TY - JOUR
T1 - Role of the myxoma virus soluble CC-chemokine inhibitor glycoprotein, M- T1, during myxoma virus pathogenesis
AU - Lalani, Alshad S.
AU - Masters, Jennefer
AU - Graham, Kathryn
AU - Liu, Liying
AU - Lucas, Alexandra
AU - McFadden, Grant
N1 - Funding Information:
We are grateful to S. Hnatiuk, H. Everett, P. Nash, and M. Barry for assistance in the animal studies; W. Zeng for expert technical support; and P. Nation for help with gross pathological and histopathological analyses. We would also like to thank D. Elias for her invaluable administrative support and H. Everett and J. Cao for critical comments on the manuscript. This work was funded by the Medical Research Council of Canada (MRC) and the National Cancer Institute of Canada. G.M. holds an MRC Senior Scientist Award, and A.L. was supported by the Alberta Heart and Stroke Foundation and by VIRON Therapeutics.
PY - 1999/4/10
Y1 - 1999/4/10
N2 - 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.
AB - 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.
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U2 - 10.1006/viro.1999.9617
DO - 10.1006/viro.1999.9617
M3 - Article
C2 - 10191189
AN - SCOPUS:0033541380
SN - 0042-6822
VL - 256
SP - 233
EP - 245
JO - Virology
JF - Virology
IS - 2
ER -