https://ir.ymlib.yonsei.ac.kr/handle/22282913/188584 2026-07-20T03:31:33Z 2026-07-20T03:31:33Z Kim, Hongmin Kim, Jong-Seok Kwon, Kee Woong Kim, Woo Sik Park, Minchul Ha, Sang-Jun Choi, Sangwon Kim, Jiseon Shin, Sung Jae https://ir.ymlib.yonsei.ac.kr/handle/22282913/212570 2026-06-11T07:30:23Z 2026-05-01T00:00:00Z

Title: Enhanced tuberculosis control via leveraging dendritic cell-mediated Th1 responses in preventive and immunotherapeutic vaccine strategies Authors: Kim, Hongmin; Kim, Jong-Seok; Kwon, Kee Woong; Kim, Woo Sik; Park, Minchul; Ha, Sang-Jun; Choi, Sangwon; Kim, Jiseon; Shin, Sung Jae Abstract: Introduction: Insufficient vaccine efficacy of the Bacillus Calmette-Gu & eacute;rin (BCG) and long, expensive tuberculosis (TB) treatments highlight the need for better TB control measures. Methods: This study evaluated whether the adoptive transfer of dendritic cell (DC)-based vaccines pulsed with culture filtrate antigens (CFA) of Mycobacterium tuberculosis (Mtb) could enhance BCG efficacy and support anti-TB drug therapy. Results: In BCG-vaccinated mice, adoptive transfer of CFA-pulsed DCs promoted swift T cell recruitment to the lung parenchyma, reducing bacterial load within 1 week post-infection, promoting the generation of tissue-resident T cells and expansion of CD4* T cells co-producing IFN-c, IL-2, and/or TNF-a. The vaccine efficacy persisted for a prolonged period post-infection, with protection found in both high dose and low dose Mtb infection models. Additionally, CFA-DC administration during chemotherapy enhanced treatment efficacy, maintaining CD4' ' T cell responses. In latent TB models, mice were protected from Mtb reactivation in both drug-sensitive , multidrug-resistant TB models. Conclusions: DC-based prophylactic and immunotherapeutic vaccine strategies enhance protective immunity during BCG vaccination and chemotherapy, offering new insights into TB control strategies. (c) 2025 The Author(s). Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

2026-05-01T00:00:00Z Kwon, Kee Woong Kim, Hongmin Kim, Hagyu Brosch, Roland Shin, Sung Jae https://ir.ymlib.yonsei.ac.kr/handle/22282913/212989 2026-07-14T07:42:13Z 2026-04-01T00:00:00Z

Title: An ESAT-6-convergent prime-boost vaccination combining recombinant BCG expressing Mycobacterium marinum ESX-1 and ESAT-6/GLA-SE improves TB protection Authors: Kwon, Kee Woong; Kim, Hongmin; Kim, Hagyu; Brosch, Roland; Shin, Sung Jae Abstract: Although Bacille Calmette-Gu & eacute;rin (BCG) protects children against disseminated tuberculosis (TB), its limited efficacy against adult pulmonary TB underscores the need for improved vaccination strategies. We previously developed a recombinant BCG strain expressing the ESX-1 type VII secretion system of Mycobacterium marinum (BCG::ESX-1Mmar), which enhances immunogenicity through cytosolic immune signaling while maintaining low virulence. Here, we evaluated an ESAT-6-convergent prime-boost vaccination strategy in which mice were primed with ESX-1-competent BCG::ESX-1Mmar and subsequently boosted with Mycobacterium tuberculosis (Mtb)-derived ESAT-6 formulated with the TLR4 agonist adjuvant GLA-SE. Compared with ESAT-6/GLA-SE boosting following parental BCG priming, the BCG::ESX-1Mmar-primed regimen robustly increased antigen-specific CD4(+) T cells localized within the lung parenchyma. This strategy markedly enhanced polyfunctional Th1 responses against ESAT-6 and PPD, exceeding those induced by BCG::ESX-1Mmar alone or the conventional BCG-prime/subunit-boost approach. Importantly, ESAT-6 boosting of recombinant BCG::ESX-1Mmar conferred superior long-term protection against hypervirulent Mtb challenge and significantly reduced pulmonary inflammation. Together, these findings demonstrate that leveraging an ESX-1-competent recombinant BCG platform for targeted ESAT-6 boosting can overcome key limitations of classical BCG vaccination and represents a promising strategy for next-generation TB immunization.

2026-04-01T00:00:00Z Kim, Hongmin Kwon, Kee Woong Kim, Hagyu Jung, Weonseok Kim, Kyungmin Hong, Jung Joo Shin, Sung Jae https://ir.ymlib.yonsei.ac.kr/handle/22282913/211742 2026-04-03T00:45:49Z 2026-02-01T00:00:00Z

Title: Exploring Host-driven Immunopathological Factors Developing Severe Tuberculosis: Insights from Comparative Mouse Models Authors: Kim, Hongmin; Kwon, Kee Woong; Kim, Hagyu; Jung, Weonseok; Kim, Kyungmin; Hong, Jung Joo; Shin, Sung Jae Abstract: Tuberculosis (TB) pathogenesis arises from complex interactions between host immune responses and the genetic diversity of Mycobacterium tuberculosis (Mtb). To elucidate host determinants of TB immunopathology, we conducted a comparative analysis of inbred mouse strains infected with the highly virulent Mtb K strain. Among the strains tested, C3H/HeJ and A/J mice exhibited markedly increased susceptibility, characterized by elevated pulmonary bacterial burdens and extensive necrotizing lung pathology. Interestingly, at 2 weeks post-infection (PI), both strains showed lower bacterial burdens, limited dissemination, and less pulmonary inflammation than C57BL/6 mice, but at 4 weeks PI, this trend reversed. The increased disease severity was closely associated with pronounced pulmonary neutrophilic infiltration, elevated systemic levels of granulocyte colony-stimulating factor (G-CSF), expansion of Lin⁻Sca-1⁻c-Kit⁺CD34⁺CD16/32⁺ granulocyte-monocyte progenitors (GMPs) in the bone marrow (BM), and a substantially increased pulmonary neutrophil-to-T cell (N/T) ratio, which positively correlated with disease progression. Depletion of neutrophils or blockade of type I IFN from 2 weeks PI significantly ameliorated disease severity, as evidenced by reduced bacterial burden, improved lung pathology, and normalization of the N/T ratio. Notably, IL-10 receptor blockade and aging specifically mitigated disease severity in A/J mice, whereas BCG vaccination conferred greater protection in C3H/HeJ mice. These strain-specific protective effects were consistently associated with restored N/T ratios, normalized GMP levels, and attenuated systemic G-CSF levels. Together, our findings identify the pulmonary N/T ratio and GMP expansion as central, mechanistically linked drivers of type I IFN signaling and neutrophil-mediated TB immunopathology. © The author(s).

2026-02-01T00:00:00Z Kwon, Kee Woong Choi, Eunsol Kim, Hagyu Kim, Hyeong Woo Choi, Sangwon Lee, Seunghyun Ha, Sang-Jun Shin, Sung Jae 권기웅 https://ir.ymlib.yonsei.ac.kr/handle/22282913/208278 2026-02-05T00:26:12Z 2025-05-01T00:00:00Z

Title: Adjunctive beneficial effect of c-di-GMP, a STING agonist, in enhancing protective efficacy of TLR4-adjuvanted tuberculosis subunit vaccine formulations Authors: Kwon, Kee Woong; Choi, Eunsol; Kim, Hagyu; Kim, Hyeong Woo; Choi, Sangwon; Lee, Seunghyun; Ha, Sang-Jun; Shin, Sung Jae; 권기웅 Abstract: BackgroundEffective subunit vaccine development requires selecting appropriate adjuvant formulations to trigger desired adaptive immune responses. This study explores the immunogenicity and tuberculosis (TB) vaccine potential of antigens (Ags) combined with Toll-like receptor 4 (TLR4) adjuvants and a stimulator of interferon genes (STING) agonist.MethodsIn this work, we investigated the combination of Ags with TLR4 adjuvants (monophosphoryl lipid A / dimethyldioctadecylammonium bromide; MPL/DDA or glucopyranosyl lipid adjuvant-stable emulsion; GLA-SE) and a STING agonist, c-di-GMP (CDG). Mice were immunized three times by intramuscular injections at 3-week intervals. The effects of integrating Ags in these adjuvant formulations on the immune response were evaluated, focusing on the generation of Th1-biased, polyfunctional Ag-specific CD4+ T cells and their localization in the lung and spleen. To assess protection, immunized mice were aerogenically challenged with either conventional or ultra-low doses of Mycobacterium tuberculosis (Mtb) 4 weeks after the last immunization. Subsequently, bacterial load and pulmonary inflammation were assessed.ResultsIntegrating ESAT6 Ag in TLR4 and CDG adjuvant formulations remarkably boosted Th1-biased, polyfunctional ESAT6-specific CD4+ T cells in the lungs and spleen, providing durable protection against Mtb infection. The inclusion of CDG promoted mucosal localization of ESAT6-specific CD4+ T cells resembling resident memory phenotypes in the lung parenchyma and increased Ag-specific CD4+ T cells in lung vasculature. Immunization with another vaccine Ag candidate, Ag85B, in GLA-SE plus CDG similarly increased Ag85B-specific CD4+ T cells in the spleen and both lung compartments. Following ultra-low dose Mtb challenge, ESAT6 or Ag85B/GLA-SE/CDG immunizations significantly reduced bacterial loads compared to non-, Bacillus Calmette-Gu & eacute;rin (BCG)-, and ESAT6 or Ag85B/GLA-SE-immunized groups. Importantly, the inclusion of CDG decreased killer cell lectin-like receptor subfamily G member 1 (KLRG1) expression among Ag-specific CD4+ T cells in the lung, correlating with enhanced lung-homing evidenced by expanded lung parenchyma Ag-specific CD4+ T cells, including less-differentiated Th1 cells.ConclusionsThis study highlights that CDG, when used in combination with TLR4 adjuvants, enhances long-term protective immunity, offering a promising strategy for subunit TB vaccine development.

2025-05-01T00:00:00Z