CeMM Adjunct PI Thijn Brummelkamp identified entrance mechanism of the Lassa Virus into Cells

In collaboration with scientists at Radboud University (Netherlands) and Harvard University (USA), the laboratory of Thijn Brummelkamp (Netherlands Cancer Institute, Adjunct Principal Investigator at CeMM) identified genes that are required for coupling sugar groups to the dystroglycan protein.

Defects in these genes make cells insensitive to infection of the hemorrhagic fever causing Lassa Fever virus but also cause severe brain, muscle and eye defects as observed in children diagnosed with Walker-Warburg syndrome. For the identification of the genes the scientists used a unique human cell line where genes are present only in a single copy. The availability of the “haploid” cell line is an achievement of Thijn Brummelkamp who circumvented the obstacle of diploidy by knocking out genes in a rare human cell line that only carries one copy for >95% of its genes. The technology is not only crucial for the current study but also being employed by several groups at CeMM to study host-pathogen interactions and mechanisms of drug action. The recent study was published advanced online in Science, on March 21st, 2013. Congratulations from CeMM!

Viruses need to enter into the cells of their host to amplify and cause disease. In order to achieve this, Lassa Fever virus binds to dystroglycan, a protein complex on the outside of the cell. After its production, this complex is heavily decorated with sugars to fulfill its function: anchoring the cell to its surrounding.

To generate a detailed map of how Lassa virus enters human cells, infection with this biosafety level 4 virus was simulated in the laboratory of Sean Whelan at Harvard Medical School in collaboration with the group of Thijn Brummelkamp.  To do so, scientists used a unique human cell line that would point out genes required for successful infection because genes are present only in a single copy and can readily inactivated. Until recently this genetic trick was only possible in model organisms such as baker’s yeast and fruit flies.

In Walker-Warburg syndrome certain genes are defective that are critical for sugar-modification of the dystroglycan complex. As a result, affected children develop severe brain, eye and muscle abnormalities and usually die at early age. Although a number of such genes are known, the genetic defects in many patients remain unsolved. Because Lassa Fever virus uses the sugar-modified dystroglycan complex for entry, the infection experiments shed light on the genes needed for its construction, as cells carrying mutations in these were able to withstand exposure to the virus. Indeed, besides pointing out all factors known to be mutated in Walker-Warburg syndrome, the experiments revealed a whole set of new genes.

Based on these findings, researchers went on the scan the genome of Walker-Warburg patients for defects in these newly identified genes in collaboration with the group of Hans van Bokhoven at Nijmegen University. Strikingly, several families affected by hereditary Walker-Warburg syndrome of previously unknown cause carried mutations in these genes.

Lassa Fever virus is endemic in regions of Africa and causes thousands of deaths every year. To enter into the cell, the virus cleverly hijacks the same factors that are critical for the development of vital organs in the human body. In communities exposed to Lassa Fever virus it will be of interest to see if the human genome shows traces of the ongoing struggle in the sections encoding the identified host factors that are involved in building the sugar trees on the dystroglycan protein.

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