Inhibition of Interferons by Ectromelia Virus

Smith, Vincent P.; Alcamı́, Antonio

doi:10.1128/jvi.76.3.1124-1134.2002

Cited by 59 publications

(66 citation statements)

References 81 publications

(108 reference statements)

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“…The latter strains make little or no IFN-␥, respectively. The importance of type I͞II IFN in ECTV infection is further highlighted by the fact that the virus itself encodes secreted receptors for IFN-␣͞␤ (14) and IFN-␥ (15,16), which bind to and modulate cytokine function. Many other poxviruses adopt similar strategies to counteract the host IFN response, most notably myxoma virus (19), vaccinia virus (16), and VARV (29).…”

Section: Discussionmentioning

confidence: 99%

“…This importance is further underscored by the fact that the virus, a natural mouse pathogen that has coevolved with the host, itself encodes viral homologs of secreted receptors for IFN-␣͞␤ (14) and IFN-␥ (15,16). These molecules are not unique to ECTV, because variola virus (VARV) and several other poxviruses also encode receptor homologs that bind to host IFN and modulate their signaling pathways.…”

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confidence: 99%

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Interferon function is not required for recovery from a secondary poxvirus infection

Panchanathan

Chaudhri

Karupiah

2005

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

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IFN function is critical for recovery from most primary viral infections, including poxvirus infection. In contrast, very little is known about the requirement for IFN function in mediating recovery from a secondary virus infection. We have used ectromelia virus (ECTV), an orthopoxvirus very closely related to variola virus, to investigate the importance of IFN function in recovery from a secondary infection. Variola virus, the causative agent of smallpox in humans, and ECTV, which causes mousepox in mice, both encode receptor homologs that are thought to interfere with host IFN function. Using a prime-challenge regime, in which avirulent ECTV is used to prime mice deficient in type I͞II IFN function or IFN regulatory factor 1 (IRF-1) and then challenging the mice with a virulent strain, we show that IFN function is redundant for virus clearance during a secondary ECTV infection. A neutralizing Ab response is generated in a secondary infection, even in the absence of IFN function, although when present, IFN strongly influences the neutralizing titer and subtype of IgG that is produced. Importantly, the depletion of CD8 ؉ T lymphocytes during a secondary challenge in IFN-deficient mice does not affect their capacity to clear ECTV, indicating that Ab is critical for the control of a secondary infection. (5), CD8 ϩ T cell numbers and survival (6), natural killer cell activity (7), and generation of a T helper 1-type of cytokine response (8), all of which are known to be crucial for recovery from a primary ectromelia virus (ECTV) infection (9-11).The importance of type I͞II IFN for the recovery of mice from a primary ECTV infection has been extensively studied through the use of IFN receptor-or ligand-deficient animals and IFNdepleting Ab (11-13). This importance is further underscored by the fact that the virus, a natural mouse pathogen that has coevolved with the host, itself encodes viral homologs of secreted receptors for IFN-␣͞␤ (14) and 16). These molecules are not unique to ECTV, because variola virus (VARV) and several other poxviruses also encode receptor homologs that bind to host IFN and modulate their signaling pathways. Recently, by using vaccinia virus recombinants encoding type III IFN (IFN-2 or IFN-3), Bartlett et al. (17) have shown that this class of IFN exhibits antiviral activity in mice.Our understanding of the pathogenesis of smallpox in humans comes from studies in animal models, such as monkeypox and mousepox. The need to rely on animal models is largely due to the fact that smallpox was eradicated before the recent advances in molecular biology, virology, and immunology. However, we are still lacking in our knowledge about the determinants of the immune response that would result in recovery after infection and those that would protect against reinfection or infection after vaccination in humans. Mousepox has been extensively studied and is arguably one of the best available small animal models to examine the immune response to poxvirus infections. Like VARV, ECTV has coevolved with its na...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Interferon function is not required for recovery from a secondary poxvirus infection

Panchanathan

Chaudhri

Karupiah

2005

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

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“…Both VARV and ECTV also encode viral IFN-␥ binding protein (vIFN-␥bp) with amino acid sequence similarity to the extracellular binding domain of IFN-␥ receptor 1 and target host IFN-␥ (31,38,40). The ECTV IFN-␥bp, which maps to open reading frame (ORF) 158 of the ECTV genome (9), is an orthologue of the B8R gene in VARV and vaccinia virus (VACV) (28).…”

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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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“…Recent studies have reported that the new retroviral restriction factor TRIM5α blocks the incoming retroviral capsid soon after entry. 22,23) As TRIM family is proteins that contain RING, B-box, and coiledcoil domains, many TRIM proteins self-associate to form homo-oligomers and hetero-oligomers. Unfortunately, the mechanism by which TRIM5α restricts retroviral infection remains mostly unknown.…”

Section: Discussionmentioning

confidence: 99%

Differentially Expressed Cellular Gene Profiles between Healthy HIV-infected Koreans and AIDS Patients

Choi

Kim

et al. 2007

Korean J Hematol

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Inhibition of Interferons by Ectromelia Virus

Abstract: Ectromelia virus (EV) is an orthopoxvirus (OPV

Cited by 59 publications

References 81 publications

Interferon function is not required for recovery from a secondary poxvirus infection

Interferon function is not required for recovery from a secondary poxvirus infection

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

Differentially Expressed Cellular Gene Profiles between Healthy HIV-infected Koreans and AIDS Patients

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