Cellular Receptors Involved in KSHV Infection

Meulen, Emma van der; Anderton, Meg; Blumenthal, Melissa J.; Schäfer, Georgia

doi:10.3390/v13010118

Cited by 12 publications

(13 citation statements)

References 87 publications

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“…KSHV infection is a complicated and multistep process involving the interaction of multiple viral glycoproteins with host receptors. KSHV infection in different target cells except for MSCs have been intensively investigated (14,15), and the receptors mediating KSHV entry in these cells, including integrins (16), Ephrin receptor family (17)(18)(19), Cystine/glutamate transporter (xCT) (20), and Dendritic cell-specific ICAM-3-grabbing non-integrin 1 (DC-SIGN) (21), have been identified. Although MSCs are highly susceptible to KSHV infection, how KSHV enters MSCs has not been explored yet.…”

Section: Introductionmentioning

confidence: 99%

Neuropilin 1 is an entry receptor for KSHV infection of mesenchymal stem cell through TGFBR1/2-mediated macropinocytosis

Lu,

Sun,

Zhang

et al. 2023

Sci. Adv.

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Kaposi’s sarcoma–associated herpesvirus (KSHV) has been implicated in the pathogenesis of Kaposi’s sarcoma (KS) and other malignancies. The cellular origin of KS has been suggested to be either mesenchymal stem cells (MSCs) or endothelial cells. However, receptor(s) for KSHV to infect MSCs remains unknown. By combining bioinformatics analysis and shRNA screening, we identify neuropilin 1 (NRP1) as an entry receptor for KSHV infection of MSCs. Functionally, NRP1 knockout and overexpression in MSCs significantly reduce and promote, respectively, KSHV infection. Mechanistically, NRP1 facilitated the binding and internalization of KSHV by interacting with KSHV glycoprotein B (gB), which was blocked by soluble NRP1 protein. Furthermore, NRP1 interacts with TGF-β receptor type 2 (TGFBR2) through their respective cytoplasmic domains and thus activates the TGFBR1/2 complex, which facilitates the macropinocytosis-mediated KSHV internalization via the small GTPases Cdc42 and Rac1. Together, these findings implicate that KSHV has evolved a strategy to invade MSCs by harnessing NRP1 and TGF-beta receptors to stimulate macropinocytosis.

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Section: Introductionmentioning

confidence: 99%

Neuropilin 1 is an entry receptor for KSHV infection of mesenchymal stem cell through TGFBR1/2-mediated macropinocytosis

Lu,

Sun,

Zhang

et al. 2023

Sci. Adv.

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“…Natural transmission of KSHV most likely occurs through salivary and sexual transmission or during transplantation of KSHV-positive organs into a naïve recipient although initial KSHV infection is normally asymptomatic (Cesarman et al, 2019; Dittmer and Damania, 2019). In experimental settings, KSHV has been shown to infect various types of cell lines and primary cells such as epithelial cells and immune cells that include B cells, monocytes, and dendritic cells through binding to specific cell surface receptors such as Siglec DC-SIGN (Decker et al, 1996; Gregory et al, 2012; Rappocciolo et al, 2006; Staskus et al, 1997; van der Meulen et al, 2021). However, it remains unclear as to whether KSHV may preferentially infect a certain cell type among PBMC.…”

Section: Introductionmentioning

confidence: 99%

KSHV uses viral IL6 to expand infected immunosuppressive macrophages

Shimoda

Inagaki

Davis

et al. 2023

Preprint

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Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus and the etiologic agent of Kaposi’s sarcoma and hyperinflammatory lymphoproliferative disorders. Understanding the mechanism by which KSHV increases the infected cell population is crucial for curing KSHV-associated diseases. Here we demonstrate that KSHV preferentially infects CD14+monocytes and sustains viral replication through the viral (v)IL6-mediated activation of STAT1 and 3. Using vIL6-sufficient and vIL6-deficient recombinant KSHV, we demonstrated that vIL6 plays a critical role in promoting the proliferation and differentiation of KSHV-infected monocytes into macrophages. Those macrophages from vIL6-sufficient (wild type) KSHV infection showed a distinct transcriptional profile of elevated IFN-pathway activation with immune suppression and were compromised in T-cell stimulation function compared to those from vIL6-deficient KSHV infection or uninfected control. These results highlight a clever strategy, in which KSHV utilizes vIL6 to secure its initial viral pool by expanding infected dysfunctional macrophages. This mechanism also facilitates KSHV to escape from host immune surveillance to establish a lifelong infection.SummaryKSHV causes multiple inflammatory diseases, however, the mechanism is not clear. Shimoda et al. demonstrate that KSHV preferentially infects monocytes and utilizes virally encoded IL6 to expand and deregulate infected monocytes. This helps the virus escape from host immune surveillance.

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“…EBV infects B lymphocytes, epithelial cells, T lymphocytes, NK cells, monocytes, smooth muscle cells and follicular dendritic cells using CD21, HLA-II, integrins and EphA2 for attachment, internalization and entry [34]. KSHV infects endothelial cells, broblasts, monocytes, epithelial cells, B lymphocytes, macrophages and dendritic cells using HSPGs, DC-SIGN, EphAs and integrins for attachment and entry [35].…”

Section: Discussionmentioning

confidence: 99%

Comparison of Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus viral load in peripheral blood mononuclear cells and oral fluids of HIV-negative individuals aged 3 to 89 years from Uganda

Nalwoga

Marshall

Miley

et al. 2023

Preprint

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We previously found that age, sex, and malaria were associated with KSHV viral load in individuals from Uganda. In this study, we have evaluated factors associated with presence of EBV DNA in blood and oral fluids among the same individuals, using the same biological samples. Overall, 74% of oral fluids samples and 46% of PBMCs had detectable EBV, compared to 24% and 11% for KSHV respectively Individuals with EBV in PBMCs were more likely to have KSHV in PBMCs (P=0.016). The peak age for detection of EBV in oral fluids was 3-5 years while that of KSHV was 6-12 years. In PBMCs, the peak age for detection of EBV was 66+ years and KSHV was 3-5 years. Individuals with malaria had higher levels of EBV in PBMCs compared to malaria-negative individuals (P=0.002). In summary, our results show that younger age and malaria are associated with higher levels of EBV and KSHV in PBMCs suggesting malaria impacts immunity to EBV and KSHV.

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Cellular Receptors Involved in KSHV Infection

Cited by 12 publications

References 87 publications

Neuropilin 1 is an entry receptor for KSHV infection of mesenchymal stem cell through TGFBR1/2-mediated macropinocytosis

Neuropilin 1 is an entry receptor for KSHV infection of mesenchymal stem cell through TGFBR1/2-mediated macropinocytosis

KSHV uses viral IL6 to expand infected immunosuppressive macrophages

Comparison of Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus viral load in peripheral blood mononuclear cells and oral fluids of HIV-negative individuals aged 3 to 89 years from Uganda

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