Monkeypox virus viral chemokine inhibitor (MPV vCCI), a potent inhibitor of rhesus macrophage inflammatory protein-1 |
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Authors: | Jones John M Messauodi Ilhem Estep Ryan D Orzechowska Beata Wong Scott W |
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Institution: | aVaccine and Gene Therapy Institute, Oregon Health & Science University, West Campus, 505 NW 185th Avenue, Room 1210, Beaverton, OR 97006, USA;bDivision of Pathobiology and Immunology, Oregon National Primate Research Center, Beaverton, OR 97006, USA;cDepartment of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR 97201, USA |
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Abstract: | Monkeypox virus (MPV) is an orthopoxvirus with considerable homology to variola major, the etiologic agent of smallpox. Although smallpox was eradicated in 1976, the outbreak of MPV in the U.S. highlights the health hazards associated with zoonotic infections. Like other orthopoxviruses, MPV encodes a secreted chemokine binding protein, vCCI that is abundantly expressed and secreted from MPV infected cells. EMSA data shows vCCI efficiently binds rhesus MIP-1α (rhMIP-1α) at near one to one stoichiometry. In vitro chemotaxis experiments demonstrate that vCCI completely inhibits rhMIP-1α mediated chemotaxis, while in vivo recruitment assays in rhesus macaques using chemokine-saturated implants show a decrease in the number of CD14+ cells responding to rhMIP-1α when vCCI is present, suggesting vCCI is effectively inhibiting chemokine function both in vitro and in vivo. More importantly, we demonstrate that vCCI can diminish the severity of the acute phase and completely inhibit the relapsing phase of experimental allergic encephalomyelitis (EAE) disease. These data represent the first in vitro and in vivo characterization of vCCI emphasizing its function as a potent inhibitor of rhMIP-1α. Furthermore, the ability of vCCI to inhibit relapsing EAE disease represents a novel therapeutic approach for treating chemokine-mediated diseases. |
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Keywords: | Chemokines Chemokine inhibitor Chemotaxis Poxviruses Multiple sclerosis |
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