Vaccinia Virus Interleukin-18-Binding Protein Promotes Virulence by Reducing Gamma Interferon Production and Natural Killer and T-Cell Activity

Reading, Patrick C.; Smith, Geoffrey L.

doi:10.1128/jvi.77.18.9960-9968.2003

Cited by 103 publications

(74 citation statements)

References 61 publications

(59 reference statements)

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“…model measuring weight loss; intracranial inoculations or measures of viral titers in organs have often been performed instead. Available data indicate that the A35⌬ virus is similar in virulence to the IL-18 binding protein knockout virus (36), more attenuated than the A46R deletion mutant (42), and less attenuated than the E3L deletion, which causes a 1,000-fold attenuation (46). The A35 gene affects the development of the host adaptive immune response.…”

Section: Discussionmentioning

confidence: 99%

The Poxvirus A35 Protein Is an Immunoregulator

Rehm

Jones

Tripp

et al. 2010

J Virol

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It was shown previously that the highly conserved vaccinia virus A35 gene is an important virulence factor in respiratory infection of mice. We show here that A35 is also required for full virulence by the intraperitoneal route of infection. A virus mutant in which the A35 gene has been removed replicated normally and elicited improved antibody, gamma interferon-secreting cell, and cytotoxic T-lymphocyte responses compared to wild-type virus, suggesting that A35 increases poxvirus virulence by immunomodulation. The enhanced immune response correlated with an improved control of viral titers in target organs after the development of the specific immune response. Finally, the A35 deletion mutant virus also provided protection from lethal challenge (1,000 50% lethal doses) equal to that of the wild-type virus. Together, these data suggest that A35 deletion viruses will make safer and more efficacious vaccines for poxviruses. In addition, the A35 deletion viruses will serve as improved platform vectors for other infectious diseases and cancer and will be superior vaccine choices for postexposure poxvirus vaccination, as they also provide improved kinetics of the immune response.

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Section: Discussionmentioning

confidence: 99%

The Poxvirus A35 Protein Is an Immunoregulator

Rehm

Jones

Tripp

et al. 2010

J Virol

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“…It is understood that production of these IL-18-binding proteins is part of the viral immune evasion strategy, to restrict the actions of IL-18, particularly the induction of IFN-g, which suggests the possibility that IL-18bp might be used as a therapeutic agent. In addition to viral IL-18bp, however, poxviruses also encode an inhibitor of caspase-1, which is required for cleavage of pro-IL-18 and pro-IL-1b to the active forms of these cytokines (47). The vaccinia virus protein C12L has homology to IL-18bp and inhibits IFN-g production, although vaccinia virus produces numerous additional immunomodulators, including proteins that bind to IFN-g, IFN-a/b, complement factors, and TNF-a [summarized in (46)].…”

Section: Discussionmentioning

confidence: 99%

Inflammation in the Central Nervous System and Th17 Responses Are Inhibited by IFN-γ–Induced IL-18 Binding Protein

Millward

Løbner

Wheeler

et al. 2010

The Journal of Immunology

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“…Although this might render the infected cell sensitive to NK cell-mediated lysis, CPXV also encodes another ORF, CPXV018, that binds in vitro with high affinity to the NKG2D activation receptor and blocks its recognition of ligands on target cells (39). Additionally, all orthopoxviruses, including CPXV, encode a number of cytokine binding proteins, which could also limit the activation of NK cells, such as one specifically targeting IL-18 (40,41), a well-known mediator of NK-cell activation. Given the potential for CPXV to encode a larger repertoire of genes for evasion of immune responses, possibly including NK cells, it was of interest to determine whether NK cells could control CPXV infection, if NK cells are recruited to the site of infection, and the basis for this potential recruitment.…”

Section: Significancementioning

confidence: 99%

Interferon-γ mediates chemokine-dependent recruitment of natural killer cells during viral infection

Pak-Wittel¹,

Yang²,

Sojka³

et al. 2012

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

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Natural killer (NK) cells provide in vivo control of orthopoxvirus infections in association with their expansion in the draining lymph node (LN), where they are normally very rare. The mechanism of this expansion is unclear. Herein, we determined that NK-cell depletion results in enhanced infection following footpad inoculation of cowpox virus, a natural pathogen of rodents. Following cowpox virus infection in normal mice, NK cells were greatly expanded in the draining LN, were not replicating, and displayed markers similar to splenic NK cells, suggesting specific recruitment of splenic NK cells rather than in situ proliferation. Moreover, NK-cell expansion was abrogated by prior injection of clodronate-loaded liposomes, indicating a role for subcapsular sinus macrophages. Furthermore, recruitment of transferred splenic NK cells to the draining LN was pertussis toxin-sensitive, suggesting involvement of chemokine receptors. Comprehensive analysis of chemokine mRNA expression in the draining LN following infection suggested the selective involvement of CCR2, CCR5, and/or CXCR3. Mice deficient for CCR2 or CCR5 had normal NK-cell recruitment, whereas CXCR3-deficient mice displayed a major defect, which was NK cell-intrinsic. Interestingly, both induction of transcripts for CXCR3 ligands (Cxcl9 and Cxcl10) and NK-cell recruitment required IFN-γ. These data indicate that NK-cell recruitment is mediated by subcapsular sinus macrophages, IFN-γ, and CXCR3 during orthopoxvirus infection.

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Vaccinia Virus Interleukin-18-Binding Protein Promotes Virulence by Reducing Gamma Interferon Production and Natural Killer and T-Cell Activity

Abstract: Interleukin-18 (IL-18

Cited by 103 publications

References 61 publications

The Poxvirus A35 Protein Is an Immunoregulator

The Poxvirus A35 Protein Is an Immunoregulator

Inflammation in the Central Nervous System and Th17 Responses Are Inhibited by IFN-γ–Induced IL-18 Binding Protein

Interferon-γ mediates chemokine-dependent recruitment of natural killer cells during viral infection

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