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Exploring infectious disease dynamics through organ-on-chip technology

Exploring infectious disease dynamics through organ-on-chip technology

In the realm of infectious disease research, understanding the interactions between pathogens and their host is of particular importance. At Dynamic42, we have put strong emphasis on developing cutting-edge infection models that shed light on the complex mechanisms underlying infectious diseases. In this blog, we explore the variety of models that we have been established together with our collaborators and their implications for scientific research.

If you don’t have much time, here is a quick overview on the established models with a link to the original publications. For anyone else, feel free to skip the table or just use it as a way to identify the section that is of interest to you.

Organ

Model

Microorganisms

Immune cells

Reference

Intestine

Transwell model

Candida albicans

Lactobacilli (different strains)

Intestine-on-chip

Candida albicans

Lactobacillus rhamnosus GG (LGG)

Macrophages Dendritic cells

Intestine-on-chip

Candida albicans

Macrophages

Lung

Alveolus-on-chip

Staphylococcus aureus

Influenza A

Macrophages

Alveolus-on-chip

Staphylococcus aureus

Influenza A

Macrophages

Alveolus-on-chip

SARS-CoV-2

Macrophages

Alveolus-on-chip

Aspergillus fumigatus

Macrophages

Liver

Liver-on-chip

Staphylococcus aureus

Macrophages

Circulating monocytes

Modeling microbial interactions and immune responses in the intestine

3D in vitro gut model with C. albicans and Lactobacilli

The human intestine is a main reservoir for trillions of microbial species and plays a crucial role in metabolization and digestion processes.

One of the members of the intestinal microbiota is C. albicans, which resides as a harmless commensal fungus in the healthy gut. However, it can become a dangerous pathogen in immunosuppressed individuals, resulting in the development of detrimental systemic infection and life-threatening conditions. To better understand pathogenic processes of C. albicans, Graf et al. (2019) established a 3D in vitro gut model to study the interactions between the fungus and the intestinal microenvironment. Unlike traditional models that focused solely on C. albicans as a pathogen, this model further studied its commensal nature, shedding light on its behavior in a more physiological environment. By incorporating a mixture of enterocyte-like and goblet-like cells to form the epithelial barrier, it was possible to limit fungal adhesion and invasion. Graf et al. also demonstrated significant protection against fungal-induced cell damage. Interestingly, the introduction of antagonistic Lactobacilli resulted in decreased C. albicans pathogenicity in a time-, dose-, and species-dependent manner. Furthermore, the study identifies bacterial-driven shedding of fungal hyphae induced by the Lactobacilli as a novel mechanism of damage protection. These findings highlight the role of microbiota antagonism and self-regulation of fungal pathogenicity to maintain the intestinal homeostasis.

Intestine-on-chip with Candida, Lactobacilli, and immune cells

Maurer et al. (2019) introduced a 3D microphysiological model of the human intestine, which recapitulated organotypic microanatomical villus- and crypt-like structures and included tissue resident innate immune cells. In contrast to monolayer layers cultured on plastic dishes or transwell inserts, this organ-on-chip model presented a near-physiological 3D-architecture. The epithelial layer showed immunotolerance to lipopolysaccharide (LPS), a bacterial endotoxin, in contrast to the vascular compartment which showed strong inflammatory response. The vascular inflammation was attributed to the presence of the immune cells, which emphasizes their role in antimicrobial tolerance and defense.

The study by Maurer et al. further demonstrated how pre-colonization of the intestinal lumen with probiotic Lactobacillus rhamnosus GG (LGG) mitigated tissue damage induced by the fungus C. albicans similarly as it was shown by in Graf et al. (2019). In comparison to the model by Graf et al., this model is in particular suitable for microbial colonization and culture due to the tissue perfusion, thereby removing overgrowing bacteria and waste products. Moreover, the organ-on-chip technology enables the analysis of host-microbiota interactions in real-time in a more physiological and immunocompetent environment.

Collectively, this intestine-on—chip model can be leveraged as a tool for microbial interaction studies. It allows the investigation of microbial pathogenicity mechanisms, host responses, and microbial composition changes.  This could pave the way for a better evaluation of infectious or inflammatory intestinal diseases.

Intestine-on-chip with C. albicans, immune cells, and antifungal treatment

In a recent study, Kaden et al. (2024) employed the previously described 3D intestine-on-chip model from Maurer et al. to mimic in vivo infection processes more accurately. Through microbiological and image-based analyses, they quantified infection processes such as invasiveness and fungal translocation across the epithelial barrier into the vascular perfusion mimicking the bloodstream. Their findings revealed that C. albicans formed microcolonies on the epithelial tissue, caused cell injury and inflammation and was able to invade and translocate across the epithelial barrier. Importantly, they demonstrated the efficacy of caspofungin treatment in reducing fungal biomass and altering microcolony morphology in a wild-type strain, although it was not effective in an antifungal-resistant strain. If you would like to learn more about this study, you can read our previews blog.

This intestine-on-chip model emerges as a valuable tool for understanding host-pathogen interactions, especially in the context of antimicrobial treatment evaluation.

Investigating bacterial and viral infections of the lung

Lung-on-chip with Staphylococcus aureus, Influenza A and Macrophages

Moving from the intestine to the lung, Deinhardt-Emmer et al. (2020) addressed the challenge of pneumonia, a global health burden exacerbated by bacterial coinfections during influenza epidemics. D42 scientists and University hospital Jena developed an alveolus-on-chip model simulating the human alveolus architecture, complete with vascular and epithelial cell structures cocultured with macrophages. The model showed high barrier integrity, which was further improved by physiological flow conditions and the presence of macrophages. It also ruled out the importance of immune cells (macrophages) for the responsiveness and suitability of the alveolus on chip model for infection modelling. The infection with the influenza virus and Staphylococcus aureus induced a robust cytokine release of epithelial cells, propagating to the endothelium, resulting in significant endothelial cell damage despite the epithelium’s integrity remaining intact. Through this, a novel immune-responsive model was established, showcasing the intricate interplay between pathogens and hosts.

In a similar study, Schicke et al. (2020) utilized the human alveolus-on-chip model to investigate the role of surfactant protein-A (SP-A) in an infection with influenza A virus and/or Staphylococcus aureus. Their findings elucidate how bacterial co-infections reduce SP-A expression, potentially contributing to the severity of pneumonia. These models provide invaluable platforms for dissecting the molecular and cellular mechanisms underlying lung infections, paving the way for novel treatment strategies.

Lung-on-chip with SARS-CoV-2 and Macrophages

The emergence of SARS-CoV-2 brought forth a pressing need to understand the intricacies of viral invasion. Deinhardt-Emmer (2021) et al. tackled this challenge by employing the previously Dynamic42 developed alveolus-on-chip model modified by using SARS-CoV-2 permissive epithelial cells (Calu-3 cells) and vascular cells cocultured with macrophages. It was shown that while SARS-CoV-2 efficiently infects epithelial cells, inducing high viral loads and an inflammatory response, adjacent endothelial cells remain uninfected and do not release interferons. However, prolonged infection damages both cell types, compromising barrier function and facilitating viral dissemination, indicating a complex interplay between epithelial and endothelial cells during SARS-CoV-2 infection.

Lung-on-chip with Aspergillus fumigatus and Macrophages

Invasive pulmonary aspergillosis poses a grave threat to immunocompromised individuals, warranting thorough investigation. To study fungal invasion of the lung in vitro, Hoang et al. (2022) developed an invasive aspergillosis-on-chip (IAC) model. The basis of this model is formed by the Dynamic42 alveolus-on-chip model, including macrophages that allow the researcher to study fungal growth behaviors from the epithelium into the endothelial cell layer. In the IAC model, human macrophages inhibit fungal growth, while releasing proinflammatory cytokines and chemokines, leading to increased invasive hyphae. Additionally, caspofungin treatment mirrors in vivo responses, limiting fungal growth and inducing morphological changes, showcasing the model’s potential for identifying infection targets and testing antifungal drugs in clinically relevant concentrations to advance our understanding of invasive aspergillosis.

Modelling bacterial infection of the liver

Lastly, Siwczak et al. (2022) elucidated the tactics employed by Staphylococcus aureus to invade and persist in the liver. Leveraging a human liver-on-chip model, their study unveils how S. aureus specifically targets macrophages to establish a niche for bacterial persistence. Moreover, M2 polarization in vitro promotes small colony variant formation, elevating intracellular bacterial loads, cell death, and hindering monocyte recruitment, offering insights into macrophage activation and its role in bacterial dissemination during infection.

Summary

The infection models developed using Dynamic42 biochips and organ models represent a paradigm shift in scientific research, offering unprecedented insights into the complexities of host-pathogen interactions. From the gut to the liver, these models provide invaluable platforms for unraveling infection mechanisms and developing novel therapeutic interventions. As we continue to navigate the ever-evolving landscape of infectious diseases, the innovative work of our customers serves as a beacon of hope for a healthier future.

Haven’t found an infection model suited to your research question yet? No worries, this was just a glimpse at what we can do. If you have specific requirements, please get in touch so we can talk about how we would be able to help you.

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