How IISc Scientists Decipher the Architecture of Viruses
At the Indian Institute of Science in Bangalore, researchers are revealing the molecular structure of viruses using cutting-edge technologies, opening new pathways for treatments and vaccines.
Imagine a world where we can observe the intricate molecular machinery of viruses in astonishing detail—seeing not just their shapes, but the very atoms that make up their structures.
This isn't science fiction; it's the cutting-edge work being done at the Indian Institute of Science (IISc) in Bangalore, where scientists are decoding the architecture of viruses that threaten human health. Their research is revealing vulnerabilities in these pathogens that could lead to more effective treatments and vaccines.
For decades, viruses remained largely mysterious due to their microscopic size and complex structures. Today, revolutionary technologies are allowing researchers to visualize these pathogens at unprecedented resolutions. At the forefront of this work, IISc has become a hub for structural virology—the science of determining the three-dimensional arrangement of viral components. This article explores how IISc scientists are pushing the boundaries of what we know about viral architecture and what their discoveries mean for the future of medicine.
Visualizing viruses at near-atomic resolution
Understanding how viruses infect cells
Developing targeted treatments and vaccines
Structural virology provides the foundation for understanding how viruses function, infect cells, and evade our immune systems. Just as knowing the precise shape of a lock helps you design the perfect key, understanding viral structures enables scientists to develop targeted therapies and vaccines. At IISc, researchers employ several powerful techniques to visualize viruses:
This technique involves flash-freezing virus samples in thin layers of ice and then using an electron microscope to capture thousands of images from different angles. These images are computationally combined to generate detailed three-dimensional structures. Recent advances in cryo-EM have been revolutionary, allowing scientists to view viruses at near-atomic resolution without the need for crystallization—a major limitation of earlier methods 1 .
Before cryo-EM became prominent, this was the primary method for determining high-resolution structures. It involves growing crystals of viral proteins and then analyzing how X-rays scatter when passed through these crystals. While still valuable for studying individual viral components, it's less suitable for large, complex viral assemblies 7 .
This specialized form of electron microscopy allows researchers to create 3D images of viruses in their natural context—sometimes even inside infected cells. By tilting the sample and collecting images at different angles, scientists can reconstruct detailed tomographic volumes that reveal how viruses interact with cellular components 9 .
These structural approaches have revealed that viruses come in various shapes and sizes, with two major categories being icosahedral enveloped viruses (like alphaviruses and flaviviruses) and non-enveloped spherical viruses (like many enteroviruses). Each presents unique challenges and opportunities for structural analysis 1 7 .
In early 2022, while the COVID-19 pandemic continued to evolve, IISc researchers embarked on a crucial investigation to understand immune responses in vaccinated individuals who experienced breakthrough infections. Their focus: how the ChAdOx vaccine (the viral vector vaccine used in India's massive immunization drive) influenced antibody responses against emerging SARS-CoV-2 variants 8 .
All serum samples were initially screened for neutralization breadth against wild-type SARS-CoV-2 and several variants of concern, including Kappa, Delta, and Omicron BA.1.
Researchers identified three serum samples with the highest neutralization breadth and potency for detailed epitope mapping.
Using an advanced technique called charged scanning mutagenesis coupled with yeast surface display and next-generation sequencing, the team precisely identified which parts of the viral spike protein were being targeted by antibodies in these potent sera.
An additional 26 broadly neutralizing sera were characterized to confirm their activity against even more recent variants, including XBB.1.5 8 .
The findings surprised the scientific community. Unlike sera from mRNA-vaccinated populations in Western countries that primarily targeted more variable regions of the virus, the Indian cohort's immune responses focused on a conserved cryptic epitope—dubbed the "class 5" region—that had been largely overlooked in previous studies.
| Variant | Neutralization Potency | Conservation of Class 5 Epitope |
|---|---|---|
| Wild-type | High | Fully conserved |
| Kappa | High | Fully conserved |
| Delta | High | Fully conserved |
| Omicron BA.1 | High | Fully conserved |
| XBB.1.5 | Moderate to High | Fully conserved |
This class 5 epitope is completely conserved across all SARS-CoV-2 variants and even among SARS-like coronaviruses that could cause future outbreaks. This conservation explains why antibodies targeting this region maintained effectiveness against evolving variants, unlike those targeting more mutable regions of the virus 8 .
| Vaccine Type | Primary Epitopes Targeted | Neutralization Breadth | Effectiveness Against XBB |
|---|---|---|---|
| ChAdOx (India breakthrough infections) | Class 5 cryptic epitope | Broad | Maintained |
| mRNA vaccines (Western populations) | Class 1 & 4 epitopes | Narrower against variants | Impaired |
The research demonstrated that two doses of the ChAdOx vaccine in a highly exposed population could drive substantial neutralization breadth against emerging variants—a finding with significant implications for future vaccine design strategies 8 .
The groundbreaking work at IISc relies on a sophisticated array of research tools and methodologies. These resources form the foundation of modern structural virology and enable the detailed characterization of viral architecture.
| Research Tool | Primary Function | Application in Viral Research |
|---|---|---|
| Cryo-Electron Microscopes | High-resolution imaging of frozen-hydrated specimens | Determining 3D structures of viruses at near-atomic resolution |
| Sub-tomogram Averaging Software | Computational enhancement of cryo-ET data | Revealing detailed architecture of viral entry machinery |
| Yeast Surface Display Libraries | Epitope mapping of antibody responses | Identifying precise regions targeted by neutralizing antibodies |
| Viral Reverse Genetics Systems | Engineering and studying recombinant viruses | Investigating virus-host interactions and viral pathogenesis |
| AI-Based Structure Prediction | Computational modeling of protein structures | Complementing experimental methods for complex viral assemblies |
Different research groups at IISc employ specialized toolkits depending on their focus. For instance, the Tripathi lab utilizes multi-omics analysis and viral reverse genetics to study virus-host interactions of emerging RNA viruses including flaviviruses, while the Prasad lab specializes in cryo-electron tomography and sub-tomogram averaging to visualize the intricate processes of viral entry into cells 2 5 9 .
The structural insights gained at IISc extend far beyond static snapshots of viral particles. Researchers are piecing together how these structures change during infection and how different components assemble to create functional viruses. Recent work has revealed:
Unlike the static structures initially revealed by early methods, we now understand that viral capsids undergo complex structural rearrangements during assembly and infection. These dynamics are crucial for understanding the viral life cycle 7 .
The process by which viral RNA or DNA is packaged into capsids involves sophisticated molecular machinery that IISc researchers are beginning to unravel through structural studies.
For enveloped viruses like flaviviruses, the process of membrane fusion—essential for cellular entry—involves dramatic structural transformations of viral envelope proteins that can be visualized through advanced imaging techniques 1 .
These insights are not merely academic; they inform the design of broad-spectrum antivirals and next-generation vaccines. For instance, understanding the conserved nature of the class 5 epitope in SARS-CoV-2 has identified it as a promising target for pan-coronavirus vaccines that could protect against future outbreaks 8 .
The work at IISc represents a paradigm shift in how we approach viral threats. Instead of playing catch-up with each new variant or emerging virus, scientists are now identifying conserved vulnerabilities that could be targeted for broader protection.
Structural insights allow for the design of immunogens that focus immune responses on conserved, critical regions of viruses rather than variable, less important areas. This approach could lead to vaccines with much broader protection against viral variants 8 .
The discovery that picolinic acid—a naturally occurring metabolite in mammals—can inhibit the entry of multiple enveloped viruses (including SARS-CoV-2 and influenza) by compromising viral membrane integrity points toward a new class of host-directed antivirals with potentially broad applicability 5 .
The finding that breakthrough infections in vaccinated individuals can generate exceptionally broad neutralizing responses suggests strategies for optimizing vaccination regimens to mimic this effect without requiring actual infection.
The future of viral research at IISc appears bright, with emerging technologies like AI-based structure prediction complementing traditional methods to accelerate discoveries 7 .
As Dr. Vidya Mangala Prasad of the Molecular Biophysics Unit notes, her lab's focus on "high resolution structural analysis of human disease causing viruses, their infection machinery and mechanisms of cellular entry across membranes" is providing fundamental insights that translate into medical advances 2 9 .
In the words of IISc researchers, each structural solution "enabled new insights into virus architecture, leading to a better understanding of their biology, pathogenesis, immune response, immunogen design, and therapeutic development" 1 . From the atomic details of viral proteins to the complex dance of infection and immunity, the work at IISc continues to illuminate the invisible world of viruses, transforming our ability to combat them.