THSTI SciSpeak – Dr. Guruprasad Medigeshi

This is the first in what is going to be a series of interviews called THSTI SciSpeak shedding the spotlight on the work being done by our scientists and students. Through this feature, we intend to reach out to students aspiring to pursue a career in science in India.

Beginnings:

Dr. Guruprasad Medigeshi (Guru to his colleagues) heads one of the ‘oldest’ labs at the very young THSTI. Currently an Associate Professor, Guru leads the cellular and clinical virology laboratory at THSTI. When asked about his tryst with science, he reminisces that they (Guru & Science) go way back and credits his teachers at school and college for this. He went on to study protein trafficking pathways and lysosomal disorders using in vitro and in vivo approaches at Georg-August University, Germany. It was this experience that kindled his interest in the ability of microorganisms to hijack and manipulate the host cell machinery (cellular pathways) to suit their own survival. The viruses’ interaction with host cells captivated him into pursuing a career that would focus on identifying: (a) host factors that determine tropism (specificity for infecting a particular type of cell or tissue) of viruses, (b) cellular pathways used for replication by viruses hailing from diverse families, and (c) contribution of pathogen per se and the host response in determining the course of the disease. His previous training in cell biology was of value when he joined Dr. Jay Nelson’s lab at Vaccine and Gene Therapy Institute, Portland, Oregon as a Post-Doctoral fellow to delineate virus-host interactions. He fondly recalls his days as post-doc, “Jay gave me the freedom to both explore and learn various aspects of flavivirus biology using West Nile virus as a model. It was during this period that I got interested in understanding the molecular mechanism by which viruses from different families use and disrupt the components of permeability barriers”.

At THSTI:

On his experience as the first faculty member of THSTI he said, “THSTI uniquely focuses on generating solutions for better health and I have had the opportunity to interact with clinicians, immunologists and infectious disease experts.” This unique environment laid the foundation for his ongoing project aimed at investigating the effect of viral infections on cellular zinc homeostasis and permeability barrier functions. “We are using multiple viruses such as dengue virus and respiratory syncytial virus to probe how changes in zinc levels during viral infections influence the functions of epithelial and endothelial barriers. Our results might decipher the molecular mechanisms behind zinc supplementation in virus infections and assist in designing strategies that could be virus-specific for beneficial outcomes”, he added.

Dr. Guru in his lab

Why Dengue?

Dengue made it to the list of the 10 factors posing threat to the global health (https://www.who.int/emergencies/ten-threats-to-global-health-in-2019) which is appalling considering that almost 250 years have passed since Dr. Benjamin Rush reported about the “break-bone fever” in 1780 (see this case history in Lancet). “The only licensed vaccine for dengue has hit a rough patch (read about the Dengue vaccine dilemma here) and some of the antivirals that showed promise in animal studies did not make it through advanced stages of clinical trials. Vector control, although is a logical solution, is practically difficult to implement in a country as diverse and vast as India”, explained Guru. He points out that the presence of four serotypes and problems associated with enhanced infection by pre-existing antibodies in subsequent and heterologous infections poses enormous challenges. He clarifies that it is not clear if one would be immune to dengue after three or more exposure with different serotypes and whether the immunity would last for life thereafter. “As observed in case of many other RNA viruses, a rapidly evolving viral genome acts as a major hurdle for development of antivirals against dengue. Lack of relevant animal models that faithfully replicate human disease is an added disadvantage”, he stated. He further adds that since dengue is largely a disease of low- and middle-income economies like India it does not attract investments from big pharmaceutical companies for research and development in antivirals.

We asked Guru how his lab’s approach has been different in filling gaps in dengue research. “We are approaching the problem of dengue holistically by blending various aspects of dengue biology into translational outcomes. We took a stand to work with clinicians to study dengue disease in patients with a focus on both the virus and the host response and further probe the biological mechanisms in in vitro model systems.” His lab is studying: (a) cellular subsets and host signatures that characterize dengue disease progression, (b) circulating virus strains and modulation of innate immune responses, (c) effects of micronutrients such as zinc on viral infections and (d) drug repurposing to fast-track antiviral discovery for dengue. Keeping in sync with the institute’s efforts to network with researchers working on similar mandates across the country, Guru has taken up the task of creating a resource platform for both clinical and academic researchers interested in arboviruses across the country to widen the translational research landscape for virus research in India.

While he is doing his part, he believes that lot remains to be done. He said, “Close to 35% of global dengue cases are here (read this review and meta analysis) and if you are a student/researcher with interest in dengue, this is where you belong. There are four serotypes of dengue and about a billion people around us are bitten by mosquitoes carrying dengue every year. In addition, other members of the same family of virus (Family: Flaviviridae), namely, Japanese encephalitis virus, Zika virus, West Nile virus also circulate in population groups in India. Researchers in India have not focused on the population-level dynamics of these viruses and the immune response in people exposed to one or more of them. We need investment both in terms of manpower and money in this direction.” He reemphasized further, “The dengue vaccine pipeline has few candidates including indigenous ones and in the next few years we will know the outcome of some of the clinical studies. We need to stay invested in this area with newer approaches, better technology and smarter strategies. Perhaps we may succeed in creating a universal flavivirus vaccine in the near future similar to the concept of universal flu vaccine!”

The teacher:

Guru is also in-charge of the academics at THSTI and has streamlined the academic process by setting up a transparent and robust academic structure in place to nurture talent and maintain high academic standards. He said, “We fail to realize that we did not have 10% of the distractions that our students experience today. We should take the responsibility for making science interesting and appealing for smart people both in terms of content and quality”. The teacher, Guru (the tautology was unintentional!), thinks students need to have a strong conceptual understanding of the problem, any problem, before they start experimentation. For this, he prescribes developing curiosity and observational skills. He added, “if the goal is to somehow finish PhD by hurrying through experiments, you miss the fun and waste the opportunity provided to you for acquiring crucial skills such as critical and analytical thinking, especially if you want to continue in academics.” In the 5-6 years’ of the PhD journey, the goal for both the student and the supervisor is to generate knowledge that takes both a few steps closer to light, “tamasomā jyotir gamaya”!

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