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. 1998 May 26;95(11):6403-7.
doi: 10.1073/pnas.95.11.6403.

Broad spectrum chemokine antagonistic activity of a human poxvirus chemokine homolog

I Damon  1 , P M Murphy, B Moss
Affiliations

Broad spectrum chemokine antagonistic activity of a human poxvirus chemokine homolog

I Damon et al. Proc Natl Acad Sci U S A. .

Abstract

A secreted CC chemokine homolog, encoded by the MC148 gene of molluscum contagiosum virus, potently interfered with the chemotaxis of human monocytes, lymphocytes, and neutrophils in response to a large number of CC and CXC chemokines with diverse receptor specificities. Evidence that the viral protein binds to human chemokine receptors was obtained by competition binding and calcium mobilization experiments. The broad spectrum chemokine antagonistic activity of MC148 can explain the prolonged absence of an inflammatory response in skin tumors that harbor replicating molluscum contagiosum virus.

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Figures

Figure 1
Figure 1
Primary structure comparisons and purification of MC148P. (A) The alignment of the deduced amino acid sequence of MC148P with those of CC (I-309, MIP1-α, RANTES, MCP-1, MCP-3) and CXC (IL8, SDF-1) chemokines and HHV 8 vMIP-II chemokine homolog was performed with the macaw multiple alignment program. Upper- and lowercase letters refer to conserved and nonconserved amino acids, respectively; dashes are alignment gaps; back slashes are signal peptide cleavage sites; and numbers on the right are amino acid numbers. The gap in the NH2-terminal region of MC148 may have special significance with regard to the absence of agonist activity. (B) Purification. SDS/PAGE and silver staining of unreduced MC148P at successive purification steps. Lanes: 1, markers; 2, clarified supernatant; 3, pooled fractions from heparin column; 4, pooled fractions from SP column. (C) Elution from a G50 Sephadex column of MC148P (solid line) and the following markers (dashed lines): chymotrypsinogen, 25 kDa; ribonuclease A, 14 kDa; insulin, 6 kDa.
Figure 2
Figure 2
Inhibition by MC148P of CC and CXC chemokine-induced migration of human monocytes, neutrophils, and lymphocytes. Cell migration was determined by using a modified Boyden chamber. Additions to the lower well are indicated below each bar. Each condition was tested in triplicate, and the data are presented as the mean ± SE. The percentage of cell migration was determined from the ratio of the number of cells on the underside of the filter (in five 40× fields) in the presence of chemokine and indicated concentrations of MC148P, and the number of cells on the underside of the filter in the presence of chemokine alone (in five 40× fields). Each experiment was performed at least three times, and results from representative ones are shown. The average number of cells and the calculated SEM counted in the absence of MC148P were: MCP-1, 533 ± 98; MCP-3, 502 ± 19; fMLF, 165 ± 15; IL-8, 305 ± 15; RANTES, 169 ± 11; MIP-1α, 217 ± 25; SDF-1 (lymphocytes), 877 ± 37; SDF-1 (monocytes), 276 ± 45; I-309, 571 ± 37.
Figure 3
Figure 3
Inhibition by MC148P of chemokine-induced calcium mobilization. MC148P (amounts indicated to the right of each curve) and MCP-1 (1 nM) or I-309 (0.5 nM) were added successively to cells that had been loaded with Fura-2. Fluorescence was measured at 510 nm after repetitive, sequential excitations at 340 nm and 380 nm and the ratios were determined. (A) Primary monocytes. (B) CCR8-transfected murine pre B cells (12). (C) CCR2B-transfected HEK 293 cells (10).
Figure 4
Figure 4
Competition between MC148P and MCP-1 for binding to CCR2B. HEK 293 cells expressing CCR2B were incubated with 0.1 nM 125I-labeled MCP-1 and indicated amounts of unlabeled MCP-1, MC148P, or IL-8. The cells were separated from unbound radioactive material, and gamma emissions were counted. Each point is the mean ± SE derived from triplicate assays of a representative experiment.
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