Survival of lethal poxvirus infection in mice depends on TLR9, and therapeutic vaccination provides protection.
Poxviruses such as the causative agent of smallpox have developed multiple strategies to suppress immune responses, including the suppression of DC activation. Since poxviruses are large DNA viruses, we hypothesized that their detection by DCs may involve the endosomal DNA recognition receptor TLR9. Indeed, we have shown here that DC recognition of ectromelia virus (ECTV), the causative agent of mousepox, completely depended on TLR9. The importance of TLR9 was highlighted by the fact that mice lacking TLR9 showed drastically increased susceptibility to infection with ECTV. In contrast, we found that the strongly attenuated poxvirus modified vaccinia virus Ankara (MVA) activated DCs by both TLR9-dependent and -independent pathways. We therefore tested whether we could use the broader induction of immune responses by MVA to protect mice from a lethal infection with ECTV. Indeed, MVA given at the same time as a lethal dose of ECTV protected mice from death. Importantly, MVA also rescued TLR9-deficient mice if administered 2 full days after an otherwise lethal infection with ECTV. Therefore, these data suggest an essential role for TLR9 in the defense against poxviruses. In addition, postexposure application of MVA may protect against lethal poxvirus infection.
Samuelsson
Christofer
C
Department of Research, Bavarian Nordic, Martinsried, Germany.
Hausmann
Jürgen
J
Lauterbach
Henning
H
Schmidt
Michaela
M
Akira
Shizuo
S
Wagner
Hermann
H
Chaplin
Paul
P
Suter
Mark
M
O'Keeffe
Meredith
M
Hochrein
Hubertus
H
D000818:Animals; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D004481:Ectromelia virus / Q000276:immunology / Q000472:pathogenicity; D006801:Humans; D007109:Immunity / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011213:Poxviridae Infections / Q000276:immunology / Q000401:mortality / Q000517:prevention & control; D015996:Survival Rate; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology*; D014611:Vaccination; D014616:Vaccinia virus / Q000276:immunology
C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9