La Crosse bunyavirus nonstructural protein NSs serves to suppress the type I interferon system of mammalian hosts.
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.
Blakqori
Gjon
G
Department of Virology, University of Freiburg, Hermann Herder Str. 11, Freiburg D-79008, Germany.
Delhaye
Sophie
S
Habjan
Matthias
M
Blair
Carol D
CD
Sánchez-Vargas
Irma
I
Olson
Ken E
KE
Attarzadeh-Yazdi
Ghassem
G
Fragkoudis
Rennos
R
Kohl
Alain
A
Kalinke
Ulrich
U
Weiss
Siegfried
S
Michiels
Thomas
T
Staeheli
Peter
P
Weber
Friedemann
F
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000473:pathology / Q000821:virology; D002460:Cell Line; D006224:Cricetinae; D009033:Culicidae; D004195:Disease Models, Animal; D004670:Encephalitis, California / Q000821:virology; D006801:Humans; D007150:Immunohistochemistry; D007370:Interferon Type I / Q000037:antagonists & inhibitors*; D018062:La Crosse virus / Q000276:immunology* / Q000472:pathogenicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000821:virology; D034622:RNA Interference; D012672:Semliki forest virus / Q000254:growth & development; D017361:Viral Nonstructural Proteins / Q000502:physiology*
D007370:Interferon Type I; D017361:Viral Nonstructural Proteins