Viral Pathogenesis Models

Recreating the respiratory tract in a dish: Modeling viral infections and testing treatments. Center for iPS Cell Research and Application, Kyoto University. April 24, 2025 Excerpt: RSV is a major respiratory pathogen, particularly among young children, causing severe lower respiratory tract diseases. Current models, such as HEp-2 cells, are commonly used for RSV research, they do not accurately mimic the complex responses of the human respiratory system. Researchers aim to evaluate the utility of respiratory organoids, which are more representative of in vivo human respiratory tract due to the presence of various cell types, in advancing understanding of RSV pathophysiology and evaluating therapeutic and preventive drugs. The study revealed RSV efficiently infected iPS cell-derived respiratory organoids, leading to high viral replication and protein expression. The infected organoids displayed respiratory epithelial layer damage, collagen accumulation, and increased levels of pro-inflammatory cytokines like IL-8 and IFN-γ. Note: Additionally, the researchers found monoclonal antibodies such as nirsevimab, palivizumab, and others targeting RSV F protein were highly effective in inhibiting RSV replication, ribavirin--an antiviral previously used for RSV treatment--showed minimal efficacy. This result highlights the limitations of ribavirin in the organoid model and suggests newer antiviral agents or antibodies may be more promising. The research team also used RNA sequencing and other assays to investigate the host response to RSV infection. RSV-induced changes included a robust innate immune response and activation of genes associated with interferon signaling. The findings demonstrate the organoids' ability to replicate inflammatory and immune responses typically seen during RSV infection in humans. Moreover, the organoids allowed for detailed analysis of cellular interactions and responses, offering an advanced platform for evaluating the effects of antiviral treatments and antibodies on different cell types within the respiratory tract. This study emphasizes the importance of using human iPS cell-derived respiratory organoids for modeling RSV infection. The results suggest organoids are a valuable tool for studying the virus's pathophysiology, testing therapeutic interventions, and advancing the development of effective drugs. The study indicates these models could be utilized to evaluate the efficacy of vaccines and other treatments, providing a more accurate reflection of the human respiratory environment compared to traditional models. Research also suggests incorporating additional immune cell types, such as T cells and neutrophils, may further enhance the model's ability to replicate the complexities of RSV infection, especially in the context of severe inflammation. Refer to enclosed press release to access the paper published 22 April 2025 online. ttps://https://lnkd.in/eSM3mpRR

An exciting development from Gabriella Worwa and Jens H. Kuhn and colleagues shows that standardized human cerebral organoids can now be used safely inside BSL-4 containment to study Nipah virus. This is a significant advancement towards more human-relevant models for studying high-risk pathogens. Using the STEMdiff Cerebral Organoid Kit, the team generated 3-month-matured iPSC-derived brain organoids and exposed them to two Nipah isolates (Malaysia and Bangladesh). The model reproduced isolate-specific replication kinetics and the same hallmark neuropathology seen in fatal human cases (syncytia, necrosis, and viral inclusions) without relying on animal models. This proof-of-principle shows how standardized organoid systems can advance new approach methodologies (NAMs) for maximum-containment virology, supporting the shift toward human-based testing envisioned in the FDA Modernization Act 2.0. https://lnkd.in/geig7SMK

EBV-Driven CNS homing of B cells May Trigger Multiple Sclerosis Pathogenesis - Epidemiological data have identified Epstein–Barr virus (EBV) infection as the main environmental risk factor for multiple sclerosis, the predominant autoimmune disease of the central nervous system (CNS). - However, how EBV infection initiates multiple sclerosis pathogenesis remains unclear. - Using a novel humanized mouse model for EBV infection, the authors demonstrate that EBV expands oligoclonal T-bet+CXCR3+ B cells that home to the CNS. - T-bet+CXCR3+ B cells can colonize submeningeal brain regions in the absence of other lymphocytes and attract activated and inflammatory T lymphocytes to the CNS. - Depletion of B cells with rituximab or blocking of CXCR3 significantly decreases lymphocyte infiltration into the CNS. - These results suggest that MS arising from EBV infection is due to a rare event in which EBV infects autoreactive B cells, endowing them with the capacity to home to the CNS and to attract and stimulate T cells. - Targeting this B cell population could modify MS pathology and needs further investigation to reveal its potential benefits for patients. https://lnkd.in/eh9yEgaf #immunology #autoimmunity #multiplesclerosis #neuroimmunology

Human organoids for Risk Group 4 virus research: a new frontier in investigating Nipah virus infection of the central nervous system. ABSTRACT New approach methodologies, such as high-complexity in vitro systems, are increasingly prioritized in biomedical research as potential alternatives to animal experimentation. We show that cerebral organoids derived from human induced pluripotent stem cells can be leveraged to (i) investigate isolate-specific replication dynamics of Nipah virus and (ii) model key histopathological lesions found in the brain tissue of infected human patients. Furthermore, we discuss the importance of organoid models for the study of Risk Group 4 viruses. IMPORTANCE Advanced development of medical countermeasures against Risk Group 4 viruses, such as the Nipah virus, historically required testing in mammals under the FDA Animal Rule and translation of data to inform clinical trials in humans. Because the application of human organoids in research on viruses pathogenic for humans is conspecific, it bears the potential to reduce, refine, or replace animal studies where unnecessary. Human cerebral organoids are three-dimensional cell aggregates that resemble the developing human brain functionally and structurally. Brain organoids may be valuable in investigating the replication, neuroinvasion, pathogenesis, virulence, and persistence of neurotropic viruses and provide scientific discernment when developing medical countermeasures destined for the human end-user. https://lnkd.in/ehnr277P

🧬 New Publication: A Bioprinted 3D Lung Model for Viral Infection Studies Our latest paper, published in International Journal of Molecular Sciences, presents a 3D bioprinted lung model composed of four human cell types—epithelial, endothelial, fibroblast, and macrophage-like cells—cultured under air–liquid interface (ALI) conditions. This model supports infection with both influenza A virus (H3N2) and SARS-CoV-2 omicron (BA.2), and addresses limitations of traditional 2D cultures and animal models by integrating key features of human lung physiology. Notable features: - Modular ALI-compatible structure - Support for both upper and lower respiratory tract simulation via Calu-3 and A549 cells - Reproducible viral infection outcomes relevant to preclinical research The model serves as a step toward scalable, human-relevant platforms for studying respiratory viruses and evaluating therapeutics. Read the full article: https://lnkd.in/gBZAhmaY