Activation of an antiviral response in normal but not transformed mouse cells: a new determinant of minute virus of mice oncotropism.
Parvovirus minute virus of mice (MVMp) is endowed with oncotropic properties so far ascribed only to the dependency of the virus life cycle on cellular factors expressed during S phase and/or modulated by malignant transformation. For other viruses oncotropism relies on their inability to circumvent type I interferon (IFN)-induced innate antiviral mechanisms, the first line of defense triggered by normal cells against viral infections. These agents propagate, therefore, preferentially in transformed/tumor cells, which often lack functional antiviral mechanisms. The present study aimed at investigating whether antiviral processes also contribute to MVMp oncotropism. Our results demonstrate that in contrast to MVMp-permissive transformed mouse A9 fibroblasts, freshly isolated normal counterparts (mouse embryonic fibroblasts [MEFs]) mount, through production and release of type I IFNs upon their infection, an antiviral response against MVMp lytic multiplication. Pretreatment of MEFs with a type I IFN-beta-neutralizing antibody, prior to MVMp infection, inhibits the virus-triggered antiviral response and improves the fulfillment of the MVMp life cycle. Our results also show that part of the A9 permissiveness to MVMp relies on the inability to produce type I IFNs upon parvovirus infection, a feature related either to an A9 intrinsic deficiency of this process or to an MVMp-triggered inhibitory mechanism, since stimulation of these cells by exogenous IFN-beta strongly inhibits the parvovirus life cycle. Taken together, our results demonstrate for the first time that parvovirus infection triggers an innate antiviral response in normal cells and suggest that the MVMp oncotropism depends at least in part on the failure of infected transformed cells to mount such a response.
Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
Svitlana
S
Grekova
Rainer
R
Zawatzky
Rita
R
Hörlein
Celina
C
Cziepluch
Michal
M
Mincberg
Claytus
C
Davis
Jean
J
Rommelaere
Laurent
L
Daeffler
D000818:Animals; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D005347:Fibroblasts / Q000276:immunology / Q000821:virology; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000096:biosynthesis; D016899:Interferon-beta / Q000494:pharmacology; D051379:Mice; D008915:Minute Virus of Mice / Q000276:immunology*; D014779:Virus Replication / Q000187:drug effects
D007370:Interferon Type I; D016899:Interferon-beta