Bacterial and synthetic DNA containing unmethylated 2´-deoxyribo(cytidine-phosphate-guanosine) (CpG) dinucleotides in specific sequence contexts activate the vertebrate innate immune system. A molecular pattern recognition receptor, Toll-like receptor 9 (TLR9), recognizes CpG DNA and initiates the signalling cascade, although a direct interaction between CpG DNA and TLR9 has not been demonstrated yet. TLR9 in different species exhibits sequence specificity. Our extensive structure–immunostimulatory activity relationship studies showed that a number of synthetic pyrimidine (Y) and purine (R) nucleotides are recognized by the receptor as substitutes for the natural nucleotides deoxycytidine and deoxyguanosine in a CpG dinucleotide. These studies permitted development of synthetic YpG, CpR and YpR immunostimulatory motifs, and showed divergent nucleotide motif recognition pattern of the receptor. Surprisingly, we found that synthetic immunostimulatory motifs produce different cytokine induction profiles compared with natural CpG motifs. Importantly, we also found that some of these synthetic immunostimulatory motifs show optimal activity in both mouse and human systems without the need to change sequences, suggesting an overriding of the species-dependent specificity of the receptor by the use of synthetic motifs. In the present paper, we review current understanding of structural recognition and functional modulation of TLR9 receptor by second-generation synthetic CpG DNAs and their potential application as wide-spectrum therapeutic agents.
Skip Nav Destination
Article navigation
Conference Article|
June 01 2003
Toll-like receptor 9: modulation of recognition and cytokine induction by novel synthetic CpG DNAs
E.R. Kandimalla;
E.R. Kandimalla
Hybridon, Inc., 345 Vassar Street, Cambridge, MA 02139, U.S.A.
Search for other works by this author on:
F.-G. Zhu;
F.-G. Zhu
Hybridon, Inc., 345 Vassar Street, Cambridge, MA 02139, U.S.A.
Search for other works by this author on:
L. Bhagat;
L. Bhagat
Hybridon, Inc., 345 Vassar Street, Cambridge, MA 02139, U.S.A.
Search for other works by this author on:
D. Yu;
D. Yu
Hybridon, Inc., 345 Vassar Street, Cambridge, MA 02139, U.S.A.
Search for other works by this author on:
S. Agrawal
S. Agrawal
1
Hybridon, Inc., 345 Vassar Street, Cambridge, MA 02139, U.S.A.
1To whom correspondence should be addressed (e-mail sagrawal@hybridon.com).
Search for other works by this author on:
Publisher: Portland Press Ltd
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2003 Biochemical Society
2003
Biochem Soc Trans (2003) 31 (3): 654–658.
Citation
E.R. Kandimalla, F.-G. Zhu, L. Bhagat, D. Yu, S. Agrawal; Toll-like receptor 9: modulation of recognition and cytokine induction by novel synthetic CpG DNAs. Biochem Soc Trans 1 June 2003; 31 (3): 654–658. doi: https://doi.org/10.1042/bst0310654
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Captcha Validation Error. Please try again.