Studying herpes encephalitis with mini-brains

Newswise — Scientists from the Rajewsky and Landthaler labs and the Organoid Platform at the Max Delbrück Center have reported in Nature Microbiology that a potentially hazardous brain infection can be caused by the herpes simplex virus-1. They suggest that a combination of an anti-inflammatory agent and an antiviral treatment may offer assistance in such situations.

Approximately 3.7 billion individuals, which accounts for around 67% of the global population, harbor the herpes simplex virus-1 within their nerve cells. The virus remains dormant in these cells until it is stimulated by factors such as stress or injury. Upon activation, it typically manifests mild symptoms, primarily appearing as cold sores or mouth ulcers.

In rare instances, the herpes simplex virus-1 can travel along the neurons to reach the brain, leading to a potentially life-threatening infection. This particular form of infection constitutes approximately 5 to 15% of all cases of infectious encephalitis observed in both children and adults. The standard medical protocol involves the administration of an antiviral medication called acyclovir. However, even with treatment, patients frequently experience persistent and debilitating symptoms such as long-term memory loss, seizures, and various cognitive disorders.

According to a recent study published in "Nature Microbiology" by scientists from the Max Delbrück Centre for Molecular Medicine in the Helmholtz Association in Berlin, there is a suggestion that in such cases, medical practitioners could consider testing a combination of an antiviral drug with an anti-inflammatory agent to determine if it leads to improved outcomes. The researchers arrived at this finding by utilizing a three-dimensional model of the brain that was developed from human stem cells. These models, known as organoids, represent an innovative approach at the forefront of clinical medicine.

Professor Nikolaus Rajewsky, the Scientific Director of the Berlin Institute for Medical Systems Biology at the Max Delbrück Center (MDC-BIMSB) and senior author of the study, emphasizes the significance of the proto-brains or organoids. These organoids contain a vast network of hundreds of thousands of interconnected neurons capable of synchronized communication. Professor Rajewsky highlights that these organoids enable conducting crucial experiments that were previously deemed impossible just a few years ago. This breakthrough opens up new possibilities for advancing research in the field.

Dr. Agnieszka Rybak-Wolf, one of the first authors of the study and the head of the Organoid Technology Platform at the Max Delbrück Center, was responsible for generating the organoids. These organoids, described as white, 0.5 cm in size, resembled blobs of tissue. Dr. Rybak-Wolf likens the appearance of these brain organoids to small clouds of tissue, highlighting their unique visual characteristics.

Closer to reality for herpes

The analysis of HSV-1-induced encephalitis poses significant challenges without the use of organoids. Obtaining brain samples from infected individuals is impractical due to the exclusive nature of the virus infecting humans. Consequently, scientists have traditionally resorted to studying the disease using cultured nerve cells or mice, which are not natural carriers of the virus. However, these models do not fully capture the natural course of the infection. The development and utilization of organoids have provided researchers with a more relevant and representative platform for studying HSV-1-induced encephalitis.

Dr. Emanuel Wyler, a virus expert and one of the first authors, working at the Landthaler lab, expresses that the organoid model offers a significant improvement in representing the reality of the herpes virus compared to previous models that have been employed. Dr. Wyler specifically focuses on studying the molecular mechanisms underlying HSV-1 infections. The utilization of organoids in their research provides a more accurate and realistic platform for investigating the virus and its effects.

In their study, the scientists deliberately infected the organoids with the HSV-1 virus and closely observed the progression of the infection. Through the use of advanced microscopy techniques, they were able to visualize the neuroepithelial and neuronal cells within the organoids as the virus ravaged them, ultimately resulting in the disintegration of the mini-brain structure. Dr. Emanuel Wyler, reflecting on the research, expressed excitement about the exceptional clarity and detail captured in the microscopy images. These images provided valuable insights into the actual processes occurring during the infection, enhancing the understanding of the virus's impact on the organoids.

In their study, the researchers further employed a single-cell analysis technique to examine and identify the various molecular pathways that become active during the infection process. By employing an unbiased approach, they aimed to uncover all the relevant pathways and genes involved in the infection. Dr. Ivano Legnini, a systems biologist and one of the first authors who was previously associated with the Rajewsky lab, emphasizes the integration of systems biology into their research. This approach allowed for a comprehensive understanding of the intricate molecular mechanisms underlying the HSV-1 infection within the organoids.

During their analysis, the researchers observed that the TNF-α signaling pathway, which plays a crucial role in inflammation, exhibited high levels of activity within the infected organoids. Upon treating the organoids with acyclovir, the standard antiviral medication for HSV-1 encephalitis, viral replication was halted. However, the tissue damage persisted despite the treatment. Further examination revealed that the TNF-α pathway remained active even after the administration of acyclovir, indicating that it might play a significant role in the ongoing tissue damage observed in the organoids. This finding suggests that targeting the TNF-α pathway alongside antiviral treatment could potentially mitigate tissue damage and improve therapeutic outcomes.

A defense that can become damaging

Dr. Tancredi Massimo Pentimalli, a medical doctor and one of the first authors, who is currently pursuing a PhD in systems medicine at the Rajewsky lab, highlights the significance of the inflammation pathway as a natural defense mechanism against the virus. However, an important observation made during the study is that when viral replication is inhibited by antiviral drugs, the inflammatory response, which is typically protective, can become excessive and potentially contribute to tissue damage. This finding suggests that striking a balance between suppressing viral replication and managing the inflammatory response is crucial in optimizing treatment outcomes for HSV-1 encephalitis.

Dr. Agnieszka Rybak-Wolf conducted an experiment where the organoids were treated with a combination of an antiviral drug and an anti-inflammatory drug. This combined treatment effectively inhibited the TNF-α pathway. As a result, the damage to the mini-brains was prevented. Dr. Rybak-Wolf explains that during infection, a specific signaling pathway in the brain becomes activated. By using these drugs to turn off the signaling pathway, the organoids remained undamaged. This finding suggests that the combined treatment approach holds promise in mitigating the detrimental effects of HSV-1 infection on brain tissue.

The scientists involved in the study express their hope that doctors and clinical investigators will conduct trials using a combination of acyclovir, an antiviral drug, and an anti-inflammatory agent as a potential treatment for HSV-1 encephalitis. Dr. Tancredi Massimo Pentimalli specifically emphasizes the importance of setting up clinical trials to evaluate the effectiveness of these novel combination therapies in patients with herpes encephalitis. The ultimate goal is to translate the promising findings obtained from the laboratory research into practical and beneficial treatments for individuals affected by this condition.