Science1 publisher2 min readPublished
Cryo-ET catches a rotavirus punching into a cell with a calcium-triggered pore
Stephen Harrison's Harvard lab imaged a rotavirus breaking into a cell and found that VP7, not the protein he expected, forms the pore that releases its genome. The team reported the mechanism Sept. 10 in Science, and Harrison sees it as a lead on delivering large gene therapies into cells.
The Scientist · Science desk
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What happened
- The trigger is a calcium leak: VP5 makes the compartment membrane permeable to calcium, and the loss of those ions is what frees VP7 from the virus particle.
- Biologists have understood how enveloped viruses like influenza and HIV get their genome across the membrane better than how nonenveloped ones such as poliovirus and adenovirus do.
- The work was led by Marilina de Sautu, a research fellow in Harrison's lab, with Simon Jenni, a Harvard Medical School research scientist.
- Cryo-electron tomography let the team reconstruct the whole sequence, from the virus attaching and being engulfed to punching through and ejecting its RNA.
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Why it matters
- capability Pushing large cargo across a cell membrane is a delivery problem gene therapy keeps hitting, and a nonenveloped virus does it naturally; the study identifies the proteins and calcium step involved.
- constraint The delivery case rests on a single rotavirus strain in the lab, so reading it as a blueprint runs ahead of what the imaging shows.
- precedent Harrison expects that working out how one virus gets in shortens the path to understanding the rest of the nonenveloped viruses.
An enveloped virus carries its genome inside a membrane; a nonenveloped one has no membrane of its own, so to deliver its genome it has to breach the cell's. [1] Earlier work from Harrison's lab and others had followed rotavirus attaching to a cell and being drawn into a membrane-bound compartment, where it then punches a hole to release its genome. [20] Which protein does the punching was one of the last pieces missing, and Harrison had worked on that gap for decades. [3][23]
Harrison, the study's senior author and a Howard Hughes Medical Institute investigator, had expected that protein to be VP5. [19] "All along I had thought it would be VP5 that punched the hole, but it's VP7," he said. [9] Earlier findings from Philip Dormitzer, a former HMS and Boston Children's colleague now a biopharmaceutical executive, and their student Shane Trask had pointed the same way. [10] Harrison called it "hole punching of a particularly satisfying type." [11]
His interest runs past rotavirus. "This work is relevant not just for understanding infection by nonenveloped viruses but for addressing the general question of what are the mechanisms for delivering large cargo into cells," Harrison said. [16]
Seeing the sequence at all depended on cryo-electron tomography. The frozen sample tilts while the microscope stays still, and the tilted views reconstruct into a 3D model, the way a CT scan builds one from many rotations. [13] "Cryo-ET allowed us to do something we wouldn't have been able to do even a few years ago," Harrison said. [17]
What to watch
- Whether developers can engineer a delivery vehicle from the VP7 pore to carry large therapeutic payloads into cells.
- Whether the same calcium-triggered VP5-to-VP7 relay operates in other nonenveloped viruses such as poliovirus or adenovirus.