Monkeypox virus viral chemokine inhibitor (MPV vCCI), a potent inhibitor of rhesus macrophage inflammatory protein-1.
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-1alpha (rhMIP-1alpha) at near one to one stoichiometry. In vitro chemotaxis experiments demonstrate that vCCI completely inhibits rhMIP-1alpha 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-1alpha 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-1alpha. Furthermore, the ability of vCCI to inhibit relapsing EAE disease represents a novel therapeutic approach for treating chemokine-mediated diseases.
Jones
John M
JM
Vaccine and Gene Therapy Institute, Oregon Health & Science University, West Campus, 505 NW 185th Avenue, Room 1210, Beaverton, OR 97006, USA; Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR 97201, USA.
Messauodi
Ilhem
I
Estep
Ryan D
RD
Orzechowska
Beata
B
Wong
Scott W
SW
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008253:Macaca mulatta; D019402:Macrophage Inflammatory Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008969:Molecular Sequence Data; D008993:Monkeypox virus / Q000378:metabolism*; D011485:Protein Binding; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D018950:Lipopolysaccharide Receptors; D019402:Macrophage Inflammatory Proteins; D014764:Viral Proteins