Importance of the anti-interferon capacity of Sendai virus C protein for pathogenicity in mice.
The Sendai virus (SeV) C protein blocks signal transduction of interferon (IFN), thereby counteracting the antiviral actions of IFN. Using HeLa cell lines expressing truncated or mutated SeV C proteins, we found that the C-terminal half has anti-IFN capacity, and that K(151)A, E(153)A, and R(154)A substitutions in the C protein eliminated this capacity. Here, we further created the mutant virus SeV Cm*, in which K(151)A, E(153)K, and R(157)L substitutions in the C protein were introduced without changing the amino acid sequence of overlapped P, V, and W proteins. SeV Cm* was found to lack anti-IFN capacity, as expected. While the growth rate and final yield of SeV Cm* were inferior to those of the wild-type SeV in IFN-responsive, STAT1-positive 2fTGH cells, SeV Cm* grew equivalently to the wild-type SeV in IFN-nonresponsive, STAT1-deficient U3A cells. SeV Cm* was thus shown to maintain multiplication capacity, except that it lacked anti-IFN capacity. Intranasally inoculated SeV Cm* could propagate in the lungs of STAT1(-/-) mice but was cleared from those of STAT1(+/+) mice without propagation. It was found that the anti-IFN capacity of the SeV C protein was indispensable for pathogenicity in mice. Conversely, the results show that the innate immunity contributed to elimination of SeV in early stages of infection in the absence of anti-IFN capacity.
Kato
Atsushi
A
Department of Virology 3, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashi-Murayama, Tokyo 208-0011, Japan. akato@nih.go.jp
Kiyotani
Katsuhiro
K
Kubota
Toru
T
Yoshida
Tetsuya
T
Tashiro
Masato
M
Nagai
Yoshiyuki
Y
D000818:Animals; D002460:Cell Line; D007372:Interferons / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D010253:Respirovirus Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D029082:Sendai virus / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D014764:Viral Proteins; C051221:nonstructural C protein, Sendai virus; D007372:Interferons