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. 2008 Apr 21:5:50.
doi: 10.1186/1743-422X-5-50.

The herpesvirus 8 encoded chemokines vCCL2 (vMIP-II) and vCCL3 (vMIP-III) target the human but not the murine lymphotactin receptor

Hans R Lüttichau  1
Affiliations

The herpesvirus 8 encoded chemokines vCCL2 (vMIP-II) and vCCL3 (vMIP-III) target the human but not the murine lymphotactin receptor

Hans R Lüttichau. Virol J. .

Abstract

Background: Large DNA-viruses such as herpesvirus and poxvirus encode proteins that target and exploit the chemokine system of their host. The Kaposi sarcoma- associated herpes virus (KSHV) encodes three chemokines. Two of these, vCCL2 and vCCL3, target the human lymphotactin receptor as an antagonist and a selective agonist, respectively. Therefore these virally endcoded chemokines have the potential to be used as tools in the study of lymphotactin receptor pathways in murine models.

Results: The activities of vCCL2, vCCL3, human lymphotactin (XCL1) and murine lymphotactin (mXCL1) were probed in parallel on the human and murine lymphotactin receptor (XCR1 and mXCR1) using a phosphatidyl-inositol assay. On the human XCR1, vCCL3, mXCL1 and XCL1 acted as agonists. In contrast, only mXCL1 was able to activate the murine lymphotactin receptor. Using the same assay, vCCL2 was able to block the response using any of the three agonists on the humane lymphotactin receptor with IC50s of 2-3 nM. However, vCCL2 was unable to block the response of mXCL1 through the murine lymphotactin receptor.

Conclusion: This study shows that vCCL2 and vCCL3 cannot be used to investigate lymphotactin receptor pathways in murine models. These results also add vCCL2 and vCCL3 to a growing list of viral chemokines with known human chemokine receptor targets, which do not target the corresponding murine receptors. This fits with the observation that viral and endogenous ligands for the same human chemokine receptor tend to have relatively divergent amino-acid sequences, suggesting that these viruses have fine-tuned the design of their chemokines such that the action of the viral encoded chemokines cannot be expected to cross species barriers.

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Figures

Figure 1
Figure 1
Alignment of human, murine and viral ligands for the human and the murine lymphotactin receptor. The upper panel shows the primary structure of the two HHV8 encoded chemokines, vCCL2, vCCL3, the human lymphotactin XCL1 and the murine lymphotactin mXCL1 aligned using CLUSTALW from Kyoto University Bioinformatics Center. Identical amino acids are shown in white on black, whereas similar amino acids are shown in black on light grey. Cysteines are shown in black on yellow and presumed disulfide bridges are marked with an asterisk. Likely O-glycosylation sites using the CBS prediction server are marked white on blue. The secondary structure of XCL1 as determined by NMR is indicated by the line above the alignment [21].
Figure 2
Figure 2
Activation of the human and murine lymphotactin receptor by human, murine and viral agonists. Dose-response experiments measuring IP3 turnover in COS-7 cells transiently transfected with the human and murine lymphotactin receptors XCR1 and mXCR1 and the promiscuous chimeric G-protein Gqi4myr using increasing concentrations of the agonists XCL1 (black square), mXCL1 (black triangle) and vCCL3 (white circle). The thin line indicate the EC50 for the particular ligand (assuming Emax equal to that of vCCL3). All assays were performed in duplicate.
Figure 3
Figure 3
Inhibition of the human and murine lymphotactin receptor by the viral antagonist vCCL2. Dose-response experiments for inhibition of IP3-turnover by the antagonist vCCL2 induced by XCL1 (black square) mXCL1 (black triangle) and vCCL3 (white circle) in COS-7 cells transiently transfected with the human and murine lymphotactin receptors XCR1 and mXCR1 and the promiscuous chimeric G-protein Gqi4myr. All assays were performed in duplicate.
Figure 4
Figure 4
Amino-acid sequence similarity of human and viral encoded chemokines compared to their chemokine receptor targets. Left side of the figure is a comparison of the similiarity of the primary protein sequence of human and virally encoded chemokines (using ClustalW 1.83 and an unbranched dendrogram) with the receptor targets of the specific chemokines seen on the right side of the figure. The names of the virally encoded chemokines are highlighted in bold. On the right hand side a line is used to illustrate that a specific chemokine is a ligand for a specific chemokine receptor. The line is unbroken for endogenous human chemokines and dotted for virally encoded chemokines. The murine lymphotactin has been included to illustrate the great similarity between XCL1 and mXCL1.
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