Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 46, Pages 17343-17348Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0605102103
Keywords
cytokines; innate immunity; Toll-like receptor; viral infection; plasmacytoid dendritic cell
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Funding
- NIAID NIH HHS [R01 AI054359, AI064705, AI054359, R01 AI064705] Funding Source: Medline
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Dendritic cells (DCs) express multiple Toll-like receptors (TLR) in distinct cellular locations. Herpes simplex viruses (HSV) have been reported to engage both the surface TLR2 and intracellular TLR9 in conventional DCs. However, the contributions of these TLRs in recognition of HSV and the induction of proinflammatory cytokines in DCs remain unclear. Here, we demonstrate that a rare population of HSV, both in laboratory strains and in primary clinical isolates from humans, has the capacity to activate TLR2. This virus population is recognized through both TLR2 and TLR9 for the induction of IL-6 and IL-12 secretion from bone marrow-derived DCs. Further, we describe a previously uncharacterized pathway of viral recognition in which TLR2 and TLR9 are engaged in sequence within the same DC. Live viral infection results in two additional agonists of TLR2 and TLR9. These results indicate, that in cells that express multiple TLRs, pathogens that contain multiple pathogen-associated molecular patterns can be detected in an orchestrate sequence and suggest that the innate immune system in DCs is optimized to linking uptake and degradation of pathogens to microbial recognition.
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