Role of the myxoma virus soluble CC-chemokine inhibitor glycoprotein, M-T1, during myxoma virus pathogenesis.
Myxoma virus is a poxvirus that causes a virulent systemic disease called myxomatosis in European rabbits. Like many poxviruses, myxoma virus encodes a variety of secreted proteins that subvert the antiviral activities of host cytokines. It was recently demonstrated that the myxoma virus M-T1 glycoprotein is a member of a large poxvirus family of secreted proteins that bind CC-chemokines and inhibit their chemoattractant activities in vitro. To determine the biological role of M-T1 in contributing to myxoma virus virulence, we constructed a recombinant M-T1-deletion mutant virus that was defective in M-T1 expression. Here, we demonstrate that M-T1 is expressed continuously during the course of myxoma virus infection as a highly stable 43-kDa glycoprotein and is dispensable for virus replication in vitro. Deletion of M-T1 had no significant effects on disease progression or in the overall mortality rate of infected European rabbits but heightened the localized cellular inflammation in primary tissue sites during the initial 2 to 3 days of infection. In the absence of M-T1 expression, deep dermal tissues surrounding the primary site of virus inoculation showed a dramatic increase in infiltrating leukocytes, particularly monocytes/macrophages, but these phagocytes remained relatively ineffective at clearing virus infection, likely due to the concerted properties of other secreted myxoma virus proteins. We conclude that M-T1 inhibits the chemotactic signals required for the influx of monocytes/macrophages during the acute-phase response of myxoma virus infection in vivo, as predicted by its ability to bind and inhibit CC-chemokines in vitro.
Lalani
A S
AS
Departments of Biochemistry, University of Alberta, Edmonton, Canada.
Masters
J
J
Graham
K
K
Liu
L
L
Lucas
A
A
McFadden
G
G
D000818:Animals; D019742:Chemokines, CC / Q000037:antagonists & inhibitors*; D005260:Female; D015967:Gene Expression Regulation, Viral; D006023:Glycoproteins / Q000235:genetics / Q000502:physiology*; D007700:Kinetics; D008264:Macrophages; D009000:Monocytes; D016296:Mutagenesis; D009233:Myxoma virus / Q000235:genetics / Q000502:physiology*; D009234:Myxomatosis, Infectious / Q000473:pathology* / Q000821:virology; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D012995:Solubility; D019562:Viral Load; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*
D019742:Chemokines, CC; D006023:Glycoproteins; C119017:M-T1 protein, myxoma virus; D011993:Recombinant Fusion Proteins; D014764:Viral Proteins