IISc researchers used cryo-EM to reveal how EMCV captures the host ribosome and initiator tRNA, opening new paths for antiviral research.
A virus that steals the cell’s machinery
Researchers at the Indian Institute of Science (IISc), Bengaluru, have uncovered how the encephalomyocarditis virus, or EMCV, hijacks a host cell’s protein-making machinery. The study shows how the virus uses a structured RNA element to take control of ribosomes and translation factors, allowing it to produce viral proteins while blocking host protein synthesis.
EMCV is a rodent-borne animal virus that can cause inflammation of the heart and brain, reproductive problems, and neurological disorders in several mammals. Like all viruses, it cannot make proteins on its own. It must borrow the host’s molecular machinery to multiply, and this new work reveals a key part of that process.
Why the discovery matters
Viruses survive by redirecting the host’s translation system for their own use. They do this through RNA genomes or mRNAs that contain Internal Ribosomal Entry Sites, or IRES, which help recruit ribosomes directly. This mechanism lets the virus bypass normal cellular controls and begin translating its genes even when host gene translation is suppressed.
The IISc team’s findings matter because IRES-driven translation supports viral multiplication and infection. If scientists can block this process, they may be able to stop EMCV and related viruses such as poliovirus, which use a similar strategy. That makes the IRES an attractive target for future antiviral therapies.
A long-standing mystery
IRES elements were first discovered in EMCV and poliovirus more than a decade ago, but scientists did not fully understand their structure or exact mode of action. Tanweer Hussain, associate professor in the Department of Developmental Biology and Genetics at IISc and the corresponding author, said little was known about how the virus captures the host ribosome in biochemical detail.
That gap left researchers with an important unanswered question: how does the viral RNA physically connect with the host translation machinery to start protein synthesis? The new study provides the clearest answer so far.
Building the complex for study
To solve the problem, Deepakash Das, a PhD student in Prof. Hussain’s lab and first author of the paper, designed a pulldown strategy using an EMCV IRES-containing mRNA. The team used this bait to isolate the EMCV IRES pre-initiation complex from cell lysate taken from rabbit reticulocytes, which are immature red blood cells rich in translation components.
This pre-initiation complex forms during the first stage of viral protein production. It includes the viral RNA and the host ribosome, along with the factors needed to start translation. By capturing the complex intact, the team created a rare opportunity to see how the virus assembles its protein-making machinery at the molecular level.
The researchers used a specially designed bait protein to pull out the complex from the lysate. They successfully captured the 40S ribosomal subunit, the initiator tRNA, and the eIF2 complex together with the viral RNA. That gave them a complete system to analyse with cryo-electron microscopy.
Cryo-EM reveals the mechanism
The team then examined the purified complex using cryo-EM, a technique that lets scientists visualise biological molecules at very high resolution. The images revealed that the EMCV IRES directly interacts with the host’s 40S ribosomal subunit and initiator tRNA. According to IISc, this mechanism had not been seen in other viruses before.
That finding is especially important because it shows that the viral RNA does more than simply attract the ribosome. It actively positions key translation components to hijack the host machinery. In effect, the IRES acts like a molecular landing pad that helps the virus start making its own proteins with remarkable precision.
Persistence behind the breakthrough
The study also shows the persistence required in structural biology research. Prof. Hussain said early purification attempts looked promising, but many later efforts failed to produce usable results. Cryo-EM grids often did not yield enough particles for a reliable structure, even after repeated attempts.
Still, the team continued refining the approach until it succeeded. That persistence paid off by revealing a mechanism that had remained hidden since the discovery of EMCV IRES elements. The work demonstrates how careful experimental design can solve problems that have resisted explanation for years.
Therapeutic potential
The discovery may now guide future antiviral strategies. If researchers can design molecules that block the EMCV IRES from binding to the ribosome or initiator tRNA, they may be able to stop the virus from making proteins and multiplying. Because poliovirus and other viruses use similar IRES-based mechanisms, the implications could extend beyond EMCV alone.
That makes the IISc study significant not just for basic virology but also for drug development. It provides a structural foundation that future researchers can build on when searching for treatments against IRES-dependent viruses.
A major step in virology
The IISc team has solved a long-standing mystery about how EMCV hijacks host protein synthesis. By combining a clever pulldown strategy with cryo-EM, the researchers have shown how the viral IRES directly engages the host ribosome and initiator tRNA to begin translation.
This discovery deepens scientific understanding of viral infection and opens a path toward new therapies. It also highlights the value of structural biology in revealing the hidden molecular tricks that viruses use to survive.
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