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December 2, 2021: Mechanism of an octopus-like virus replication machinery unraveled

Thursday, 02. December 2021

Hamburg/Grenoble. A research team from the Bernhard Nocht Institute for Tropical Medicine (BNITM), EMBL Grenoble and the HPI/UHH Department "Structural Cell Biology of Viruses" at the CSSB have studied nine structures of an essential Lassa virus protein in different functional states. The protein is necessary for virus replication and thus provides excellent targets for antiviral agents. The results have now been published in the journal Nature Communications.

Endemic in Western African countries, Lassa virus is transmitted to humans through food or household items that are contaminated with the urine or faeces of Mastomys rats. Although many human infections with Lassa virus are asymptomatic, about one in five patients develops a severe haemorrhagic disease, attacking vital organs like the liver, spleen, and kidneys. The World Health Organization lists Lassa fever as a significant public health threat. The infectious disease has a high epidemic potential; without a vaccine or reliably effective drugs.

"Although research groups worldwide are working on a vaccine, an effective antiviral drug is urgently needed to reduce the number of severe cases and deaths," explains Dr. Maria Rosenthal, BMBF junior research group leader at the BNITM. This is where structural biology can help.

Promising Lassa virus targets for science

The collaboration between the research groups at EMBL Grenoble, BNITM, and the HPI/UHH research department “Structural Cell Biology of Viruses” at the CSSB resulted in a paper recently published in Nature Communications. It details nine structures of the Lassa viral polymerase in different functional configurations. In an infected cell, this enzyme replicates the virus’s genetic information and ensures the production of building blocks for the construction of new viruses - it is therefore essential for the survival of the virus.

The polymerase has a peculiar architecture with a core and flexible outer components. “We call the Lassavirus polymerase an 'octopus' because it looks like it has arms that swim around, which makes it very hard to fix it in one position,” explains one of the three lead authors, Dr. Tomas Kouba of the EMBL group. “When you observe this ‘octopus’, you also want to see how it behaves, how it moves its arms to eat or catch something,” explained Kouba. "However, these movements are very fast, which makes them difficult to visualize with sufficient precision."

To further investigate the polymerase, the international research group used the modern technique of cryo-electron microscopy: “The power of cryo-EM is that you take millions of pictures of the protein. Then you can sort them into several boxes: one box with an arm up, and then one box with the arm down,” Rosenthal added. "You end up with high-resolution individual images of the octopus’ arms in different positions instead of a washed-out image of all the positions of the arm at the same time. That way you can model the arms reliably."

These studies provide crucial insights into the Lassa virus, which has only four different viral proteins ‒ very few compared to other viruses, such as herpes or SARS-CoV-2, which have dozens of components. The proteins make up for their small number by assuming multiple functions simultaneously, like a Swiss Army knife.

One Health: preparedness

The researchers supplemented their findings on the structure of Lassa polymerase with further experiments on the regulation of enzyme function and the importance of individual components of the enzyme. "Only through the combined expertise of all partners, was it possible to visualize and understand this complex enzyme," Rosenthal emphasizes. "Structural biology is important to understand what we are dealing with," she explains further. Because how can you win a fight if you don't really know who you're fighting? With the knowledge of how these viruses work exactly, science can develop more ideas on how people can fight these viruses in a sustainable, global and coordinated way.

 

The BNITM and the HPI are already long-standing partner institutes: Since the founding of the Leibniz Center Infection (LCI) in 2005, groups of the two institutes have been conducting joint research on topics of "Global and Emerging Infections" as a core competence in the Hamburg scientific area.

 

Publication:

Kouba T, Vogel D, Thorkelsson SR, Quemin ERJ, Williams HM, Milewski M, Busch C, Günther S, Grünewald K, Rosenthal M & Cusack S. Conformational changes in Lassa virus L protein associated with promoter binding and RNA synthesis activity. Nat Commun 12, 7018 (2021).

https://doi.org/10.1038/s41467-021-27305-5