Blocking of the TLR5 Activation Domain Hampers Protective Potential of Flagellin DNA Vaccine

@article{citeulike:1531102, abstract = {Flagellin is a key component of the flagella of many pathogens, including Pseudomonas aeruginosa. Flagellin is an attractive vaccine candidate because it is readily produced and manipulated as a recombinant protein and has intrinsic adjuvant activity mediated through TLR5. Although DNA vaccines encoding native Pseudomonas B-type (FliC) or A-type (FlaA) flagellin are strongly immunogenic, the resultant Ab response interferes with the interaction of homologous flagellin with TLR5. This reduces the ability of the host to clear homologous, but not heterologous, flagellin-expressing P. aeruginosa. To circumvent this problem, a DNA vaccine encoding a mutant FliC R90A flagellin was developed. The mutant Ag encoded by this vaccine was highly immunogenic, but its ability to interact with TLR5 was reduced by >100-fold. Vaccination with this flagellin mutant DNA vaccine induced cross-reactive Abs against both FliC and FlaA, but few Abs capable of interfering with TLR5 activation. The flagellin mutant DNA vaccine provided excellent protection against both FliC- and FlaA-expressing P. aeruginosa. These findings suggest that vaccines against flagellated pathogens should avoid inducing Abs against TLR5 and raise the possibility that flagellated bacteria evade host elimination by facilitating the production of Abs that reduce the host's ability to mount an innate immune response.}, author = {Saha, Sukumar and Takeshita, Fumihiko and Matsuda, Tomoko and Jounai, Nao and Kobiyama, Kouji and Matsumoto, Tetsuya and Sasaki, Shin and Yoshida, Atsushi and Xin, Ke-Qin and Klinman, Dennis M. and Uematsu, Satoshi and Ishii, Ken J. and Akira, Shizuo and Okuda, Kenji }, citeulike-article-id = {1531102}, journal = {J Immunol}, keywords = {flagellin-tumor, tlr5-flagellin}, month = {July}, number = {2}, pages = {1147--1154}, posted-at = {2007-08-02 19:43:19}, priority = {2}, title = {Blocking of the TLR5 Activation Domain Hampers Protective Potential of Flagellin DNA Vaccine}, url = {http://www.jimmunol.org/cgi/content/abstract/179/2/1147}, volume = {179}, year = {2007} }

TY - JOUR ID - citeulike:1531102 L3 - citeulike-article-id:1531102 TI - Blocking of the TLR5 Activation Domain Hampers Protective Potential of Flagellin DNA Vaccine JF - J Immunol VL - 179 IS - 2 SP - 1147 EP - 1154 N2 - Flagellin is a key component of the flagella of many pathogens, including Pseudomonas aeruginosa. Flagellin is an attractive vaccine candidate because it is readily produced and manipulated as a recombinant protein and has intrinsic adjuvant activity mediated through TLR5. Although DNA vaccines encoding native Pseudomonas B-type (FliC) or A-type (FlaA) flagellin are strongly immunogenic, the resultant Ab response interferes with the interaction of homologous flagellin with TLR5. This reduces the ability of the host to clear homologous, but not heterologous, flagellin-expressing P. aeruginosa. To circumvent this problem, a DNA vaccine encoding a mutant FliC R90A flagellin was developed. The mutant Ag encoded by this vaccine was highly immunogenic, but its ability to interact with TLR5 was reduced by >100-fold. Vaccination with this flagellin mutant DNA vaccine induced cross-reactive Abs against both FliC and FlaA, but few Abs capable of interfering with TLR5 activation. The flagellin mutant DNA vaccine provided excellent protection against both FliC- and FlaA-expressing P. aeruginosa. These findings suggest that vaccines against flagellated pathogens should avoid inducing Abs against TLR5 and raise the possibility that flagellated bacteria evade host elimination by facilitating the production of Abs that reduce the host's ability to mount an innate immune response. KW - flagellin-tumor KW - tlr5-flagellin AU - Saha, Sukumar AU - Takeshita, Fumihiko AU - Matsuda, Tomoko AU - Jounai, Nao AU - Kobiyama, Kouji AU - Matsumoto, Tetsuya AU - Sasaki, Shin AU - Yoshida, Atsushi AU - Xin, Ke-Qin AU - Klinman, Dennis AU - Uematsu, Satoshi AU - Ishii, Ken AU - Akira, Shizuo AU - Okuda, Kenji PY - 2007/07/15/ UR - http://www.jimmunol.org/cgi/content/abstract/179/2/1147 ER -