Helicobacter pylori flagellin: TLR5 evasion and fusion-based conversion into a TLR5 agonist

Helicobacter pylori is a flagellated bacterium of the Epsilonproteobacteria class that causes peptic ulcers. Flagellin is a primary structural protein that assembles into the flagellar filament. Flagellins from bacteria that belong to the Gammaproteobacteria and Firmicutes groups are detected by Tol...

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Published in:Biochemical and biophysical research communications 2018-11, Vol.505 (3), p.872-878
Main Authors: Kim, Jee-Hyeon, Namgung, Byeol, Jeon, Ye Ji, Song, Wan Seok, Lee, Jeonghyun, Kang, Seung Goo, Yoon, Sung-il
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
BACILLUS SUBTILIS
Flagellin
Fusion
Helicobacter pylori
TLR5
ULCERS
Vaccine
VACCINES
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Summary:Helicobacter pylori is a flagellated bacterium of the Epsilonproteobacteria class that causes peptic ulcers. Flagellin is a primary structural protein that assembles into the flagellar filament. Flagellins from bacteria that belong to the Gammaproteobacteria and Firmicutes groups are detected by Toll-like receptor 5 (TLR5) in the host, triggering the innate immune response, and thus have been studied for the development of vaccines against diverse infections through fusion with protein antigens. However, H. pylori flagellin (hFlg) does not stimulate TLR5, allowing H. pylori to evade TLR5-mediated immune surveillance. The unresponsiveness of TLR5 to hFlg, along with the tendency of the hFlg protein to precipitate, limits the utility of hFlg for H. pylori vaccine development. Here, we report a soluble hFlg derivative protein that activates TLR5. We performed expression and purification screens with full-length and fragment hFlg proteins and identified the hypervariable domains as the soluble part of hFlg. The hypervariable domains of hFlg were engineered into a TLR5 agonist through fusion with the TLR5-activating Bacillus subtilis flagellin. Furthermore, based on comparative sequence and mutation analyses, we reveal that hFlg evolved to evade TLR5 detection by modifying residues that correspond to a TLR5-activation hot spot. •Helicobacter flagellin (hFlg) evades TLR5 by modifying a TLR5-activation hot spot.•The hypervariable domains of hFlg were identified as the soluble part of hFlg.•hFlg was engineered to activate TLR5 through fusion with Bacillus flagellin.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2018.09.179