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2005 ; 79
(5
): 2847-58
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Involvement of the Toll-like receptor 9 signaling pathway in the induction of
innate immunity by baculovirus
#MMPMID15709004
Abe T
; Hemmi H
; Miyamoto H
; Moriishi K
; Tamura S
; Takaku H
; Akira S
; Matsuura Y
J Virol
2005[Mar]; 79
(5
): 2847-58
PMID15709004
show ga
We have previously shown that mice inoculated intranasally with a wild-type
baculovirus (Autographa californica nuclear polyhedrosis virus [AcNPV]) are
protected from a lethal challenge by influenza virus. However, the precise
mechanism of induction of this protective immune response by the AcNPV treatment
remained unclear. Here we show that AcNPV activates immune cells via the
Toll-like receptor 9 (TLR9)/MyD88-dependent signaling pathway. The production of
inflammatory cytokines was severely reduced in peritoneal macrophages (PECs) and
splenic CD11c(+) dendritic cells (DCs) derived from mice deficient in MyD88 or
TLR9 after cultivation with AcNPV. In contrast, a significant amount of alpha
interferon (IFN-alpha) was still detectable in the PECs and DCs of these mice
after stimulation with AcNPV, suggesting that a TLR9/MyD88-independent signaling
pathway might also participate in the production of IFN-alpha by AcNPV. Since
previous work showed that TLR9 ligands include bacterial DNA and certain
oligonucleotides containing unmethylated CpG dinucleotides, we also examined the
effect of baculoviral DNA on the induction of innate immunity. Transfection of
the murine macrophage cell line RAW264.7 with baculoviral DNA resulted in the
production of the inflammatory cytokine, while the removal of envelope
glycoproteins from viral particles, UV irradiation of the virus, and pretreatment
with purified baculovirus envelope proteins or endosomal maturation inhibitors
diminished the induction of the immune response by AcNPV. Together, these results
indicate that the internalization of viral DNA via membrane fusion mediated by
the viral envelope glycoprotein, as well as endosomal maturation, which releases
the viral genome into TLR9-expressing cellular compartments, is necessary for the
induction of the innate immune response by AcNPV.