receptor along with EphA2. Interestingly, we found that EphA4 does not function as an entry 43 receptor for EBV whereas EphA2 does. The discovery of EphA4 as KSHV entry receptor has 44 important implications for KSHV pathogenesis in humans and may prove useful in understanding the 45 unique pathogenesis of KSHV infection in humans and may uncover new potential targets that can be 46 used for the development of novel interventional strategies. 47 48 49 50 51 Herpesviruses are enveloped double-stranded DNA viruses capable of infecting a wide range of 52 hosts and cause a variety of diseases (1). There are nine human herpesviruses that infect humans 53 establishing lifelong latent infections (2). The -herpesviruses Kaposi's sarcoma-associated 54 herpesvirus (KSHV) and Epstein-Barr virus (EBV) are associated with human cancer (1, 3). Kaposi's 55 sarcoma (KS) is a cancer that develops from the endothelium that lines lymph or blood vessels. It 56 usually appears as tumors on the skin or on mucosal surfaces such as inside the mouth, lungs, liver, 57 ...

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supporting

confidence: 81%

Ephrin receptor A4 (EphA4) is a new Kaposi’s sarcoma-associated herpesvirus virus entry receptor

Chen¹,

Zhang²,

Schaller³

et al. 2019

Preprint

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“…Although it was shown that host cell entry, assembly and release of various viruses are mediated by the Tspans in a dependent or independent manner (through their partners such as integrins), there is currently no evidence, other than the FimH/Tspan21 complex, that bacteria interact with Tspans directly. The major function of Tspans during bacterial infection may rely on connecting bacterial ligands to additional surface proteins belonging to TEMs platforms, such as integrins (Rajan et al, 2018; Storm et al, 2017; TerBush, Hafkamp, Lee, & Coscoy, 2018). Thus, further work is required to unravel the contribution of individual Tspans or their cognate partners in the different processes leading to bacterial colonisation of the host.…”

Section: Discussionmentioning

confidence: 99%

The roles of tetraspanins in bacterial infections

Karam

Méresse

Kremer

et al. 2020

Cellular Microbiology

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Tetraspanins, a wide family composed of 33 transmembrane proteins, are associated with different types of proteins through which they arbitrate important cellular processes such as fusion, adhesion, invasion, tissue differentiation and immunological responses. Tetraspanins share a comparable structural design, which consists of four hydrophobic transmembrane domains with cytoplasmic and extracellular loops. They cooperate with different proteins, including other tetraspanins, receptors or signalling proteins to compose functional complexes at the cell surface, designated tetraspanin‐enriched microdomains (TEM). Increasing evidences establish that tetraspanins are exploited by numerous intracellular pathogens as a doorway for entering and replicating within human cells. Although previous surveys focused mainly on viruses and parasites, it is now becoming clear that bacteria interact with tetraspanins, using TEM as a “gateway” to infection. In this review, we examine the biological functions of tetraspanins that are relevant to bacterial infective procedures and consider the available data that reveal how different bacteria benefit from host cell tetraspanins in infection and in the pathogenesis of diseases. We will also emphasise the stimulating potentials of targeting tetraspanins for preventing bacterial infectious diseases, using specific neutralising antibodies or anti‐adhesion peptide‐based therapies. Such innovative therapeutic opportunities may deliver alternatives for fighting difficult‐to‐manage and drug‐resistant bacterial pathogens.

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“…Because EphA2 recognizes b-glucans on pathogenic fungi other than C. albicans, such as Aspergillus fumigatus and Rhizopus oryzae (Swidergall et al, 2018), it is probable that it enhances the neutrophil response to these organisms too. Moreover, EphA2 has been found to recognize Plasmodium, Chlamydia trachomatis, and several viruses (Chen et al, 2018;Kaushansky et al, 2015;Lupberger et al, 2011;Subbarayal et al, 2015;TerBush et al, 2018;Zhang et al, 2018). However, the studies with these organisms were performed using normally nonphagocytic host cells, such as hepatocytes or epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

EphA2 Is a Neutrophil Receptor for Candida albicans that Stimulates Antifungal Activity during Oropharyngeal Infection

et al. 2019

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SUMMARY During oropharyngeal candidiasis (OPC), Candida albicans proliferates and invades the superficial oral epithelium. Ephrin type-A receptor 2 (EphA2) functions as an oral epithelial cell β-glucan receptor that triggers the production of proinflammatory mediators in response to fungal infection. Because EphA2 is also expressed by neutrophils, we investigated its role in neutrophil candidacidal activity during OPC. We found that EphA2 on stromal cells is required for the accumulation of phagocytes in the oral mucosa of mice with OPC. EphA2 on neutrophils is also central to host defense against OPC. The interaction of neutrophil EphA2 with serum- opsonized C. albicans yeast activates the MEK-ERK signaling pathway, leading to NADPH subunit p47 phox site-specific phospho-priming. This priming increases intracellular reactive oxygen species production and enhances fungal killing. Thus, in neutrophils, EphA2 serves as a receptor for β-glucans that augments Fcγ receptor-mediated antifungal activity and controls early fungal proliferation during OPC.

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

Cited by 9 publications

References 74 publications

Ephrin receptor A4 (EphA4) is a new Kaposi’s sarcoma-associated herpesvirus virus entry receptor

Ephrin receptor A4 (EphA4) is a new Kaposi’s sarcoma-associated herpesvirus virus entry receptor

The roles of tetraspanins in bacterial infections

EphA2 Is a Neutrophil Receptor for Candida albicans that Stimulates Antifungal Activity during Oropharyngeal Infection

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