Biology subjects

Wolthers, K. C.

Publications and source records attributed to Wolthers, K. C..

4 recordsLinked to original sources

bioRxiv2024

Parechovirus-3 infection disrupts immunometabolism and leads to glutamate excitotoxicity in neural organoids

Parechovirus ahumpari 3 (HPeV-3), is among the main agents causing severe neonatal neurological infections such as encephalitis and meningitis. However, the underlying molecular mechanisms and changes to the host cellular landscape leading to neurological disease has been understudied. Through quantitative proteomic analysis of HPeV-3 infected neural organoids, we identified unique metabolic changes following HPeV-3 infection that indicate immunometabolic dysregulation. Protein and pathway analyses showed significant alterations in neurotransmission and potentially, neuronal excitotoxicity. Elevated levels of extracellular glutamate, lactate dehydrogenase (LDH), and neurofilament light (NfL) confirmed glutamate excitotoxicity to be a key mechanism contributing to neuronal toxicity in HPeV-3 infection and can lead to apoptosis induced by caspase signaling. These insights are pivotal in delineating the metabolic landscape following severe HPeV-3 CNS infection and may identify potential host targets for therapeutic interventions.

neuroscience↗

bioRxiv2024

A Human Biomimetic Intestinal Mucosa Model to Study Gastrointestinal Development and Disease

The intestinal mucosa plays a vital role in nutrient absorption, drug metabolism, and pathogen defence. Advances in single-cell technologies have highlighted the specialised roles of various cell types that execute these diverse functions. Aside from intestinal epithelial cells, fibroblasts play an essential role in regulating the extracellular matrix and controlling pro- inflammatory signalling, and antigen-presenting cells (macrophages and dendritic cells) maintain intestinal homeostasis and immune responses. The incorporation of such cellular complexity within the existing in vitro models of the human intestine is currently challenging. To address this, we developed a human intestinal model that accurately mimics the mucosal cellular environment comprising intestinal epithelial cells, intestinal fibroblasts, and antigen presenting cells. This model includes co-cultures of adult and foetal cells, facilitating studies on barrier function, inflammation, and viral infections. It replicates extracellular matrix deposition, Paneth cell differentiation, immune interactions, and can be used to model host- pathogen interactions. Our advanced co-culture model improves the physiological relevance of in vitro studies, enabling the exploration of epithelial-mesenchymal-immune crosstalk and its role in intestinal health and disease.

cell biology↗

bioRxiv2023

Ecological interactions between host, commensal and pathogenic bacteria in models for the intestinal epithelium.

Gut host physiology and the microbiome intricately interact in the complex ecosystem of the human digestive tract, playing a crucial role in maintaining overall health. In recent decades, the role of the gut microbiota in the defence against pathogens and modulating local and distal immunity has been well-established. The interactions between commensal and potential pathogenic bacteria with the intestinal epithelium can initiate immune responses in the epithelial cells, which, in turn, activate downstream immune responses in other immune cells. These intricate processes involved, especially when multiple microorganisms are present as seen in the intestinal microbiome, remain only partially understood. Previously, it was observed that in adults aged 60 years or older, the commensal Ruminococcus torques (Rt) and Escherichia coli were associated with influenza-like illness and a heightened pro-inflammatory immune profile. In this study, we used a CaCo-2 cell-based model and a human intestinal enteroid (HIE) model to explore epithelial responses to Rt and an adherent invasive E. coli (AIEC) both individually and in co-cultures under anaerobic conditions. Additionally, CaCo-2 cells were co-cultured with peripheral blood mononuclear cells, revealing downstream activation of immune cells. While both systems showed comparable cytokine profiles, they differed in their responses to the different bacteria, with the organoid system being more representative for intestinal epithelial cells in humans. We provide mechanistic evidence of the pro-inflammatory responses associated with these bacteria in the intestinal ecosystem. These models, particularly in the context of combined infections, represent a valuable and promising avenue for future research. They contribute to a deeper understanding of the complex interactions between the gut microbiota, epithelial intestinal cells and immune cells in the gut ecosystem, thereby promoting advances in the field of gut health and host response.

microbiology↗

bioRxiv2023

Assessment of The Broad-Spectrum Host Targeting Antiviral Efficacy of Halofuginone Hydrobromide in Human Airway, Intestinal and Brain Organoid Models.

Halofuginone hydrobromide has shown potent antiviral efficacy against a variety of viruses such as SARS-CoV-2, dengue, or chikungunya virus, and has, therefore, been hypothesized to have broad-spectrum antiviral activity. In this paper, we tested this broad-spectrum antiviral activity of Halofuginone hydrobomide against viruses from different families (Picornaviridae, Herpesviridae, Orthomyxoviridae, Coronaviridae, and Flaviviridae). To this end, we used relevant human models of the airway and intestinal epithelium and regionalised neural organoids. Halofuginone hydrobomide showed antiviral activity against SARS-CoV-2 in the airway epithelium with no toxicity at equivalent concentrations used in human clinical trials but not against any of the other tested viruses. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/565121v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@10d562eorg.highwire.dtl.DTLVardef@94f903org.highwire.dtl.DTLVardef@683b6forg.highwire.dtl.DTLVardef@11620ba_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIHalofuginone hydrobromide was identified as a possible broad-spectrum host targeting antiviral drug. C_LIO_LIHuman organoid models offer a physiologically relevant and clinically translatable model for antiviral research. C_LIO_LIHalofuginone hydrobromide shows antiviral efficacy against SARS-CoV-2, but not against EV-A71, PeV-A1, IAV, RV-A16, HCMV or ZIKV in relevant organoid models. C_LIO_LIThe efficacy of Halofuginone hydrobromide is concentration dependent as well as on proline content of the host receptor(s) or host factors for the specific virus in question. C_LI

microbiology↗