Analysis of host response modifier ORFs of ectromelia virus, the causative agent of mousepox

Chen, Nanhai; Buller, R. Mark; Wall, Erika M.; Upton, Chris

doi:10.1016/s0168-1702(99)00135-5

Cited by 25 publications

(24 citation statements)

References 74 publications

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“…These and earlier studies (14,22,23,47,52,68,69) cytokine response modifier B (CrmB) (38), CrmC (65), and CrmE (62), whose activities overlap to some extent those of CrmD, the sole vTNFR identified in EV (47,62). All of the factors are expressed by all of the EV isolates examined to date (68,69), with the exception of EV Mill Hill, a laboratorypassaged derivative of EV Hampstead that lacks a functional vCKBP (68).…”

Section: Discussionmentioning

confidence: 81%

“…We amplified the region of the EV Hampstead and EV Naval genomes containing the EV vIFN-␣/␤R gene by PCR and sequenced the PCR products using flanking and internal oligonucleotide primers. The predicted amino acid sequences of the EV Hampstead and Naval vIFN-␣/␤Rs were compared with published vIFN-␣/␤R sequences from EV Moscow (22), VaV (strain Bangladesh 1975 [BSH]) (49), CPV strain GRI-90 (64), and VV WR (67) (Fig. 5).…”

Section: Methodsmentioning

confidence: 99%

“…Binding and sequencing studies have indicated that the Moscow strain of EV expresses homologs of the OPV vIFN-␣/␤R and vIFN-␥R (22,23,52), but nothing is known of their ability to block the biological activities of mouse IFNs.…”

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confidence: 99%

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Inhibition of Interferons by Ectromelia Virus

Smith

Alcamı́

2002

J Virol

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Section: Discussionmentioning

confidence: 81%

Section: Methodsmentioning

confidence: 99%

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Inhibition of Interferons by Ectromelia Virus

Smith

Alcamı́

2002

J Virol

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“…ECTV IFN-␥bp is a 266-amino-acid glycoprotein that exists both within the infected cell and as a secreted molecule (1,8,9,33). It binds with very high affinity to murine and human IFN-␥ and prevents ligation of the cytokine with specific cell surface receptors (31,40).…”

mentioning

confidence: 99%

Poxvirus-Encoded Gamma Interferon Binding Protein Dampens the Host Immune Response to Infection

Sakala

Chaudhri

Buller

et al. 2007

J Virol

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Ectromelia virus (ECTV), a natural mouse pathogen and the causative agent of mousepox, is closely related to variola virus (VARV), which causes smallpox in humans. Mousepox is an excellent surrogate small-animal model for smallpox. Both ECTV and VARV encode a multitude of host response modifiers that target components of the immune system and that are thought to contribute to the high mortality rates associated with infection. Like VARV, ECTV encodes a protein homologous to the ectodomain of the host gamma interferon (IFN-␥) receptor 1. We generated an IFN-␥ binding protein (IFN-␥bp) deletion mutant of ECTV to study the role of viral IFN-␥bp (vIFN-␥bp) in host-virus interaction and also to elucidate the contribution of this molecule to the outcome of infection. Our data show that the absence of vIFN-␥bp does not affect virus replication per se but does have a profound effect on virus replication and pathogenesis in mice. BALB/c mice, which are normally susceptible to infection with ECTV, were able to control replication of the mutant virus and survive infection. Absence of vIFN-␥bp from ECTV allowed the generation of an effective host immune response that was otherwise diminished by this viral protein. Mice infected with a vIFN-␥bp deletion mutant virus, designated ECTV-IFN-␥bp⌬ , produced increased levels of IFN-␥ and generated robust cell-mediated and antibody responses. Using several strains of mice that exhibit differential degrees of resistance to mousepox, we show that recovery or death from ECTV infection is determined by a balance between the host's ability to produce IFN-␥ and the virus' ability to dampen its effects.

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“…The poxvirus genome contains ϳ200 distinct open reading frames (ORFs), 25% of which are "nonessential" for virus replication in cell culture (25); however, these ORFs are believed to play an important role in establishing productive viral infec- FIG. 4.…”

Section: Discussionmentioning

confidence: 99%

The Poxvirus p28 Virulence Factor Is an E3 Ubiquitin Ligase

Huang

Zhou

et al. 2004

Journal of Biological Chemistry

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A majority of the orthopoxviruses, including the variola virus that causes the dreaded smallpox disease, encode a highly conserved 28-kDa protein with a classic RING finger sequence motif (C 3 HC 4 ) at their carboxylterminal domains. The RING domain of p28 has been shown to be a critical determinant of viral virulence for the ectromelia virus (mousepox virus) in a murine infection model (Senkevich, T. G., Koonin, E. V., and Buller, R. M. (1994) Virology 198, 118 -128). Here, we demonstrate that the p28 proteins encoded by the ectromelia virus and the variola virus possess E3 ubiquitin ligase activity in biochemical assays as well as in cultured mammalian cells. Point mutations disrupting the RING finger domain of p28 completely abolish its E3 ligase activity. In addition, p28 functions cooperatively with Ubc4 and UbcH5c, the E2 conjugating enzymes involved in 26 S proteasome degradation of protein targets. Moreover, p28 catalyzes the formation of Lys-63-linked polyubiquitin chains in the presence of Ubc13/Uev1A, a heterodimeric E2 conjugating enzyme, indicating that p28 may regulate the biological activity of its cognate viral and/or host cell target(s) by Lys-63-linked ubiquitin multimers. We thus conclude that the poxvirus p28 virulence factor is a new member of the RING finger E3 ubiquitin ligase family and has a unique polyubiquitylation activity. We propose that the E3 ligase activity of the p28 virulence factor may be targeted for therapeutic intervention against infections by the variola virus and other poxviruses.

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Analysis of host response modifier ORFs of ectromelia virus, the causative agent of mousepox

Cited by 25 publications

References 74 publications

Inhibition of Interferons by Ectromelia Virus

Inhibition of Interferons by Ectromelia Virus

Poxvirus-Encoded Gamma Interferon Binding Protein Dampens the Host Immune Response to Infection

The Poxvirus p28 Virulence Factor Is an E3 Ubiquitin Ligase

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