title: Flagellin-dependent TLR5/caveolin-1 as a promising immune activator in immunosenescence.
abstract: The age-associated decline of immune responses causes high susceptibility to infections and reduced vaccine efficacy in the elderly. However, the mechanisms underlying age-related deficits are unclear. Here, we found that the expression and signaling of flagellin (FlaB)-dependent Toll-like receptor 5 (TLR5), unlike the other TLRs, were well maintained in old macrophages, similar to young macrophages. The expression and activation of TLR5/MyD88, but not TLR4, were sensitively regulated by the upregulation of caveolin-1 in old macrophages through direct interaction. This interaction was also confirmed using macrophages from caveolin-1 or MyD88 knockout mice. Because TLR5 and caveolin-1 were well expressed in major old tissues including lung, skin, intestine, and spleen, we analyzed in vivo immune responses via a vaccine platform with FlaB as a mucosal adjuvant for the pneumococcal surface protein A (PspA) against Streptococcus pneumoniae infection in young and aged mice. The FlaB-PspA fusion protein induced a significantly higher level of PspA-specific IgG and IgA responses and demonstrated a high protective efficacy against a lethal challenge with live S. pneumoniae in aged mice. These results suggest that caveolin-1/TLR5 signaling plays a key role in age-associated innate immune responses and that FlaB-PspA stimulation of TLR5 may be a new strategy for a mucosal vaccine adjuvant against pneumococcal infection in the elderly.
authors.affiliation: Department of Biochemistry, Chonnam National University Medical School, Gwangju, 501-746, South Korea.
authors.forename: Jae Sung
authors.initials: JS
authors.lastname: Lim
authors.affiliation: Department of Biochemistry, Chonnam National University Medical School, Gwangju, 501-746, South Korea.|Center for Creative Biomedical Scientists, Chonnam National University Medical School, Gwangju, 501-746, South Korea.
authors.forename: Kim Cuc Thi
authors.initials: KC
authors.lastname: Nguyen
authors.affiliation: Clinical Vaccine R&D Center, Chonnam National University Hwasun Hospital, 160 Ilsim-Ri, Hwasun-gun, Jeonnam, 519-809, South Korea.
authors.forename: Chung Truong
authors.initials: CT
authors.lastname: Nguyen
authors.affiliation: Division of Life Science, Korea Basic Science Institute, Daejeon, 305-333, South Korea.
authors.forename: Ik-Soon
authors.initials: IS
authors.lastname: Jang
authors.affiliation: Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul, 120-749, South Korea.|College of Pharmacy, Yonsei University, Incheon, 406-840, South Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Han
authors.affiliation: Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology (IZI), University of Leipzig, 04103, Leipzig, Germany.|Translational Center for Regenerative Medicine (TRM), University of Leipzig, 04103, Leipzig, Germany.
authors.forename: Claire
authors.initials: C
authors.lastname: Fabian
authors.affiliation: Clinical Vaccine R&D Center, Chonnam National University Hwasun Hospital, 160 Ilsim-Ri, Hwasun-gun, Jeonnam, 519-809, South Korea.|Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju, 500-757, South Korea.
authors.forename: Shee Eun
authors.initials: SE
authors.lastname: Lee
authors.affiliation: Clinical Vaccine R&D Center, Chonnam National University Hwasun Hospital, 160 Ilsim-Ri, Hwasun-gun, Jeonnam, 519-809, South Korea.|Department of Microbiology, Chonnam National University Medical School, Gwangju, 501-746, South Korea.
authors.forename: Joon Haeng
authors.initials: JH
authors.lastname: Rhee
authors.affiliation: Department of Biochemistry, Chonnam National University Medical School, Gwangju, 501-746, South Korea.|Center for Creative Biomedical Scientists, Chonnam National University Medical School, Gwangju, 501-746, South Korea.|Clinical Vaccine R&D Center, Chonnam National University Hwasun Hospital, 160 Ilsim-Ri, Hwasun-gun, Jeonnam, 519-809, South Korea.|Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, 501-746, South Korea.
authors.forename: Kyung A
authors.initials: KA
authors.lastname: Cho
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000172:deficiency / Q000276:immunology*; D005260:Female; D005408:Flagellin / Q000276:immunology*; D000068884:Immunosenescence; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013296:Streptococcus pneumoniae / Q000737:chemistry / Q000276:immunology / Q000302:isolation & purification; D051198:Toll-Like Receptor 5 / Q000276:immunology*
chemical_list: D051242:Caveolin 1; D051198:Toll-Like Receptor 5; D005408:Flagellin
keywords: TLR5; caveolin-1; flagellin; immunosenescence; vaccine adjuvant