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Published: 2023-06-07 Updated: 2023-06-12, 11:32

Thesis about how a mosquito-borne virus hijacks human cells

NEWS The chikungunya virus is spread by mosquitoes in tropical and subtropical regions. When it infects a cell, it creates factories where its genes are copied. In his PhD thesis, Timothée Laurent reveals new insights into these factories, including detailed 3D images that show how they are built up.

Text: Ola Nilsson

In his doctoral thesis Timothée Laurent has studied the chikungunya virus (CHIKV), that is transmitted through mosquito bites and is responsible for the crippling chikungunya fever. This sickness is characterized by fever, rashes and long-lasting join pain.

A particularity of CHIKV is that it is able to change the morphology of membranes surrounding cells. The remodeling of membranes yields small balloon-shaped structures known as “spherules”. The virus uses spherules to replicate its genome while hiding it from the rest of the cell to minimize the immune response. Spherules have been studied for nearly four decades using electron microscopy and it brought valuable knowledge regarding their morphology. But electron microscopy methods used prior to the research did not permit to study in detail how viral proteins and the viral genome are arranged in spherules.

In the research in Timothée Laurents thesis, he and the research group used cryo-electron microscopy, which relies on imaging frozen infected cells. This method allows to take snapshots of spherules at the instant they were frozen, preserving the details of the organization of viral proteins and genome. They found that viral proteins in charge of replicating the genome arrange themselves in a superstructure, also referred to as a protein complex, located at the junction between spherules and the interior of the cell.

The protein complex allowed the viral genome to form spherules by acting as a molecular engine, pushing the genome onto the membrane of the cell to deform it, yielding these characteristic balloon-shaped structures. To aid this process, the composition of the cell’s membrane is locally altered, facilitating the formation and maintenance of spherules onto its surface. The researchers could quantify the amount of genome of the virus insides spherules by measuring it inside 3D volumes reconstructed from cryo-electron microscopy images. Each spherule contained a single copy of the viral genome, the researchers found.

They were further interested in understanding how the genome occupied the interior of spherules and discovered that it occupied homogenously their interior but exhibited a preferential folding due to its constant replication by viral proteins. Prior to Timothée Laurent’s research, the mechanism behind the formation and maintenance of spherules was unknown. The protein complex sitting at the entrance of spherules was never reported and it was unknown how the genome of CHIKV arranged itself in spherules. This research is an important step in the understanding of the molecular mechanism of the replication of CHIKV.

Timothée Laurent was born in France and has studied biochemistry at Université de Lorraine.

About the public defence of the doctoral thesis

Timothée Laurent, Department of Medical Chemistry and Biophysics, Thursday 8 June at 13.00 defends his doctoral thesis Macromolecular organization of the chikungunya virus replication organelle. Opponent Alex Evilevitch, professor, Department of Experimental Medical Science, Lund University. Principal supervisor Lars-Anders Carlsson. Place: KBE303 - Large lecture hall