Human Cytomegalovirus-Encoded pUL7 Is a Novel CEACAM1-Like Molecule Responsible for Promotion of Angiogenesis

MacManiman, Jason D.; Meuser, Andrew; Botto, Sara; Smith, Patricia P.; Liu, Fenyong; Jarvis, Michael A.; Nelson, Jay A.; Caposio, Patrizia

doi:10.1128/mbio.02035-14

Cited by 35 publications

(50 citation statements)

References 44 publications

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“…Until now, 3-OS HS has been known to mediate herpes simplex virus (HSV) entry in primary cultures of corneal stroma derived from human eye donors (28). Since 3-OS HS facilitates HCMV infection, its further potential in overall disease development, especially in immune modulation or angiogenesis, can be further investigated using corneal endothelial cells (42). Several lines of evidence already suggest that sulfated HS plays a critical role during multiple pathophysiological processes, including inflammation and vascular angiogenesis (43)(44)(45).…”

Section: Expression Of 3-ost Enzymes In His Cells Enhances Fusion Witmentioning

confidence: 99%

A Role for 3- O -Sulfated Heparan Sulfate in Promoting Human Cytomegalovirus Infection in Human Iris Cells

Baldwin

Maus

Zanotti

et al. 2015

J Virol

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H uman cytomegalovirus (HCMV), a member of the betaherpesvirus family, is the leading cause of congenital neurological complications in neonates as a result of maternal infection (1-4). Among immunocompromised patients-especially those with an organ transplant, chemotherapy, or AIDS-the reactivation of virus causes life-threatening diseases, such as gastroenteritis, encephalitis, pneumonitis, and graft rejection (5-7). In addition, HCMV infection is also implicated in widespread ocular damage and potential vision loss from retinitis, anterior uveitis, and corneal endotheliitis (8-11). Because HCMV infection of the iris is a risk factor during anterior uveitis, understanding the dynamics of viral infection at the molecular level becomes relevant for understanding the viral pathogenesis in general and developing novel strategies to prevent blindness. Therefore, we used primary cultures of human iris stromal (HIS) cells as a model to determine the susceptibility and role of 3-O-sulfated heparan sulfate (3-OS HS) during HCMV uveitis.Although HCMV entry into host cells is poorly understood (12, 13), it is clearly a multistep process that requires complex interactions between viral envelope glycoproteins and the host cell receptors (12). It has been suggested that HCMV glycoprotein B (gB) binds to heparan sulfate (HS) during viral attachment, resulting in a high virion concentration at the cell surface and further binding to the cellular receptor (14-17). This interaction has been proposed to modulate immune responses (14, 18). To date, three receptors, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor ␣ (PDGFR␣), and cellular integrins (␣2␤1, ␣6␤1, and ␣v␤3), have been implicated during HCMV entry (19)(20)(21)(22)(23)(24). In addition, recent studies have suggested the potential role of a sulfated form of HS during HCMV entry. For instance, a library of peptides derived from human hemofiltrate and screened for inhibitory effects on HCMV infection implicated the role of 6-O-sulfated HS (6-OS HS) (25) in HCMV entry. Similarly, a peptide generated against 3-OS HS using phage display library screening blocked HCMV entry (26). In addition, several sulfated polysaccharides (dextran sulfate, pentosan polysulfate, and heparin), copolymers of acrylic acid with vinyl alcohol sulfate, and 3-O-sulfated saccharide have proved to be potent inhibitors of HCMV infectivity in vitro (17,27). In this study, we investigated the susceptibility of HIS cells to HCMV infection and the role of 3-OS HS during this process. Our data demonstrate the significance of 3-OS HS during HCMV entry, and we propose a unique in vitro model for future studies related to 3-OS HS-dependent induction of proinflammatory cytokines and virus tropism.Susceptibility of primary cultures of HIS cells to HCMV infection. The HIS cultures were prepared in accordance with institutional review board-approved protocols and were isolated from anonymously donated human eyes (provided by the Illinois Eye Bank, Chicago, IL) via sterile dissecti...

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Section: Expression Of 3-ost Enzymes In His Cells Enhances Fusion Witmentioning

confidence: 99%

A Role for 3- O -Sulfated Heparan Sulfate in Promoting Human Cytomegalovirus Infection in Human Iris Cells

Baldwin

Maus

Zanotti

et al. 2015

J Virol

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“…Although various HCMV proteins increase GBM cell proliferation, invasion, and angiogenesis (20,21), a mechanistic link between HCMV and cancer in vivo has not been established, and the role of HCMV in GBM remains a subject of debate, with some groups unable to detect the presence of CMV in tumor specimens (22,23). The use of mouse models to investigate the role of CMV in tumor growth would therefore be helpful in understanding the potential importance of CMV in GBM as well as providing an opportunity to rationally investigate antiviral therapeutic approaches.…”

Section: Introductionmentioning

confidence: 99%

Cytomegalovirus promotes murine glioblastoma growth via pericyte recruitment and angiogenesis

Krenzlin¹,

Behera²,

Lorenz³

et al. 2019

Journal of Clinical Investigation

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“…Furthermore, we showed that, when ectopically expressed, UL7 attenuates the production of tumor necrosis factor alpha (TNF-␣), IL-8, and IL-6 in primary monocyte-derived dendritic cells. Subsequent studies by MacManiman and coworkers (22) have indicated that soluble UL7 could be involved in inducing endothelial cell angiogenesis. Lastly and more recently, another RL11 gene family member, the UL10 gene, also has been reported to encode a soluble protein able to interfere with the activation, proliferation, and cytokine production of T cells (23).…”

mentioning

confidence: 98%

A Prominent Role of the Human Cytomegalovirus UL8 Glycoprotein in Restraining Proinflammatory Cytokine Production by Myeloid Cells at Late Times during Infection

Pérez-Carmona

Martínez-Vicente

Farré

et al. 2018

J Virol

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Human cytomegalovirus (HCMV) persistence in infected individuals relies on a plethora of mechanisms to efficiently reduce host immune responses. To that end, HCMV commits a variety of gene products, some of which have not been identified yet. Here we characterized the gene, which consists of two exons, sharing the first with the HCMV RL11 family member UL8 is a transmembrane protein with an N-terminal immunoglobulin (Ig)-like domain in common with UL7 but with an extended stalk and a distinctive cytoplasmic tail. The open reading frame gives rise to a heavily glycosylated protein, predominantly expressed on the cell surface, from where it can be partially endocytosed and subsequently degraded. Infections with UL8-tagged viruses indicated that UL8 was synthesized with late phase kinetics. By virtue of its highly conserved Ig-like domain, this viral protein interacted with a surface molecule present on activated neutrophils. Notably, when ectopically expressed in THP-1 myeloid cells, UL8 was able to significantly reduce the production of a variety of pro-inflammatory cytokines. Mutations in UL8 indicated that this functional effect was mediated by the cell surface expression of its Ig-like domain. To investigate the impact of the viral protein in the infection context, we engineered HCMVs lacking the gene, and demonstrated that UL8 decreases the release of a large number of pro-inflammatory factors at late times after infection of THP-1 cells. Our data indicate that UL8 may exert an immunosuppressive role key for HCMV survival in the host. Human cytomegalovirus (HCMV) is a major pathogen that causes life-threatening diseases and disabilities in infected newborns and immunocompromised individuals. Containing one of the largest genomes among all reported human viruses, HCMV encodes an impressive repertoire of gene products. However, the functions of a large proportion of them remain still unknown, a fact that complicates the design of new therapeutic approaches to prevent or treat HCMV associated diseases. In this report, we have conducted an extensive study of , one of the previously uncharacterized HCMV open reading frames. We found that the UL8 protein is expressed at late times post infection and utilized by HCMV to reduce the production of pro-inflammatory factors by infected myeloid cells. Thus, the work presented here points to a key role of UL8 as a novel HCMV immune modulator capable to restrain host antiviral defenses.

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Human Cytomegalovirus-Encoded pUL7 Is a Novel CEACAM1-Like Molecule Responsible for Promotion of Angiogenesis

Cited by 35 publications

References 44 publications

A Role for 3- O -Sulfated Heparan Sulfate in Promoting Human Cytomegalovirus Infection in Human Iris Cells

A Role for 3- O -Sulfated Heparan Sulfate in Promoting Human Cytomegalovirus Infection in Human Iris Cells

Cytomegalovirus promotes murine glioblastoma growth via pericyte recruitment and angiogenesis

A Prominent Role of the Human Cytomegalovirus UL8 Glycoprotein in Restraining Proinflammatory Cytokine Production by Myeloid Cells at Late Times during Infection

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