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Journal of Virology, May 2007, p. 4991-4999, Vol. 81, No. 10
0022-538X/07/$08.00+0     doi:10.1128/JVI.01933-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

La Crosse Bunyavirus Nonstructural Protein NSs Serves To Suppress the Type I Interferon System of Mammalian Hosts{triangledown}

Gjon Blakqori,1,{dagger} Sophie Delhaye,2 Matthias Habjan,1 Carol D. Blair,3 Irma Sánchez-Vargas,3 Ken E. Olson,3 Ghassem Attarzadeh-Yazdi,4 Rennos Fragkoudis,4 Alain Kohl,4 Ulrich Kalinke,5 Siegfried Weiss,6 Thomas Michiels,2 Peter Staeheli,1 and Friedemann Weber1*

Department of Virology, University of Freiburg, D-79008 Freiburg, Germany,1 Université Catholique de Louvain, Christian de Duve Institute of Cellular Pathology, Brussels, Belgium,2 Colorado State University, Fort Collins, Colorado 80523,3 Centre for Infectious Diseases, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh EH9 1QH, United Kingdom,4 Paul Ehrlich Institut, Langen, Germany,5 Helmholtz Zentrum für Infektionsforschung, Braunschweig, Germany6

Received 5 September 2006/ Accepted 12 February 2007

La Crosse virus (LACV) is a mosquito-transmitted member of the Bunyaviridae family that causes severe encephalitis in children. For the LACV nonstructural protein NSs, previous overexpression studies with mammalian cells had suggested two different functions, namely induction of apoptosis and inhibition of RNA interference (RNAi). Here, we demonstrate that mosquito cells persistently infected with LACV do not undergo apoptosis and mount a specific RNAi response. Recombinant viruses that either express (rLACV) or lack (rLACVdelNSs) the NSs gene similarly persisted and were prone to the RNAi-mediated resistance to superinfection. Furthermore, in mosquito cells overexpressed LACV NSs was unable to inhibit RNAi against Semliki Forest virus. In mammalian cells, however, the rLACVdelNSs mutant virus strongly activated the antiviral type I interferon (IFN) system, whereas rLACV as well as overexpressed NSs suppressed IFN induction. Consequently, rLACVdelNSs was attenuated in IFN-competent mouse embryo fibroblasts and animals but not in systems lacking the type I IFN receptor. In situ analyses of mouse brains demonstrated that wild-type and mutant LACV mainly infect neuronal cells and that NSs is able to suppress IFN induction in the central nervous system. Thus, our data suggest little relevance of the NSs-induced apoptosis or RNAi inhibition for growth or pathogenesis of LACV in the mammalian host and indicate that NSs has no function in the insect vector. Since deletion of the viral NSs gene can be fully complemented by inactivation of the host's IFN system, we propose that the major biological function of NSs is suppression of the mammalian innate immune response.

* Corresponding author. Mailing address: Department of Virology, University of Freiburg, Hermann Herder Str. 11, Freiburg D-79008, Germany. Phone: 49 761 203 6614. Fax: 49 761 203 6634. E-mail: friedemann.weber{at}uniklinik-freiburg.de

{triangledown} Published ahead of print on 7 March 2007.

{dagger} Present address: Centre for Biomolecular Sciences, School of Biology, University of St. Andrews, North Haugh, St. Andrews KY16 9ST, Scotland, United Kingdom.

Journal of Virology, May 2007, p. 4991-4999, Vol. 81, No. 10
0022-538X/07/$08.00+0     doi:10.1128/JVI.01933-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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