Alternate mechanisms of initial pattern recognition drive differential immune responses to related poxviruses.
Vaccinia immunization was pivotal to successful smallpox eradication. However, the early immune responses that distinguish poxvirus immunization from pathogenic infection remain unknown. To address this, we developed a strategy to map the activation of key signaling networks in vivo and applied this approach to define and compare the earliest signaling events elicited by immunizing (vaccinia) and lethal (ectromelia) poxvirus infections in mice. Vaccinia induced rapid TLR2-dependent responses, leading to IL-6 production, which then initiated STAT3 signaling in dendritic and T cells. In contrast, ectromelia did not induce TLR2 activation, and profound mouse strain-dependent responses were observed. In resistant C57BL/6 mice, the STAT1 and STAT3 pathways were rapidly activated, whereas in susceptible BALB/c mice, IL-6-dependent STAT3 activation did not occur. These data link early immune signaling events to infection outcome and suggest that activation of different pattern-recognition receptors early after infection may be important in determining vaccine efficacy.
O'Gorman
William E
WE
Department of Microbiology and Immunology, Baxter Lab in Genetic Pharmacology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Sampath
Padma
P
Simonds
Erin F
EF
Sikorski
Rachel
R
O'Malley
Mark
M
Krutzik
Peter O
PO
Chen
Hannah
H
Panchanathan
Vijay
V
Chaudhri
Geeta
G
Karupiah
Gunasegaran
G
Lewis
David B
DB
Thorne
Steve H
SH
Nolan
Garry P
GP
D000818:Animals; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology; D004481:Ectromelia virus / Q000276:immunology*; D004482:Ectromelia, Infectious / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D058507:Host Specificity / Q000276:immunology; D006801:Humans; D007114:Immunization; D015850:Interleukin-6 / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000502:physiology; D014615:Vaccinia / Q000276:immunology*; D014616:Vaccinia virus / Q000276:immunology*
D015850:Interleukin-6; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2