title: Rv2299c, a novel dendritic cell-activating antigen of Mycobacterium tuberculosis, fused-ESAT-6 subunit vaccine confers improved and durable protection against the hypervirulent strain HN878 in mice.
abstract: Understanding functional interactions between DCs and antigens is necessary for achieving an optimal and desired immune response during vaccine development. Here, we identified and characterized protein Rv2299c (heat-shock protein 90 family), which effectively induced DC maturation. The Rv2299c-maturated DCs showed increased expression of surface molecules and production of proinflammatory cytokines. Rv2299c induced these effects by binding to TLR4 and stimulating the downstream MyD88-, MAPK- and NF-κB-dependent signaling pathways. The Rv2299c-maturated DCs also showed an induced Th1 cell response with bactericidal activity and expansion of effector/memory T cells. The Rv2299c-ESAT-6 fused protein had greater immunoreactivity than ESAT-6. Furthermore, boosting BCG with the fused protein significantly reduced hypervirulent Mycobacterium tuberculosis HN878 burdens post-challenge. The pathological study of the lung from the challenged mice assured the efficacy of the fused protein. The fused protein boosting also induced Rv2299c-ESAT-6-specific multifunctional CD4+ T-cell response in the lungs of the challenged mice. Our findings suggest that Rv2299c is an excellent candidate for the rational design of an effective multiantigenic TB vaccine.
authors.affiliation: Department of Microbiology, and Medical Science, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Han-Gyu
authors.initials: HG
authors.lastname: Choi
authors.affiliation: Department of Microbiology, and Medical Science, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Seunga
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Microbiology, and Medical Science, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Yong Woo
authors.initials: YW
authors.lastname: Back
authors.affiliation: Department of Microbiology, and Medical Science, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Seungwha
authors.initials: S
authors.lastname: Paik
authors.affiliation: Department of Microbiology, and Medical Science, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Hye-Soo
authors.initials: HS
authors.lastname: Park
authors.affiliation: Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Woo Sik
authors.initials: WS
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Seung Bin
authors.initials: SB
authors.lastname: Cha
authors.affiliation: Department of Microbiology, and Medical Science, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Chul Hee
authors.initials: CH
authors.lastname: Choi
authors.affiliation: Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Sung Jae
authors.initials: SJ
authors.lastname: Shin
authors.affiliation: Department of Microbiology, and Medical Science, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Hwa-Jung
authors.initials: HJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D001500:BCG Vaccine / Q000008:administration & dosage / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D007156:Immunologic Memory / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity; D011993:Recombinant Fusion Proteins / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D022223:Vaccines, Subunit / Q000627:therapeutic use*
chemical_list: D000942:Antigens, Bacterial; D001500:BCG Vaccine; D001426:Bacterial Proteins; D016207:Cytokines; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D011993:Recombinant Fusion Proteins; D022223:Vaccines, Subunit
keywords: DC maturation; Toll-like receptor 4; multifunctional T cell; subunit vaccine; tuberculosis