Sequential Activation of Two Pathogen-Sensing Pathways Required for Type I Interferon Expression and Resistance to an Acute DNA Virus Infection.

Abstract

Toll-like receptor 9 (TLR9), its adaptor MyD88, the downstream transcription factor interferon regulatory factor 7 (IRF7), and type I interferons (IFN-I) are all required for resistance to infection with ectromelia virus (ECTV). However, it is not known how or in which cells these effectors function to promote survival. Here, we showed that after infection with ECTV, the TLR9-MyD88-IRF7 pathway was necessary in CD11c(+) cells for the expression of proinflammatory cytokines and the recruitment of inflammatory monocytes (iMos) to the draining lymph node (dLN). In the dLN, the major producers of IFN-I were infected iMos, which used the DNA sensor-adaptor STING to activate IRF7 and nuclear factor κB (NF-κB) signaling to induce the expression of IFN-α and IFN-β, respectively. Thus, in vivo, two pathways of DNA pathogen sensing act sequentially in two distinct cell types to orchestrate resistance to a viral disease.

• Authors: Ren-Huan Xu, Eric B Wong, Daniel Rubio, Felicia Roscoe, Xueying Ma, Savita Nair, Sanda Remakus, Reto Schwendener, Shinu John, Mark Shlomchik, Luis J Sigal
• Journal: Immunity (Immunity) Vol. 43 Issue 6 Pg. 1148-59 (Dec 15 2015) ISSN: 1097-4180 [Electronic] United States
• PMID: 26682986 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Interferon Regulatory Factor-7
• Interferon Type I
• Irf7 protein, mouse
• Membrane Proteins
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• Sting1 protein, mouse
• Tlr9 protein, mouse
• Toll-Like Receptor 9

Topics

• Animals
• DNA Virus Infections (immunology)
• Ectromelia virus
• Ectromelia, Infectious (immunology)
• Flow Cytometry
• Interferon Regulatory Factor-7 (immunology)
• Interferon Type I (biosynthesis, immunology)
• Lymph Nodes (immunology)
• Membrane Proteins (immunology)
• Mice
• Mice, Knockout
• Mice, Mutant Strains
• Monocytes (immunology)
• Myeloid Differentiation Factor 88 (immunology)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (immunology)
• Toll-Like Receptor 9 (immunology)