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- 학과정보 : 의학과 미생물학전공 (검색결과 949 건)
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호사인모하마드 순천향대학교 일반대학원 2026 국내박사
Development of Microbiome-Based Therapeutics for Metabolic and Infectious Disease Mohammed Solayman Hossain Department of Medicine Graduate School Soonchunhyang University (Supervised by Professor Ho-Yeon Song) Immune-associated diseases remain major global health challenges, while the limitations of current therapeutic approaches, including reduced efficacy, adverse effects, and the emergence of drug resistance, highlight the urgent need for innovative treatment strategies. Advances in microbiome research have revealed the potential of microbial therapeutics as next-generation interventions capable of modulating host physiology and immune responses. This study aimed to develop microbiome-based therapeutics for representative metabolic and infectious diseases through a reverse translational research approach integrating microbiome analysis, strain discovery, functional validation, and mechanistic investigation. For metabolic disease, gout was selected as a target condition due to its increasing prevalence and the limitations associated with conventional urate-lowering therapies. Microbiome analysis of fecal samples from healthy individuals and gout patients identified Bifidobacterium as a key microbial biomarker associated with disease status. A novel strain, Bifidobacterium longum PMC72, was isolated and evaluated in a potassium oxonate (PO)-induced hyperuricemia mouse model. PMC72 significantly improved disease symptoms, including nausea, gait disturbances, ankle inflammation, and renal impairment. Therapeutic efficacy was accompanied by reductions in serum uric acid, blood urea nitrogen, hepatic xanthine oxidase activity, and oxidative stress markers, including malondialdehyde levels in serum, liver, and joint tissues. Furthermore, PMC72 downregulated inflammatory and uric acid transport-related gene expression in kidney tissues. Notably, these effects were comparable to those observed with Febuxostat treatment. Gut microbiome analysis further demonstrated restoration of hyperuricemia-induced dysbiosis by PMC72, whereas Febuxostat treatment alone reduced microbial diversity, and combination treatment achieved recovery toward eubiosis. For infectious disease, tuberculosis (TB), caused by Mycobacterium tuberculosis, was selected due to the increasing burden of drug-resistant strains and the need for alternative therapeutic strategies. A panel of probiotic strains was screened using an M. tuberculosis H37Rv-infected macrophage model, leading to the identification of Bifidobacterium bifidum PMC207 as a promising candidate with favorable efficacy and safety profiles. Whole-genome sequencing confirmed PMC207 as a novel strain. PMC207 extracts significantly reduced intracellular bacterial burden in macrophages infected with both drug-sensitive and extensively drug-resistant (XDR) strains. Furthermore, extracellular vesicles (EVs) isolated from PMC207 exhibited significant anti-tuberculosis activity. Mechanistic investigations demonstrated that PMC207 enhanced autophagic activity in infected macrophages while modulating host immune responses through suppression of pro-inflammatory cytokines and restoration of anti- inflammatory mediators. PMC207 also alleviated oxidative stress by reducing intracellular reactive oxygen species and normalizing nitric oxide production. Safety evaluation confirmed the absence of hemolytic activity, toxin-related genes, and other adverse probiotic characteristics. Collectively, these findings demonstrate that microbiome-derived therapeutics exert beneficial effects against both metabolic and infectious diseases through multi-modal mechanisms involving microbial modulation, immune regulation, oxidative stress reduction, and host-directed activity. This work highlights the potential of microbiome-based therapeutic development as a versatile platform for addressing diverse disease conditions and provides a framework for reverse translational approaches toward next-generation microbial therapeutics.
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말라리아는 말라리아 원충이 감염된 학질모기에 의해 인간에게 전파되는 벡터 매개 감염병이다. 세계보건기구에 따르면 현재 세계 인구의 절반이 말라리아 감염의 위험에 노출되어 있으며, 특히 열대열말라리아의 경우, 아프리카의 어린이 환자군에서 높은 치사율을 보이고 있다. 말라리아의 박멸을 위해서 반드시 선행되어야 하는 효과적인 치료제와 예방백신의 개발이 여전히 과제로 남아 있다. 따라서, 본 논문에서는 말라리아 치료약물 후보물질을 발굴하기 위해 허브의 일종인 미나리아재비 추출물의 항말라리아 효과를 평가하고, 백신 후보물질 발굴의 기초자료를 마련하기 위해 말라리아 백신 후보물질에 의해 유도되는 숙주 면역반응을 조사하였다. 미나리아재비는 중국 전통 의학에서 말라리아를 포함한 다양한 질병을 치료했다는 보고가 있으나, 아직까지 실험적 연구보고는 없었다. 따라서, 본 연구에서 in vitro와 in vivo에서 미나리아재비의 항말라리아 효과를 다음과 같이 입증하였다. 먼저, 미나리아재비의 어린 줄기 추출물은 in vitro에서 클로로퀸 민감성 및 내성 열대열말라리아 원충의 성장을 모두 유의하게 억제했다. 또한, 말라리아에 감염된 마우스에 미나리아재비 추출물을 경구투여 했을 때, 높은 말라리아 치료효과와 함께 간, 신장, 혈액 수치의 개선 및 높은 생존율을 확인할 수 있었다. 다음으로, VIR(variant interspersed repeats)의 백신 항원 후보 가능성을 조사하기 위해, 한국의 삼일열말라리아 환자 681명을 대상으로 VIR 단백질에 대한 자연획득 면역반응과 감염 단핵세포에 항원을 처리한 세포 면역반응을 평가하였다. 자연획득 면역반응에서는 환자군의 52.4%에서 VIR 단백질 특이 IgM 또는 IgG가 검출되었고, 항원 VIR25는 환자군의 27.8% 및 29.2%에서 IgG 및 IgM 반응이 관찰되었다. 세포 면역반응에서는 VIR-C2와 PvLP2에서 대조군인 MSP1-19와 비교하여 높은 세포활성화를 보였고, 또한 IL-2, IL-6, IL-10, G-CSF의 분비를 유도하고 있음을 확인하였다. 결론적으로, 미나리아재비는 in vitro 및 in vivo 모두에서 뚜렷한 독성없이 높은 항말라리아 효과를 보였으며, 이는 현재 항말라리아 약물로 널리 사용되고 있는 아르테미시닌의 원재료인 Artemisia annua L. (Qinghao) 추출물이 개발 초기에 12-40%의 말라리아 원충 억제 효과를 보였던 것을 고려할 때, 주목할 만한 결과다. 또한, 삼일열말라리아에 감염된 한국 말라리아 환자에서 VIR 항원에 대한 자연적 항체 획득 및 세포 면역반응이 관찰되었으며, 그 결과는 다른 국가에서 확인된 결과와 유사했다. 이는 VIR 유전자의 높은 유전적 다양성에도 불구하고 VIR 항원에 대한 면역반응이 여러 국가의 말라리아 원충 사이에서 보존되고 있다는 점에서 매우 흥미롭다. Malaria is among the most severe vector-borne infections; the disease ensues upon transferring Plasmodium sporozoites from infected Anopheles mosquitoes to human targets. According to the World Health Organization (WHO), half of the world’s population is currently at risk of malaria with high morbidity and mortality, and malaria remains a major challenge for healthcare providers. To control this threatening disease, accurate diagnostic tools, effective regimens, and preventive vaccines would be necessitated. Therefore, to improve the control strategy for malaria elimination, this thesis evaluated the anti-malarial effects of herb extract to discover anti-malarial drug candidates and host immune responses induced by malaria vaccine candidates. Following a brief description of malaria in Chapter I, Chapter II identified Ranunculus japonicus as the novel anti-malarial candidate, which has been used to treat various diseases as traditional Chinese medicine. First, the anti-malarial activity of the extract of the young stem of R. japonicus was evaluated in vitro using chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strains, and then, in vivo activity was evaluated in Plasmodium berghei (P. berghei)-infected mice via oral administration followed by a 4-day suppressive test focused on biochemical and hematological parameters. Exposure to extracts of R. japonicus resulted in significant inhibition of both chloroquine-sensitive (3D7) and resistant (Dd2) strains of P. falciparum. Administrating R. japonicus also resulted in potent anti-malarial activity against P. berghei in infected mice with no associated toxicity; treatment also resulted in improved hepatic, renal, and hematological parameters. In Chapter III, to investigate the potential of variant interspersed repeats (VIR) as a vaccine candidate, the naturally acquired immune response to VIR proteins has been evaluated in vivax malaria-infected individuals in the Republic of Korea. In 681 P. vivax-infected people, IgM or IgG was detected in 52.4% of the population. Among the VIR antigens, seven recombinant VIR proteins and two synthetic peptides, VIR25 elicited the highest humoral immune response in the whole population with IgG and IgM prevalence of 27.8% and 29.2%, respectively. In contrast, PvMSP1-19 elicited an even higher prevalence (92%) of IgG in the population. As for the cellular immune response, VIR-C2, PvLP2, and PvMSP1-19 induced high cell activation and secretion of IL-2, IL-6, IL10, and G-CSF in mononuclear cells from the P. vivax-infected population, comparable with results from PvMSP1-19. However, no significant proliferation response to these antigens was observed between the malaria-infected and healthy groups. Conclusively, the anti-malarial effects of R. japonicus were found both in vitro and in vivo with no evident toxicity, which is noteworthy considering that artemisinin, the current critical anti-malarial drug, began with the observation of only 12% – 40% parasite growth inhibition in vitro with an extract of Artemisia annua L. (Qinghao). Furthermore, moderate natural acquisition of antibody and cellular responses against VIR antigen as observed in P. vivax-infected Korean malaria patients, similar to that in other countries. Interestingly, the immune response to VIR antigens is conserved among malaria parasites in different countries, considering that VIR genes are highly polymorphic.
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