Primate Cytomegaloviruses Encode and Express an IL-10-like Protein

Lockridge, Kristen M.; Zhou, Shan; Kravitz, Rachel H.; Johnson, Jennifer L.; Sawai, Earl T.; Blewett, Earl L.; Barry, Peter A.

doi:10.1006/viro.2000.0195

Cited by 145 publications

(134 citation statements)

References 41 publications

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“…Both the UL36 (viral inhibitor of caspase-8-induced apoptosis, vICA) and UL37 (mitochondria inhibitor of apoptosis, vMIA) homologs in RhCMV were able to prevent Fas-mediated apoptosis in HeLa cells, whereas the MCMV UL37 homolog M37 was not [59]. The IL-10 homolog of CMVs was Wrst identiWed in RhCMV and was shown to be expressed in vivo, targeted by the humoral immune response, and to have [14] and [50] immunosuppressive properties [60,61]. RhCMV also contains homologs of HCMV US2, US3, US6, and US11 [53].…”

Section: Functional Characterizations Of Rhcmv Proteinsmentioning

confidence: 99%

Rhesus CMV: an emerging animal model for human CMV

Powers

Früh

2008

Med Microbiol Immunol

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Human CMV is the predominant infectious cause of congenital birth defects and an opportunistic pathogen in immunosuppressed individuals, including AIDS patients. Most individuals are infected early during their life followed by life-long latent infection. During this latent phase, frequent reactivation and antigen production continue to stimulate the immune system. While the immune response is able to control the virus, it is unable to eradicate it. Moreover, super-infection by diVerent CMV strains has been observed despite a strong immune response. Longterm immune stimulation by CMV has also been implicated in immune senescence and chronic conditions such as atherosclerosis. CMVs are highly species-speciWc and the relatedness of CMV genomes exactly mirrors the relatedness of their hosts. Thus, each CMV species is highly adapted to its respective host species, but is unable to infect other, even closely related hosts. While fascinating from an evolutionary perspective, this host restriction prevents studying HCMV in experimental animals. Exceptions are severely immunocompromised mice, e.g. SCID mice, or SCID/NOD mice, which might allow partial reconstitution of CMV infection in rodents. More practical however, is to study CMVs in their natural host, e.g. murine, rat or guinea pig CMVs. However, while these small animal models have many advantages, such as the availability of inbred animals as well as lower cost, the limited homology of the viral genomes with HCMV limits the functional analysis of homologous gene products. The closest relative to HCMV is chimpanzee CMV (CCMV), but this is not a practical animal model since chimps are a protected species, extremely expensive and of very limited availability. In contrast, rhesus macaques are a more widely used experimental animal species and, while more distant than CCMV, rhesus CMV (RhCMV) contains most of the HCMV gene families thus allowing the study of their role in acute and latent CMV infection. In this review we will discuss the current state of developing RhCMV as a model for HCMV.

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Section: Functional Characterizations Of Rhcmv Proteinsmentioning

confidence: 99%

Rhesus CMV: an emerging animal model for human CMV

Powers

Früh

2008

Med Microbiol Immunol

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“…Some DNA viruses, including EBV and human CMV, encode viral IL-10 homologs to engage the cellular IL-10R (16,17). Although human CMV-encoded IL-10 (cmvIL-10) shares only 27% amino acid sequence with its cellular counterpart (16,18), its homodimer engages the ligand-binding subunit of IL-10R with as high affinity as human IL-10 (hIL-10; Ref. 19).…”

Section: Endritic Cells (Dc)mentioning

confidence: 99%

Exposure of Myeloid Dendritic Cells to Exogenous or Endogenous IL-10 during Maturation Determines Their Longevity

Chang¹,

Baumgarth²,

Eberhardt³

et al. 2007

The Journal of Immunology

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Dendritic cells (DC) are essential for the initiation of primary adaptive immune responses, and their functionality is strongly down-modulated by IL-10. Both innate and adaptive immune signals trigger the up-regulation of antiapoptotic Bcl-2 family members to facilitate the survival of DCs after maturation. However, whether IL-10 alters the expression of apoptotic-related genes in maturing DCs has not been determined. In this study, we demonstrate that spontaneous apoptosis rapidly occurred in myeloid DCs exposed to exogenous IL-10 upon maturation. Microarray analysis indicates that IL-10 suppressed the induction of three antiapoptotic genes, bcl-2, bcl-x, and bfl-1, which was coincident with the increased sensitivity of mature DCs to spontaneous apoptosis. IL-10 markedly inhibited the accumulation of steady state Bcl-2 message and protein in myeloid DCs activated through TLRs or TNFR family members, whereas exogenous IL-10 affected Bcl-xL expression in a moderate manner. In contrast, bcl-2 expression of plasmacytoid DCs was less sensitive to the effects of IL-10. We further show that autocrine IL-10 significantly limited the longevity of myeloid DCs and altered the expression kinetics of Bcl-2 but not Bcl-xL in maturing DCs. We conclude that the degree of IL-10 exposure and/or the level of endogenous IL-10 production upon myeloid DC maturation play a critical role in determining DC longevity. This regulatory mechanism of IL-10 is associated with the dynamic control of antiapoptotic Bcl-2 proteins.

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“…To this end, many viruses have acquired homologs of host cytokines or cytokine receptors, among which is IL10 (1,2). Indeed, IL10-like open reading frames (ORFs) have been identified in multiple members of the Poxviridae and in members of the Herpesvirales, including human CMV and EBV (3)(4)(5). Almost all viruses for which IL10 homologs have been described are viruses infecting mammalian hosts, with only two reported exceptions, both in fish: anguillid herpesvirus 1 (Herpesvirales, Alloherpesviridae), infecting European eel (Anguilla anguilla) (6), and cyprinid herpesvirus 3 (CyHV-3, Herpesvirales, Alloherpesviridae), infecting common carp (Cyprinus carpio) (7).…”

mentioning

confidence: 99%

Cyprinid Herpesvirus 3 Il10 Inhibits Inflammatory Activities of Carp Macrophages and Promotes Proliferation of Igm+ B Cells and Memory T Cells in a Manner Similar to Carp Il10

Piazzon

Wentzel

Tijhaar

et al. 2015

The Journal of Immunology

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Cyprinid herpesvirus 3 (CyHV-3) is the causative agent of a lethal disease of carp and encodes for an Il10 homolog (ORF134). Our previous studies with a recombinant ORF134-deleted strain and the derived revertant strain suggested that cyprinid herpesvirus 3 Il10 (CyHV-3 Il10 [cyhv3Il10]) is not essential for viral replication in vitro, or virulence in vivo. In apparent contrast, cyhv3Il10 is one of the most abundant proteins of the CyHV-3 secretome and is structurally very similar to carp Il10 and also human IL10. To date, studies addressing the biological activity of cyhv3Il10 on cells of its natural host have not been performed. To address the apparent contradiction between the presence of a structurally conserved Il10 homolog in the genome of CyHV-3 and the lack of a clear phenotype in vivo using recombinant cyhv3Il10-deleted viruses, we used an in vitro approach to investigate in detail whether cyhv3Il10 exerts any biological activity on carp cells. In this study, we provide direct evidence that cyhv3Il10 is biologically active and, similarly to carp Il10, signals via a conserved Stat3 pathway modulating immune cells of its natural host, carp. In vitro, cyhv3Il10 deactivates phagocytes with a prominent effect on macrophages, while also promoting proliferation of Igm+ B cells and memory T cells. Collectively, this study demonstrates a clear biological activity of cyhv3Il10 on cells of its natural host and indicates that cyhv3Il10 is a true viral ortholog of carp Il10. Furthermore, to our knowledge, this is the first report on biological activities of a nonmammalian viral Il10 homolog.

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Primate Cytomegaloviruses Encode and Express an IL-10-like Protein

Cited by 145 publications

References 41 publications

Rhesus CMV: an emerging animal model for human CMV

Rhesus CMV: an emerging animal model for human CMV

Exposure of Myeloid Dendritic Cells to Exogenous or Endogenous IL-10 during Maturation Determines Their Longevity

Cyprinid Herpesvirus 3 Il10 Inhibits Inflammatory Activities of Carp Macrophages and Promotes Proliferation of Igm+ B Cells and Memory T Cells in a Manner Similar to Carp Il10

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