India Alliance Fellow Spotlight: Shashank Tripathi, IISc, Bengaluru


23 May 2020

India Alliance Fellow Spotlight: Shashank Tripathi, IISc, Bengaluru

"With my research experience so far, I’ve learnt that viruses are largely unpredictable, and one risks being stupefied in making bold statements about their future." says Shashank Tripathi, this month's Fellow in Spotlight, on being asked about what to look forward to in the progression of COVID-19.

Please tell us what you are working on and what impact do you hope it will have.

We study virus-host interactions of emerging RNA viruses, primarily Influenza and Flaviviruses. In the India Alliance supported study, we are exploring the molecular mechanisms underlying wide range of virulence manifested by different strains of Influenza A viruses. For example, mortality rates in humans due to H1N1 Swine Flu infection is ~0.03%, however in case of H5N1 Avian Flu infection it can be up to ~ 60%. For this we plan to use ‘Omics’ technologies to generate big data for different Influenza strains and do comparative study to develop a hypothesis. Afterwards we will use conventional tools of virology such as cell culture and animal models to validate the hypothesis. Beyond that we are looking at broad themes of virus-host interactions (using RNA viruses), and we aim to achieve a translatable result which could be disease severity biomarker, broad spectrum antivirals or improved vaccines.

You have also started research efforts towards COVID19. Could you tell us more about the work and the challenges?

So far, my efforts were focussed on setting up COVID-19 Diagnostic facility in IISc, which is operating in full swing now. On research front I am interested in testing host-directed antivirals and studying cellular innate immune responses against SARS-Co-V2. This will be an extension of ongoing Influenza research in my lab. Work on these lines has started using individual SARS-Co-V2 viral proteins and pseudotyped viruses, which can be done in BSL2 containment. A dedicated Viral BSL3 facility is being constructed in CIDR, IISc, where we will work with the SARS-Co-V2 virus isolates for validation experiments. Getting the reagents to initiate SARS-Co-V2 research has been a major challenge. There are a lot of regulatory restrictions in terms of sharing reagents between labs and working with infectious material. In a pandemic situation, regulatory approvals can be streamlined and expedited to facilitate fast paced research.

Can you share a few interesting facts about the new coronavirus? How is it different from the influenza virus?

Corona viruses are not new to humans. Apart from SARS, MERS and COVID-19, there are at least 4 other known Corona viruses which routinely cause seasonal flu like illness in humans and it is not clear at what point in history they were introduced in-to humans. An interesting feature of corona viruses is that different strains can undergo recombination between their genomes to give rise to a novel strain abruptly. Such recombination event has most likely contributed to emergence of SARS-Co-V2.

Superficially, influenza virus and SARS-Co-V2 are similar in many ways. Both are enveloped, have RNA genome, spread by air droplets and contact, infect respiratory tract, and have zoonotic origin. The initial diseases symptoms caused by both viruses are similar and for both, severe cases are associated with pneumonia and cytokine storm. A very interesting feature shared by SARS-CoV2 and highly pathogenic Influenza (Bird Flu) is presence of a Furin cleavage site in their receptor binding proteins (Hemagglutinin for Influenza and Spike for SARS-Co-V2). Presence of this site expands tissue tropism of the virus and facilitates systemic infection. Most likely, this feature contributes to severe SARS-Co-V2 pathogenesis.

However, if one looks deeper into the biology of Influenza and SARS-Co-V2, they are very different viruses and belong to different families (Influenza: Orthomyxoviridae; SARS: Coronaviridae). Influenza viruses bind to sialic acid molecules on cell surface whereas SARS-Co-V2 binds to ACE2. Influenza has segmented RNA genome that is replicated in the host cell nucleus, whereas SARS-Co-V2 has single RNA genome that is replicated in the cytoplasm. Influenza codes for up to a dozen different proteins, whereas SARS-Co-V2 makes more than two dozen viral proteins. Influenza gets out of the cells by budding from cell surface, whereas SARS-Co-V2 is released through exosome machinery. Overall, their genome, proteome and replication mechanisms are quite different.

The Dutch minister Bergansius and Hendrik Pieter Tindal visit an influenza hospital populated with representations of the countries of Europe; Bergansius points to the Dutch representative, attempting to persuade the apocalyptic Tindal that all is indeed well. (Reproduction of a lithograph by J. Braakensiek, 1889. Credit: Wellcome Collection. CC BY 4.0)

 

What according to you are some research opportunities offered by this outbreak? How can India leverage them? 

Obviously, this pandemic has educated everyone a lot about Viruses. People are more aware and appreciative of the importance of research on emerging viruses with pandemic potential. There has been a lot of interest in predictive modelling of the disease. However, if you want a weather-like prediction about the virus, you need satellite surveillance quality data too.

This pandemic has forced us to scale up the number of diagnostic facilities across the nation. Many of them can be equipped with sequencing facilities to increase the viral surveillance resolution. We need to invest resources in viral pathogen discovery and recording the ‘Virome’ present in our country to learn potential threats and prepare in advance. The advances in information technology have shown tremendous promise in current crisis, be it data management in diagnostic labs and hospitals or delivery of benefits to the marginalized people. Efforts on these fronts should be intensified.

Also, this pandemic has shown that putting entire onus on one institute (NIV) and agency (ICMR) to tackle a pandemic can cripple the response. Eventually other research agencies and Institutions were roped in to ramp up the research activities, however this delay can be avoided in future by creating dedicated regional pandemic preparedness research hubs. Once the pandemic is over, these hubs should continue to develop plug-and-play kind of diagnostic and vaccine platforms and broad-spectrum antivirals which can be delivered quickly if another pandemic emerges.

How has the India Alliance fellowship helped you & your research? Any tips for those aspiring for India Alliance Fellowships?

India alliance funding has helped me setup the Influenza research program and CRISPR-Cas screening platform in my lab. This will allow me to study the different aspects of Influenza biology in future, beyond what’s proposed in Intermediate Fellowship application. Also, the CRISPR-Cas screening platform will be easily repurposed to study other viral pathogens in addition to influenza. For intermediate fellowship aspirants, I would suggest proposing a research project which (1) allows you to create your own niche (2) has long term prospects and impact. Other than that, when writing or presenting your project, try to make it simple and easy to understand for the reader/audience.

What is it about your work that keeps you going every day, even during these tough times?

Virus research is incremental and time-consuming, more so if you are trying translation to clinic. Finding a reliable disease marker, an effective antiviral or developing a potent vaccine can take years. Success stories are the aberrations, not the norm. For me, I find fun in troubleshooting, which we need to do regularly and if things go well, once in a while we get to experience thrill of discovery too. Besides, I’m just discovering the joys of teaching and training students and watching them get better than yourself. 

Once things get better, what do you look forward to doing the most? What do you think the 'new' normal will look like?

Pandemic or not, I love to study viruses, and that I’ll continue to do. I will certainly be more focused on pandemic preparedness aspect by developing broad spectrum antivirals/vaccines which can counter newly emerged viruses. With my research experience so far, I’ve learnt that viruses are largely unpredictable, and one risks being stupefied in making bold statements about their future. However, based on our current knowledge about SARS-Co-V2 and other emerging viruses, it seems that new ‘normal’ will be a restricted and cautious co-existence with COVID-19 for quite some time.