A Small Molecule Inhibits Virion Attachment to Heparan Sulfate- or Sialic Acid-Containing Glycans

Colpitts, Che C.; Schang, Luis M.

doi:10.1128/jvi.00896-14

Cited by 127 publications

(126 citation statements)

References 70 publications

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“…The primary cultures used in the present study are relevant to further investigate the permissiveness to HCMV since they are derived from human eye donors. Future screening of a library of small molecules or peptide-targeting sulfate moieties on HIS cells will likely advance our current understanding of HCMV cell-specific interactions and the development of novel inhibitors (39,40). Similarly, understanding the involvement of 3-OS HS for the induction of proinflammatory cytokines is worth investigating.…”

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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“…These results reinforce the conclusion that ESCd are significantly more susceptible to ZIKV U than to ZIKV C . Discussion ZIKV entry into target cells is a complex, multistep process and has implicated several host molecules, including the TAM receptors, HAVCR1 (the hepatitis C receptor, sometimes known as TIM1 or TIMD1), CD209 (DC-SIGN1), attendant linker proteins PROS1 and GAS6 that associate with phosphatidylserine on the capsid surface, and proteoglycans, especially heparan sulfates that appear to form the primary attachment sites for many kinds of viruses (45)(46)(47)(48), including DENV2 (49). Villous trophoblast cells obtained from term placentas, which are resistant to a wide range of viruses (23), including ZIKV (24), appear to lack most, if not all, these candidate attachment factors ( Fig.…”

Section: Release Of Infection-competent Virus By Esc and Esc-derived mentioning

confidence: 99%

Vulnerability of primitive human placental trophoblast to Zika virus

Sheridan

Yunusov

Balaraman

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

157

155

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Infection of pregnant women by Asian lineage strains of Zika virus (ZIKV) has been linked to brain abnormalities in their infants, yet it is uncertain when during pregnancy the human conceptus is most vulnerable to the virus. We have examined two models to study susceptibility of human placental trophoblast to ZIKV: cytotrophoblast and syncytiotrophoblast derived from placental villi at term and colonies of trophoblast differentiated from embryonic stem cells (ESC). The latter appear to be analogous to the primitive placenta formed during implantation. The cells from term placentas, which resist infection, do not express genes encoding most attachment factors implicated in ZIKV entry but do express many genes associated with antiviral defense. By contrast, the ESC-derived trophoblasts possess a wide range of attachment factors for ZIKV entry and lack components of a robust antiviral response system. These cells, particularly areas of syncytiotrophoblast within the colonies, quickly become infected, produce infectious virus and undergo lysis within 48 h after exposure to low titers (multiplicity of infection > 0.07) of an African lineage strain (MR766 Uganda: ZIKVU) considered to be benign with regards to effects on fetal development. Unexpectedly, lytic effects required significantly higher titers of the presumed more virulent FSS13025 Cambodia (ZIKVC). Our data suggest that the developing fetus might be most vulnerable to ZIKV early in the first trimester before a protective zone of mature villous trophoblast has been established. Additionally, MR766 is highly trophic toward primitive trophoblast, which may put the early conceptus of an infected mother at high risk for destruction.

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“…Epigallocatechin gallate (EGCG), a green tea catechin, was recently shown to be able to block HAdV attachment to the host receptors at low micromolar concentration [75]. This small molecule competes with heparan sulfate and sialic acid for binding many unrelated enveloped and nonenveloped viruses.…”

Section: Adenovirus Entrymentioning

confidence: 99%