title: Antigen replacement of domains D2 and D3 in flagellin promotes mucosal IgA production and attenuates flagellin-induced inflammatory response after intranasal immunization.
abstract: Targeting early infection in mucosal sites is one of the primary goals for mucosal vaccines so as to prevent pathogen mucosal transmission and infection. The TLR5 agonist flagellin was deemed to be a mucosal adjuvant candidate for clinical usage. However, the high antigenicity of flagellin and the possible inflammatory injury induced by flagellin might restrict its clinical usage. Here HIV-1 p24 protein was selected as an antigen model and we replaced the main antigenicity region domains D2 and D3 of non-pathogenic E.coli-derived flagellin (KF). The derived soluble protein KFD-p24 3D was then compared with KF-p24, which fused p24 directly to the C-terminal of KF. In vitro and ex vivo experiments showed that KFD-p24 3D has lower TLR5 agonist efficacy and less immunocyte-activating efficacy. Interestingly, the production of KF- specific antibody was highly reduced, and KFD-p24 3D induced IgA-biased antibody responses in mucosal sites. Moreover, KFD-p24 3D induced far fewer systemic inflammatory responses and abrogated detectable inflammatory side effects on mice, even at the high dose. The properties of enhanced IgA generation and attenuated inflammatory responses broaden the safe-dose range of KFD-p24 3D flagellin, creating a potentially promising mucosal adjuvant.
authors: Mucosal Immunity Research Group; State Key Laboratory of Virology; Wuhan Institute of Virology; Chinese Academy of Sciences; Wuhan, P.R. China.
authors: Jingyi
authors: J
authors: Yang
authors: Maohua
authors: M
authors: Zhong
authors: Yan
authors: Y
authors: Zhang
authors: Ejuan
authors: E
authors: Zhang
authors: Ying
authors: Y
authors: Sun
authors: Yuan
authors: Y
authors: Cao
authors: Yaoming
authors: Y
authors: Li
authors: Dihan
authors: D
authors: Zhou
authors: Benxia
authors: B
authors: He
authors: Yaoqing
authors: Y
authors: Chen
authors: Yi
authors: Y
authors: Yang
authors: Jie
authors: J
authors: Yu
authors: Huimin
authors: H
authors: Yan
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology* / Q000633:toxicity; D000281:Administration, Intranasal; D000818:Animals; D005260:Female; D005408:Flagellin / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology* / Q000633:toxicity; D016655:HIV Core Protein p24 / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D018928:Immunity, Mucosal; D007114:Immunization / Q000379:methods*; D007070:Immunoglobulin A / Q000032:analysis*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D016655:HIV Core Protein p24; D007070:Immunoglobulin A; D011993:Recombinant Fusion Proteins; D005408:Flagellin
keywords: IgA; adjuvant; flagellin; inflammatory response; mucosal
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