https://ir.ymlib.yonsei.ac.kr/handle/22282913/188584 2026-04-20T08:49:49Z https://ir.ymlib.yonsei.ac.kr/handle/22282913/211742 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 https://ir.ymlib.yonsei.ac.kr/handle/22282913/208278 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 https://ir.ymlib.yonsei.ac.kr/handle/22282913/206521 Title: Neutrophil Migration Is Mediated by VLA-6 in the Inflamed Adipose Tissue Authors: 현영민 Abstract: Adipose tissue, well known for its endocrine function, plays an immunological role in the body. The inflamed adipose tissue under LPS-induced systemic inflammation is characterized by the dominance of pro-inflammatory immune cells, particularly neutrophils. Although migration of macrophages toward damaged or dead adipocytes to form a crown-like structure in inflamed adipose tissue has been revealed, the neutrophilic interaction with adipocytes or the extracellular matrix remains unknown. Here, we demonstrated the involvement of adhesion molecules, particularly integrin α6β1, of neutrophils in adipocytes or the extracellular matrix of inflamed adipose tissue interaction. These results suggest that disrupting the adhesion between adipose tissue components and neutrophils may govern the accumulation of excessive neutrophils in inflamed tissues, a prerequisite in developing anti-inflammatory therapeutics by inhibiting inflammatory immune cells. 2024-06-01T00:00:00Z https://ir.ymlib.yonsei.ac.kr/handle/22282913/200162 Title: Immunogenicity and protective efficacy of RipA, a peptidoglycan hydrolase, against Mycobacterium tuberculosis Beijing outbreak strains Authors: 권기웅; 신성재 Abstract: Given that individuals with latent tuberculosis (TB) infection represent the major reservoir of TB infection, latency-associated antigens may be promising options for development of improved multi-antigenic TB subunit vaccine. Thus, we selected RipA, a peptidoglycan hydrolase required for efficient cell division of Mycobacterium tuberculosis (Mtb), as vaccine candidate. We found that RipA elicited activation of dendritic cells (DCs) by induction of phenotypic maturation, increased production of inflammatory cytokines, and prompt stimulation of MAPK and NF-κB signaling pathways. In addition, RipA-treated DCs promoted Th1-polarzied immune responses of naïve CD4+ T cells with increased proliferation and activated T cells from Mtb-infected mice, which conferred enhanced control of mycobacterial growth inside macrophages. Moreover, mice immunized with RipA formulated in GLA-SE adjuvant displayed remarkable generation of Ag-specific polyfunctional CD4+ T cells in both lung and spleen. Following an either conventional or ultra-low dose aerosol challenges with 2 Mtb Beijing clinical strains, RipA/GLA-SE-immunization was not inferior to BCG by mediating protection as single Ag. Collectively, our findings highlighted that RipA could be a novel candidate as a component of multi-antigenic TB subunit vaccines. 2024-03-01T00:00:00Z