Immunomodulation by herpesvirus U51A chemokine receptor <i>via</i> CCL5 and FOG‐2 down‐regulation plus XCR1 and CCR7 mimicry in human leukocytes

Catusse, Julie; Spinks, Jenny; Mattick, C; Dyer, Angela P.; Laing, Ken; Fitzsimons, Carlos P.; Smit, Martine J.; Gompels, Ursula A.

doi:10.1002/eji.200737618

Cited by 36 publications

(49 citation statements)

References 65 publications

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“…The U21 protein has been shown to reduce the expression of HLA class I expression as mentioned above. As other examples, the U83 gene encodes a chemotactic protein which is an agonist for several human CC chemokine receptors (CCRs) and the U12 and U51 genes encode chemokine receptors which presumably activate and recruit host cells (105,106). The U24 gene product induces the internalization of the T cell receptor/CD3 complex, which may alter the patterns of T cell activation.…”

Section: Interactions With the Immune Systemmentioning

confidence: 99%

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

2015

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SUMMARY Human herpesvirus 6 (HHV-6) is a widespread betaherpesvirus which is genetically related to human cytomegalovirus (HCMV) and now encompasses two different species: HHV-6A and HHV-6B. HHV-6 exhibits a wide cell tropism in vivo and, like other herpesviruses, induces a lifelong latent infection in humans. As a noticeable difference with respect to other human herpesviruses, genomic HHV-6 DNA is covalently integrated into the subtelomeric region of cell chromosomes (ciHHV-6) in about 1% of the general population. Although it is infrequent, this may be a confounding factor for the diagnosis of active viral infection. The diagnosis of HHV-6 infection is performed by both serologic and direct methods. The most prominent technique is the quantification of viral DNA in blood, other body fluids, and organs by means of real-time PCR. Many active HHV-6 infections, corresponding to primary infections, reactivations, or exogenous reinfections, are asymptomatic. However, the virus may be the cause of serious diseases, particularly in immunocompromised individuals. As emblematic examples of HHV-6 pathogenicity, exanthema subitum, a benign disease of infancy, is associated with primary infection, whereas further virus reactivations can induce severe encephalitis cases, particularly in hematopoietic stem cell transplant recipients. Generally speaking, the formal demonstration of the causative role of HHV-6 in many acute and chronic human diseases is difficult due to the ubiquitous nature of the virus, chronicity of infection, existence of two distinct species, and limitations of current investigational tools. The antiviral compounds ganciclovir, foscarnet, and cidofovir are effective against active HHV-6 infections, but the indications for treatment, as well as the conditions of drug administration, are not formally approved to date. There are still numerous pending questions about HHV-6 which should stimulate future research works on the pathophysiology, diagnosis, and therapy of this remarkable human virus.

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Section: Interactions With the Immune Systemmentioning

confidence: 99%

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

2015

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“…Similar to the HCMV-encoded US28 receptor, the HHV-6-encoded U51 gene was shown to scavenge CCL5 from the supernatant of U51-expressing and HHV-6-infected cells (Milne et al, 2000;Catusse et al, 2008). In contrast to US28, U51 chemokine sink function was attributed to both transcriptional repression of the CCL5 gene and the scavenging of CCL5 protein.…”

Section: Hhv-6-encoded U51 Contributes To Immune Evasionmentioning

confidence: 97%

“…U12 and U51 genes from HHV-6 and HHV-7 bind different broad spectra of human chemokines. HHV-6 U51 binds chemokines from the CC (CCL2,5,7,11,13,19,and 22), CX3C (CX3CL1), and XC (XCL1) families, as well as the KSHVencoded chemokine vCXCL2 (Milne et al, 2000;Catusse et al, 2008), whereas HHV-7 U51 ligands are strictly from the CC family (CCL17, 19, 21, and 22) (Tadagaki et al, 2005).…”

Section: Hhv-6-and -7-encoded Gpcrsmentioning

confidence: 99%

“…The U51-expressing myeloid cell line K562 exhibited constitutive G␣ q protein activation as measured by inositol phosphate formation, and CCL5 stimulation further increased U51 signaling. To identify targets of constitutive signaling, a microarray analysis restricted to targets of infection and immunity indicated that U51 down-regulated the transcription of the friend of GATA2, zinc finger protein (FOG-2) gene (Catusse et al, 2008). FOG-2 belongs to the family of FOG proteins that are transcriptional repressors involved in the development of Th1 and Th2 immune responses (Kurata et al, 2002;Mariani et al, 2004).…”

Section: Hhv-6-encoded U51 Contributes To Immune Evasionmentioning

confidence: 99%

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Herpesvirus-Encoded G Protein-Coupled Receptors as Modulators of Cellular Function

Maussang¹,

Vischer²,

Leurs³

et al. 2009

Mol Pharmacol

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Human herpesviruses (HHVs) are widespread pathogens involved in proliferative diseases, inflammatory conditions, and cardiovascular diseases. During evolution, homologs of human chemokine receptors were integrated into the HHV genomes. In addition to binding endogenous chemokines, these viral G protein-coupled receptors (vGPCRs) have acquired the ability to signal in a constitutive manner. Ligand-induced and ligandindependent and autocrine and paracrine signaling properties of vGPCRs modify the functions of the expressing cells and lead to transformation and escape from immune surveillance. Furthermore, cross-talk or heterodimerization with endogenous chemokine receptors represent other ways for vGPCRs to modify intracellular signaling and cellular functions. As such, these viral receptors seem to play a prominent role during viral pathogenesis and life cycle and thus represent innovative antiviral therapies.G protein-coupled receptors (GPCRs) are essential mediators of cellular communication. Their cell surface expression allows easy access and activation by their extracellular ligands to initiate intracellular signaling cascades. The physiological role of GPCR activation ranges from gene transcription to cellular migration and proliferation. Besides being activated by their cognitive ligands, GPCRs can signal independently from ligand activation. This so-called constitutive activity is the molecular basis of various pathologies (Smit et al., 2007). It is noteworthy that, during evolution, human herpesviruses (HHV) of the ␤ and ␥ families hijacked human GPCR while coexisting with their host (Brunovskis and Kung, 1995). These viral GPCRs (vGPCRs) show considerable homology to chemokine receptors, which are essential in the development of the hematopoietic system and regulation of cellular homeostasis (Mackay, 2001). In addition, chemokine receptors play a prominent role in cancer development (e.g., by inducing cellular proliferation or by modifying cellular migration patterns), resulting in cancer metastasis (Balkwill, 2004). Although human chemokine receptors require ligand activation to exert a physiological function, most of the vGPCRs show high levels of constitutive activity (Vischer et al., 2006b). As for human GPCRs, the constitutive modulation of signaling pathways by vGPCRs may play a role in the development of HHV-related diseases. As such, these vGPCRs may serve as therapeutic targets for the intervention of viral pathogenesis. ␥-Herpesvirus-Encoded G Protein-Coupled ReceptorsThe Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) and the Epstein-Barr virus (EBV or HHV-4) are lymphotropic viruses that are involved in proliferative dis- Article, publication date, and citation information can be found at

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“…Both viruses encode potent immunomodulators. These include chemokines plus their receptors, which could dysregulate the inflammatory response, and these have different specificities (Catusse et al, 2008(Catusse et al, , 2009Dewin et al, 2006;Fitzsimons et al, 2006;Lüttichau et al, 2003). Studies in countries where HHV-6B is prevalent show that complications include childhood febrile status epilepticus, linked to hippocampus involvement and a risk factor for temporal lobe epilepsy development (Epstein et al, 2012), as well as cognitive dysfunction or fatal encephalitis in haematopoietic stem cell transplantation patients (Zerr, 2006;Zerr et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Analyses of germline, chromosomally integrated human herpesvirus 6A and B genomes indicate emergent infection and new inflammatory mediators

Tweedy

Spyrou

Hubáček

et al. 2015

Journal of General Virology

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Human herpesvirus-6A (HHV-6A) is rarer than HHV-6B in many infant populations. However, they are similarly prevalent as germline, chromosomally integrated genomes (ciHHV-6A/B). This integrated form affects 0.1-1 % of the human population, where potentially virus gene expression could be in every cell, although virus relationships and health effects are not clear. In a Czech/ German patient cohort ciHHV-6A was more common and diverse than ciHHV-6B. Quantitative PCR, nucleotide sequencing and telomeric integration site amplification characterized ciHHV-6 in 44 German myocarditis/cardiomyopathy and Czech malignancy/inflammatory disease (MI) patients plus donors. Comparisons were made to sequences from global virus reference strains, and blood DNA from childhood-infections from Zambia (HHV-6A mainly) and Japan (HHV-6B). The MI cohort were 86 % (18/21) ciHHV-6A, the cardiac cohort 65 % (13/20) ciHHV-6B, suggesting different disease links. Reactivation was supported by findings of 1) recombination between ciHHV-6A and HHV-6B genes in 20 % (4/21) of the MI cohort; 2) expression in a patient subset, of early/late transcripts from the inflammatory mediator genes chemokine receptor U51 and chemokine U83, both identical to ciHHV-6A DNA sequences; and 3) superinfection shown by deep sequencing identifying minor virus-variants only in ciHHV-6A, which expressed transcripts, indicating virus infection reactivates latent ciHHV-6A. Half the MI cohort had more than two copies per cell, median 5.2, indicative of reactivation. Remarkably, the integrated genomes encoded the secreted-active form of virus chemokines, rare in virus from childhoodinfections. This shows integrated virus genomes can contribute new human genes with links to inflammatory pathology and supports ciHHV-6A reactivation as a source for emergent infection.

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Immunomodulation by herpesvirus U51A chemokine receptor via CCL5 and FOG‐2 down‐regulation plus XCR1 and CCR7 mimicry in human leukocytes

Cited by 36 publications

References 65 publications

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

Herpesvirus-Encoded G Protein-Coupled Receptors as Modulators of Cellular Function

Analyses of germline, chromosomally integrated human herpesvirus 6A and B genomes indicate emergent infection and new inflammatory mediators

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