Bio Patrika interviews Dr. Mishra on her thoughts about “how dengue virus activates human microglial cells?”

Dr. Ritu Mishra’s interview with Bio Patrika hosting “Vigyan Patrika”, a series of author interviews. Dr. Mishra has completed her Ph.D from CCMB, Hyderabad and moved to Max Planck Institute of Molecular Biomedicine, Germany for her post-doctoral work. She is currently working as DST-INSPIRE faculty at National Institute of Immunology, New Delhi. She has expertise in Virology, immunology and neurological research and have done extensive research on HIV, Dengue, JEV and SARS-CoV-2 viruses. She published paper titled “Dengue Virus Degrades USP33–ATF3 Axis via Extracellular Vesicles to Activate Human Microglial Cells” as a first author in The Journal of Immunology (2020).

How would you explain your paper’s key results to the non-scientific community?

Many viral infections which infect one type of tissues and organs are known to indirectly influence the homeostasis and health of other organs. Like in the current pandemic, corona viruses primarily infect lung cells but can adversely affect the health of human brain, gut and heart cells.

Our recent research findings are explaining that how multiple organs (including our brain) are affected even after the recovery from Dengue viral disease; when patients plasma is still enriched with circulating viral proteins such as NS1 (non-structural protein) and various other host factors such as microRNA (in our study, miR-148a), transcription factors etc. It can trigger a cascade of hyperinflammation in distant located organs. Our study also reveals that extracellular vesicles/exosomes released from dengue infected cells carry crucial cargo like miR-148a. These extracellular vesicles carrying miR-148a are internalized by microglia, which are human brain cells. After internalization, miR-148a can degrade the molecular signaling pathway of USP33-ATF3, which is needed to suppress brain inflammation. By this route, the characteristic hyperinflammation also known as ‘Cytokine Storm’ happens during Dengue hemorrhagic fever. It can adversely affect the human brain functions, a situation collectively known as Neuroinflammation.

Dengue Recovered Plasma: A Pandora-Box with inflammatory activators.
Our recent findings suggesting a potential role of plasma circulating host microRNA-148a travelling in exosomes, getting internalized by human brain cells, triggering the neuroinflammatory cascade. As a post-viral dynamic, our results provide novel insight into how neurological anomalies can emerge even in recovered patients of viral diseases.

“Our work is providing a novel insight on how after a viral disease, certain circulating plasma factors packaged into exosomes does contribute towards multi-organ dysfunctions.”

What are the possible consequences of these findings for your research area?

Our work provides a novel insight into how after a viral disease, certain circulating plasma factors packaged into exosomes contribute to multi-organ dysfunctions. Our results are advancing the understanding of those pathogenic outcomes of Dengue fever, arising after the viral load from patients has gone down. Recently in the case of recovered COVID19 patients, many patients have been reported to experience many complications related to heart, kidney and neurological anomalies after recovering from the disease and tested negative for viral replication. Our results are also cautioning the currently ongoing ‘Plasma Therapy’ which is recommended for treatment of the critical COVID-19 patients. Since the plasma from a recovered patient can be a ‘Pandora-Box’ of inflammation triggering molecules; its indiscriminate administration to an infected patient might backfire by exploding the Cytokine Storm.

What was the exciting moment (eureka moment) during your research?

Eureka moments are quite common in our research life. Whenever we hypothesize and imagine that this pathological change might be happening through this route, we test it in the lab. The moment we observe the same trends of results on animal or cellular models, we feel like jumping to the skies. Similarly, this study also had its share of exciting moments where new trends and pathways were revealing themselves.

What do you hope to do next?

Since my Ph.D work, I am focused on understanding the impact of multiple viral infections on the human brain. I have studied HIV-1, Japanese encephalitis virus (JEV), Dengue virus (DENV); they all have shown clear neuropathological manifestations in patients. So far, I have used cellular and available animal models but now I plan to shift my neuropathological studies by changing my model to 3D human brain organoid system or ‘Mini-Brain’. This is a stem cell derived organoid system where we get an abundant supply of human brain tissues, which is not possible otherwise. I am planning to use these organoids to test the neurological anomalies observed during various viral infections. I would also extend my studies of brain organoid in candidate drug testing and drug-repurposing to find a cure against various neuro-viral infections and neuroinflammation.

Where do you seek scientific inspiration?

As a scientist, we have a process of reading and digging the remaining questions of any field we take over. In my case, the neuro-viral infections and brain dysfunctions have always fascinated me and somehow triggers me to go deeper into the issues.

I believe my ever-searching mind always wander around and look for the satisfactory answers to all those bubbling questions (to understand human brain functions) in my head. It simply connects the dots and helps me see the bigger picture and underlying pathological processes of human diseases.

How do you intend to help Indian science improve?

Government Funding is something we all feel is the most important. Because there are many crucial ideas and projects, people are carrying around and not timely materializing the experiments. A centralized core-facility system of all state of art instruments significantly enhances the chances for everyone. But apart from all these external influences, I feel we still need the sensitization of our younger kids towards science and motivating the whole society to adopt a logic-based mindset and lifestyle. As a society, we still don’t value our education for our holistic evolution and development but just as a tool for getting a job and livelihood. In science, the job mind-set is doomed to fail. Even at the school level we seriously need to teach our students to take education to find joy and meaning in their lives. Students need to migrate towards their true passion and stream of studies and then only they can excel in their respective fields.

Therefore, I feel I would take my ongoing research projects as well as science teaching both in equal vigour. I hope I can do at least my share of inspiring and teaching to the next generation.

Reference

Ritu Mishra, Anismrita Lahon, Akhil C. Banerjea. Dengue Virus Degrades USP33–ATF3 Axis via Extracellular Vesicles to Activate Human Microglial Cells. The Journal of Immunology 2020, 205 (7) 1787-1798.

Author introduction and research interests

Ritu Mishra has completed her Ph.D from CCMB, Hyderabad and moved to Max Planck Institute of Molecular Biomedicine, Germany for her post-doctoral work. She is currently working as DST-INSPIRE faculty at National Institute of Immunology, New Delhi. She has expertise in Virology, immunology and neurological research and have done extensive research on HIV, Dengue, JEV and SARS-CoV-2 viruses.

Email: ritubhu4@gmail.com, ritu4@nii.ac.in

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