Viral Heparin-Binding Complement Inhibitors – A Recurring Theme

Blom, Anna M.; Mark, Linda; Spiller, O. Brad

doi:10.1007/978-0-387-71767-8_9

Cited by 6 publications

(5 citation statements)

References 96 publications

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“…Therefore, RCP may lack one important function of KCP, and in vivo experiments with RRV lacking RCP will specifically assess only the role of viral complement inhibitors of RCP as immune regulators. Furthermore, RCP is the first complement inhibitor described to date that is not able to bind heparin, negating a hypothesis that structural properties of binding sites for C3b and C4b inadvertently create interaction sites for heparin (34). Therefore, binding of heparin is obviously a specific event for these inhibitors.…”

Section: Discussionmentioning

confidence: 94%

Characterization of the Complement Inhibitory Function of Rhesus Rhadinovirus Complement Control Protein (RCP)

Okrój

Mark

Stokowska

et al. 2009

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 94%

Characterization of the Complement Inhibitory Function of Rhesus Rhadinovirus Complement Control Protein (RCP)

Okrój

Mark

Stokowska

et al. 2009

Journal of Biological Chemistry

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“…The binding to heparin and related GAGs by SPICE is a functional attribute that provides a mechanism for a secreted virulence factor to anchor to host tissues, the microbe itself, and infected cells (35). This scenario is analogous to that of factor H, a major regulator of the alternative pathway (reviewed in Ref.…”

Section: Discussionmentioning

confidence: 99%

“…SPICE binds to multiple cell types via heparin and related sulfated GAGs and inhibits complement regulation similarly to related host regulators (34). Heparin binding is likely an important functional feature by providing a means for a secreted regulator to anchor to host cells, viruses, or virally infected cells where it can then down-regulate complement (33, 35). …”

mentioning

confidence: 99%

Smallpox Inhibitor of Complement Enzymes (SPICE): Dissecting Functional Sites and Abrogating Activity

Liszewski

Leung

Hauhart

et al. 2009

The Journal of Immunology

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Although smallpox was eradicated as a global illness more than 30 years ago, variola virus and other related pathogenic poxviruses, such as monkeypox, remain potential bioterrorist weapons or could re-emerge as natural infections. Poxviruses express virulence factors that down-modulate the host’s immune system. We previously compared functional profiles of the poxviral complement inhibitors of smallpox, vaccinia, and monkeypox known as SPICE, VCP (or VICE), and MOPICE, respectively. SPICE was the most potent regulator of human complement and attached to cells via glycosaminoglycans. The major goals of the present study were to further characterize the complement regulatory and heparin binding sites of SPICE and to evaluate a mAb that abrogates its function. Using substitution mutagenesis, we established that (1) elimination of the three heparin binding sites severely decreases but does not eliminate glycosaminoglycan binding, (2) there is a hierarchy of activity for heparin binding among the three sites, and (3) complement regulatory sites overlap with each of the three heparin binding motifs. By creating chimeras with interchanges of SPICE and VCP residues, a combination of two SPICE amino acids (H77 plus K120) enhances VCP activity ∼200-fold. Also, SPICE residue L131 is critical for both complement regulatory function and accounts for the electrophoretic differences between SPICE and VCP. An evolutionary history for these structure-function adaptations of SPICE is proposed. Finally, we identified and characterized a mAb that inhibits the complement regulatory activity of SPICE, MOPICE, and VCP and thus could be used as a therapeutic agent.

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“…Murid Herpesvirus-4 (MuHV-4) is highly dependent on GAGs for cell binding and infection [1]. Its ORF4 encodes a strong GAG-binding virion glycoprotein, gp70 [2], which is homologous to the Kaposi's Sarcoma-associated Herpesvirus ORF4 gene product [3], and analogous to the Herpes Simplex virus gC [4]: all are complement control proteins that also bind to GAGs [5]. But if a need for GAG binding by gp70 explained MuHV-4 GAG-dependence, then gp70-deficient MuHV-4 should bind poorly to GAG + cells, much as the wild-type binds poorly to GAG − cells [6].…”

Section: Introductionmentioning

confidence: 99%

The Murid Herpesvirus-4 gH/gL Binds to Glycosaminoglycans

2008

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The first contact a virus makes with cells is an important determinant of its tropism. Murid Herpesvirus-4 (MuHV-4) is highly dependent on glycosaminoglycans (GAGs) for cell binding. Its first contact is therefore likely to involve a GAG-binding virion glycoprotein. We have previously identified two such proteins, gp70 and gp150. Gp70 binds strongly to GAGs. However, deleting it makes little difference to MuHV-4 cell binding or GAG-dependence. Deleting gp150, by contrast, frees MuHV-4 from GAG dependence. This implies that GAGs normally displace gp150 to allow GAG-independent cell binding. But the gp150 GAG interaction is weak, and so would seem unlikely to make an effective first contact. Since neither gp70 nor gp150 matches the expected profile of a first contact glycoprotein, our understanding of MuHV-4 GAG interactions must be incomplete. Here we relate the seemingly disconnected gp70 and gp150 GAG interactions by showing that the MuHV-4 gH/gL also binds to GAGs. gH/gL-blocking and gp70-blocking antibodies individually had little effect on cell binding, but together were strongly inhibitory. Thus, there was redundancy in GAG binding between gp70 and gH/gL. Gp150-deficient MuHV-4 largely resisted blocks to gp70 and gH/gL binding, consistent with its GAG independence. The failure of wild-type MuHV-4 to do the same argues that gp150 is normally engaged only down-stream of gp70 or gH/gL. MuHV-4 GAG dependence is consequently two-fold: gp70 or gH/gL binding provides virions with a vital first foothold, and gp150 is then engaged to reveal GAG-independent binding.

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Viral Heparin-Binding Complement Inhibitors – A Recurring Theme

Cited by 6 publications

References 96 publications

Characterization of the Complement Inhibitory Function of Rhesus Rhadinovirus Complement Control Protein (RCP)

Characterization of the Complement Inhibitory Function of Rhesus Rhadinovirus Complement Control Protein (RCP)

Smallpox Inhibitor of Complement Enzymes (SPICE): Dissecting Functional Sites and Abrogating Activity

The Murid Herpesvirus-4 gH/gL Binds to Glycosaminoglycans

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