IISc scientists reveal how encephalomyocarditis virus commandeers host cells

Researchers at the Indian Institute of Science (IISc) in Bengaluru have decoded how the encephalomyocarditis virus (EMCV) hijacks a host's protein synthesis machinery. The study, published in the journal eLife, uses cryo-electron microscopy (cryo-EM) to visualise the molecular interaction between the virus and host ribosomes.

EMCV is a rodent-borne animal virus that causes heart and brain inflammation, reproductive problems, and neurological disorders in many mammals. Like all viruses, EMCV lacks its own machinery for protein synthesis and must hijack the host's ribosomes and translational factors to multiply.

Viruses often contain structured regions in their RNA called Internal Ribosomal Entry Sites (IRES), which capture host ribosomes to translate viral genes while blocking the translation of host genes. IRES were first discovered more than a decade ago in EMCV and the poliovirus, but their precise structure and mechanism remained unclear.

'Nothing was known in terms of the details of how the virus captures the host ribosome — other than the translational factors involved — and exactly how it does so biochemically,' said Tanweer Hussain, associate professor in the Department of Developmental Biology and Genetics (DBG) at IISc and corresponding author of the study.

To fill this gap, Deepakash Das, a PhD student in Hussain's lab and first author of the study, devised a 'pulldown' strategy using an EMCV IRES-containing mRNA. This allowed him to isolate the EMCV IRES pre-initiation complex from cell lysate of rabbit reticulocytes (immature red blood cells). The pre-initiation complex is the assembly that viral RNA forms with host ribosome – the first step in making viral proteins.

Using a specially designed bait protein, the team captured the entire IRES complex intact, including key components of translation initiation: the 40S ribosomal subunit, initiator tRNA, and the eIF2 (eukaryotic initiation factor 2) complex. They then used cryo-EM to examine the structure.

'Early purification attempts went well — something of a beginner's luck — but many subsequent rounds failed to produce usable results. Cryo-EM grids frequently failed to yield enough particles for a reliable structure, but we persisted,' Hussain said.

Eventually, the cryo-EM images revealed that the EMCV IRES directly interacts with the 40S ribosomal unit and initiator tRNA of the host — a mechanism not seen in other viruses – to hijack host translational machinery. This detailed understanding opens new possibilities for therapeutic intervention.

Targeting the IRES could lead to new antiviral strategies against EMCV and similar viruses, such as poliovirus, that employ the same mechanism, the researchers said.