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* Department of Medicine and
Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, Worcester, MA 01655
TLR7 senses RNA in endosomal compartments. TLR7 expression and signaling have been demonstrated in plasmacytoid and myeloid dendritic cells, B cells, and T cells. The regulation of TLR7 signaling can play a crucial role in shaping the immune response to RNA viruses with different cellular tropisms, and in developing adjuvants capable of promoting balanced humoral and cell-mediated immunity. We used unique characteristics of two ssRNA viruses, dengue virus and influenza virus, to delineate factors that regulate viral RNA-human TLR7 signaling beyond recognition in endosomal compartments. Our data show that TLR7 recognition of enveloped RNA virus genomes is linked to virus fusion or uncoating from the endosome. The signaling threshold required to activate TLR7-type I IFN production is greater than that required to activate TLR7-NF-
B-IL-8 production. The higher order structure of viral RNA appears to be an important determinant of TLR7-signaling potency. A greater understanding of viral RNA-TLR7 activity relationships will promote rational approaches to interventional and vaccine strategies for important human viral pathogens.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the National Institutes of Health (NIH U19 AI57319, R21 AI060791, and K08AI053542). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Jennifer P. Wang, Department of Medicine, University of Massachusetts Medical School, LRB 219, 55 Lake Avenue North, Worcester, MA 01655. E-mail address: jennifer.wang{at}umassmed.edu
3 Abbreviations used in this paper: DC, dendritic cell; pDC, plasmacytoid DC; mDC, myeloid DC; vRNA, viral RNA; D2V, dengue-2 virus; siRNA, short-interfering RNA; ODN, oligodeoxyribonucleotide; MOI, multiplicity of infection; ER, endoplasmic reticulum; SNV, Sin Nombre virus.
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