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September 12, 2018

Rotavirus Study Could Lead to Development of New Treatments for Disease

This is an artistic rendition of the rotavirus particle dissection process, performed with atomic force microscopy. [Scixel, under the instructions of D. Luque and P. J. de Pablo.]

  • Scientists have provided new insight on the mechanics of a virus that causes severe diarrhea and sickness in young children, according to a report (“Biophysical properties of single rotavirus particles account for the functions of protein shells in a multilayered virus”) published in eLife.

    The study, from the Autonomous University of Madrid, Carlos III Health Institute, and National Center for Biotechnology, Spain, could open up new avenues for developing effective treatments for rotavirus, which commonly infects children up to five years old, according to the researchers, who add that it is the first paper to detail the interplay between the function and mechanical properties of a multilayered virus.

    Virus particles enclose their genetic material in a protein shell designed to protect, shuttle, and release its genome at the host cell. The structure of virus particles, therefore, needs to be strong enough to protect the viral genome in environments outside the cell, and to withstand attacks from the host immune system to ensure successful infection.

    Many double-stranded RNA viruses, such as rotavirus, isolate their genome within a core shell that incorporates its own molecular machinery to allow the genome to replicate and spread. Some viruses take this a step further and build extra concentric protein layers that function in other ways, such as to help bind and penetrate their target cells.

    “The functions performed by the concentric shells of multilayered dsRNA viruses require specific protein interactions that can be directly explored through their mechanical properties. We studied the stiffness, breaking force, critical strain, and mechanical fatigue of individual triple-, double-, and single-layered rotavirus (RV) particles. Our results, in combination with Finite Element simulations, demonstrate that the mechanics of the external layer provides the resistance needed to counteract the stringent conditions of extracellular media,” write the investigators.

    “Our experiments, in combination with electrostatic analyses, reveal a strong interaction between the two outer layers and how it is suppressed by the removal of calcium ions, a key step for transcription initiation. The intermediate layer presents weak hydrophobic interactions with the inner layer that allow the assembly and favor the conformational dynamics needed for transcription. Our work shows how the biophysical properties of the three shells are finely tuned to produce an infective RV virion.”

    “The complete particle of rotavirus is formed by three independent protein shells. This particle and the subviral particles containing one or two protein layers play distinct roles during infection," explains lead author Manuel Jiménez-Zaragoza, Ph.D., research assistant in the department of physics of condensed matter at the Autonomous University of Madrid. "We wanted to see how the interactions between the layers that define these different particles work together during the virus replication cycle."

    Although previous studies have revealed how to purify two-layer protein particles, the team developed a novel way to purify single-layer particles, allowing them to be studied individually. After purifying these subviral particles, the team used atomic force microscopy, which involves using a small, sharp stylus to deform the virus particles. This allowed them to study the strength and stability of individual triple-, double-, and single-layered particles.

    They discovered a strong interaction between the external and middle layers, which they say is critical for the protection of the complete virus particle. Meanwhile, the interactions that take place between the middle and inner layers help the virus to replicate its genome among host cells, a process known as transcription.

    "Our findings reveal how the biophysical properties of the three protein shells are fine-tuned to enable rotavirus to be carried among host cells," says senior author Pedro de Pablo, Ph.D., associate professor at the Autonomous University of Madrid. "We believe this could prove valuable in offering new venues for the development of novel antiviral strategies."

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