Gachon University Gil Medical Center

Helicobacter pylori (H. pylori) infection has been associated with gastric carcinogenesis. However, the precise involvement of LRP8, the low-density lipoprotein receptor-related protein 8, in H. pylori pathogenesis and gastric cancer (GC) remains poorly understood.To investigate the potential roles of LRP8 in H. pylori infection and gastric carcinogenesis.Three-dimensional human-derived gastric organoids (hGO) and gastric cancer organoids (hGCO) were synthesized from the tissues obtained from human donors. In this work, multi-omics combined with in vivo and in vitro studies were conducted to investigate the potential involvement of LRP8 in H. pylori-induced GC.We found that H. pylori infection significantly upregulated the expression of LRP8 in human GC tissues, cells, organoids, and mouse gastric mucous. In particular, LRP8 exhibited a distinct enrichment in cancer stem cells (CSC). Functionally, silencing of LRP8 affected the formation and proliferation of tumor spheroids, while increased expression of LRP8 was associated with increased proliferation and stemness of GC cells and organoids. Mechanistically, LRP8 promotes the binding of E-cadherin to β-catenin, thereby promoting nuclear translocation and transcriptional activity of β-catenin. Furthermore, LRP8 interacts with the cytotoxin-associated gene A (CagA) to form the CagA/LRP8/β-catenin complex. This complex further amplifies H. pylori-induced β-catenin nuclear translocation, leading to increased transcription of inflammatory factors and CSC markers. Clinical analysis demonstrated that abnormal overexpression of LRP8 is correlated with a poor prognosis and resistance to 5-Fluorouracil in patients with GC.Our findings provide valuable information on the molecular intricacies of H. pylori-induced gastric carcinogenesis, offering potential therapeutic targets and prognostic markers for GC.

Owing to its high mortality rate, lung cancer (LC) remains the most common cancer worldwide, with the highest malignancy diagnosis rate. The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling (PAM) pathway is a critical intracellular pathway involved in various cellular functions and regulates numerous cellular processes, including growth, survival, proliferation, metabolism, apoptosis, invasion, and angiogenesis. This review aims to highlight preclinical and clinical studies focusing on the PAM signaling pathway in LC and underscore the potential of natural products targeting it. Additionally, this review synthesizes the existing literature and discusses combination therapy and future directions for LC treatment while acknowledging the ongoing challenges in the field. Continuous development of novel therapeutic agents, technologies, and precision medicine offers an increasingly optimistic outlook for the treatment of LC.

Toll-like receptors (TLRs) are central to initiate immune responses against invading pathogens. To ensure host defense while avoiding aberrant activation leading to pathogenic inflammation and autoimmune diseases, TLRs are tightly controlled by multilevel regulatory mechanisms. Through a loss-of-function genetic screen in a reporter cell line engineered to undergo cell death upon TLR7-induced IRF5 activation, we identified here CCDC134 as an essential factor for TLR responses. CCDC134 deficiency impaired endolysosomal TLR-induced NF-κB, MAPK, and IRF5 activation, as well as downstream production of proinflammatory cytokines and type I interferons. We further demonstrated that CCDC134 is an endoplasmic reticulum (ER)–resident interactor of Gp96 (HSP90B1/Grp94), an ER chaperone essential for folding and trafficking of plasma membrane and endolysosomal TLRs. CCDC134 controlled Gp96 stability as its loss led to Gp96 hyperglycosylation and ER-associated protein degradation (ERAD)-mediated clearance. Accordingly, CCDC134 deficiency impaired the folding, maturation, and trafficking of TLRs, resulting in blunted inflammatory responses upon stimulation. Altogether, this study reveals CCDC134 as a central regulator of the chaperone Gp96, thereby controlling TLR biogenesis and responses.

AbstractWhile apoptosis dismantles the cell to enforce immunological silence, pyroptotic cell death provokes inflammation. Little is known of the structural architecture of cells undergoing pyroptosis, and whether pyroptotic corpses are immunogenic. Here we report that inflammasomes trigger the Gasdermin-D- and calcium-dependent eruption of filopodia from the plasma membrane minutes before pyroptotic cell rupture, to crown the resultant corpse with filopodia. As a rich store of F-actin, pyroptotic filopodia are recognized by dendritic cells through the F-actin receptor, CLEC9A (DNGR1). We propose that cells assemble filopodia before cell rupture to serve as a posthumous mark for a cell that has died by gasdermin-induced pyroptosis, or MLKL-induced necroptosis, for recognition by dendritic cells. This study reveals the spectacular morphology of pyroptosis and identifies a mechanism by which inflammasomes induce pyroptotic cells to construct a de novo alarmin that activates dendritic cells via CLEC9A, which coordinates the transition from innate to adaptive immunity1,2.

Deeper understanding of the crosstalk between host cells and Mycobacterium tuberculosis (Mtb) provides crucial guidelines for the rational design of novel intervention strategies against tuberculosis (TB). Mycobacteria possess a unique complex cell wall with arabinogalactan (AG) as a critical component. AG has been identified as a virulence factor of Mtb which is recognized by host galectin-9. Here, we demonstrate that galectin-9 directly inhibited mycobacterial growth through AG-binding property of carbohydrate-recognition domain 2. Furthermore, IgG antibodies with AG specificity were detected in the serum of TB patients. Based on the interaction between galectin-9 and AG, we developed a monoclonal antibody (mAb) screening assay and identified AG-specific mAbs which profoundly inhibit Mtb growth. Mechanistically, proteomic profiling and morphological characterizations revealed that AG-specific mAbs regulate AG biosynthesis, thereby inducing cell wall swelling. Thus, direct AG-binding by galectin-9 or antibodies contributes to protection against TB. Our findings pave the way for the rational design of novel immunotherapeutic strategies for TB control.

Deeper understanding of the crosstalk between host cells and Mycobacterium tuberculosis (Mtb) provides crucial guidelines for the rational design of novel intervention strategies against tuberculosis (TB). Mycobacteria possess a unique complex cell wall with arabinogalactan (AG) as a critical component. AG has been identified as a virulence factor of Mtb which is recognized by host galectin-9. Here, we demonstrate that galectin-9 directly inhibited mycobacterial growth through AG-binding property of carbohydrate-recognition domain 2. Furthermore, IgG antibodies with AG specificity were detected in the serum of TB patients. Based on the interaction between galectin-9 and AG, we developed a monoclonal antibody (mAb) screening assay and identified AG-specific mAbs which profoundly inhibit Mtb growth. Mechanistically, proteomic profiling and morphological characterizations revealed that AG-specific mAbs regulate AG biosynthesis, thereby inducing cell wall swelling. Thus, direct AG-binding by galectin-9 or antibodies contributes to protection against TB. Our findings pave the way for the rational design of novel immunotherapeutic strategies for TB control.

Abstract Eosinophils control many aspects of the vertebrate innate immune response. They contribute to homeostasis, inflammatory conditions and defense against pathogens. With the varied functions of eosinophils, they have been found to play both protective and pathogenic roles in many diseases. The zebrafish (Danio rerio) has emerged as a useful model organism for human diseases but tools to study eosinophils in this model are severely limited. Here, we characterize a new and highly specific marker gene, embp, for eosinophils in zebrafish and report a new transgenic reporter line using this gene to visualize eosinophils in vivo. In addition, we created an Embp-specific polyclonal Ab that allows the identification of eosinophils ex vivo. These new tools expand the approaches for studying eosinophils in the zebrafish model. Using these reagents, we have been able to identify Embp as a constituent of eosinophil granules in zebrafish. These advances will allow for the investigation of eosinophil biology in the zebrafish model organism, allowing researchers to identify the contribution of eosinophils to the many diseases that are modeled within zebrafish and also shed light on the evolution of eosinophils within vertebrates.

Cells that lack p53 signaling frequently occur in ulcerative colitis (UC) and are considered early drivers in UC-associated colorectal cancer (CRC). Epithelial injury during colitis is associated with transient stem cell reprogramming from the adult, homeostatic to a “fetal-like” regenerative state. Here, we use murine and organoid-based models to study the role of Trp53 during epithelial reprogramming. We find that p53 signaling is silent and dispensable during homeostasis but strongly up-regulated in the epithelium upon DSS-induced colitis. While in WT cells this causes termination of the regenerative state, crypts that lack Trp53 remain locked in the highly proliferative, regenerative state long-term. The regenerative state in WT cells requires high Wnt signaling to maintain elevated levels of glycolysis. Instead, Trp53 deficiency enables Wnt-independent glycolysis due to overexpression of rate-limiting enzyme PKM2. Our study reveals the context-dependent relevance of p53 signaling specifically in the injury-induced regenerative state, explaining the high abundance of clones lacking p53 signaling in UC and UC-associated CRC.

Host–microorganism encounters take place in many different ways and with different types of outcomes. Three major types of microorganisms need to be distinguished: (1) pathogens that cause harm to the host and must be controlled; (2) environmental microorganisms that can be ignored but must be controlled at higher abundance; and (3) symbiotic microbiota that require support by the host. Recent evidence indicates that the aryl hydrocarbon receptor (AHR) senses and initiates signalling and gene expression in response to a plethora of microorganisms and infectious conditions. It was originally identified as a receptor that binds xenobiotics. However, it was subsequently found to have a critical role in numerous biological processes, including immunity and inflammation and was recently classified as a pattern recognition receptor. Here we review the role of the AHR in host–pathogen interactions, focusing on AHR sensing of different microbial classes, the ligands involved, responses elicited and disease outcomes. Moreover, we explore the therapeutic potential of targeting the AHR in the context of infection. The aryl hydrocarbon receptor (AHR) can sense and initiate immune responses to many different infectious organisms. Here, Moura-Alves and colleagues review the role of the AHR in host–pathogen interactions and explore the therapeutic potential of targeting the AHR in the context of different infectious diseases.

Goats are natural hosts of Mycobacterium (M.) bovis, and affected herds can be the cause of significant economic losses. Similarites in disease course and lesions of M. bovis infections in goats and M. tuberculosis in humans make goats good models for human tuberculosis. The aim of this investigation was to characterize M. bovis challenge models in goats. For this, goats were endobronchially inoculated with three doses of M. bovis or culture medium. Clinical signs, shedding, and immune responses were monitored until 146 days post inoculation (dpi). At necropsy, lesions were examined by computed tomography, histology, and bacteriological culture. Infected goats did not develop clinical signs. M. bovis was cultured from feces, but never from nasal swabs. IGRAs were positive from 28 dpi onwards, antibodies at 140 dpi, and SICCT at 146 dpi. The increase in CD25+, IFN-γ+, and IFN-γ-releasing T-cell subpopulations was time-related, but not dose-dependent. All infected goats developed paucibacillary granulomas in the lungs and regional lymph nodes. M. bovis was regularly cultured. Dose-dependent effects included the size of pulmonary lesions, caverns, intestinal lesions, and early generalization in the high-dose group. In summary, reproducible challenge models with dose-dependent differences in lesions were established, which may serve for testing vaccines for veterinary or medical use.

Background An estimated one fourth of the world's population is infected with Mycobacterium tuberculosis, and 5–10% of those infected develop tuberculosis in their lifetime. Preventing tuberculosis is one of the most underutilized but essential components of curtailing the tuberculosis epidemic. Moreover, current evidence illustrates that tuberculosis manifestations occur along a dynamic spectrum from infection to disease rather than a binary state as historically conceptualized. Elucidating determinants of transition between these states is crucial to decreasing the tuberculosis burden and reaching the END-TB Strategy goals as defined by the WHO. Vaccination, detection of infection, and provision of preventive treatment are key elements of tuberculosis prevention. Objectives This review provides a comprehensive summary of recent evidence and state-of-the-art updates on advancements to prevent tuberculosis in various settings and high-risk populations. Sources We identified relevant studies in the literature and synthesized the findings to provide an overview of the current state of tuberculosis prevention strategies and latest research developments. Content We present the current knowledge and recommendations regarding tuberculosis prevention, with a focus on M. bovis Bacille-Calmette-Guérin vaccination and novel vaccine candidates, tests for latent infection with M. tuberculosis, regimens available for tuberculosis preventive treatment and recommendations in low- and high-burden settings. Implications Effective tuberculosis prevention worldwide requires a multipronged approach that addresses social determinants, and improves access to tuberculosis detection and to new short tuberculosis preventive treatment regimens. Robust collaboration and innovative research are needed to reduce the global burden of tuberculosis and develop new detection tools, vaccines, and preventive treatments that serve all populations and ages.