With the help of light and electron microscopy, scientists from the Department of Molecular Virology at the Department for Infectious Diseases of the Heidelberg University Hospital show how the Zika virus takes over control of the human liver cells and nerve stem cells. They discovered that the two known strains of the virus rearrange their host cells in a way that allows the development of factories for the replication of the pathogen. “These structures correspond to those we already know from the dengue virus. Both virus types are very closely related”, says Prof. Dr. Ralf Bartenschlager, Director of the Department of Molecular Virology and senior author of the new study.
Just like the dengue virus, Zika captures the so-called endoplasmic reticulum, a membrane system connected to the nucleus, where proteins are formed. The viruses replicate their genetic material in the protected membrane vesicles they produce at the endoplasmic reticulum and – though various stages – create readily packed replicates. What is special about the Zika virus though, is that it reshapes the cytoskeleton in a unique way. The various parts of the cytoskeleton have different tasks: For example, they control the form, growth and movement of the host cells, ensure mechanical stability and coordinate transport processes in the cell. “Infections with the Zika virus cause a drastic disturbance of these networks in the cells. They transform the normally loosely distributed elements into something like a cage that surrounds their replication centers”, adds Bartenschlager.
The cytoskeleton – an involuntary aid to the Zika virus?
The scientists are now interested in finding the reason for the reshaping in the cell. Is it a simple displacement of the cellular organelles due to the growth of the virus factories? Prof. Dr. Ralf Bartenschlager suspects there to be more: “We assume that the cytoskeleton takes on an active role during the replication of the virus. For example, it could transport certain substances the viruses need. But it could also function as a form of protection against attacks from the body’s own immune system which controls the cell and destroys foreign genetic material.
Comparison of the cytoskeleton (red) in a normal (left) and in an liver cell infected by the Zika virus (right). The green dots in the cell correspond to the viral replication factories that accumulate closely to the nucleus (blue) and are tightly surrounded by the cytskeleton. Picture: M. Cortese and R. Bartenschlager, Depeartment for Infectious Diseases, Molecular Virology, Heidelberg University Hospital
The Zika virus is known since 1947, but received global attention only in 2015 when it was linked to damages of newborns in Latin America. Zkia viruses infect only certain types of cells, among those the precursors of nerve cells in embryos. “The cytoskeleton plans an important role in the development of nerve cells”, says Dr. Mirko Cortese, first author of the publication. “There is a possible connection between the changes of the cytoskeleton triggered by the Zika virus and the microcephaly and the neurodegenerative damages that exist with a congenital Zika virus infection.”
A drug against cancer inhabits the replication of the virus
With the help of animal tests, the scientists now want to investigate if certain drugs that inhabit the activity of the cytoskeleton also help against the Zkia virus. The focus is on substances like Paclitaxel which is primarily used for the treatment of various forms of cancer, but which can also be taken at late stages of a pregnancy and during breastfeeding. “Our cell cultures already show that there is a connection between the dynamic of the cytoskeleton and the replication of the Zika virus. We therefore hope to identify new ways for a treatment”, says Bartenschlager.
Prof. Dr. Ralf Bartenschlager
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Cell Reports, Cortese et al.: "Ultrastructural characterization of Zika virus replication factories" www.cell.com/cell-reports/fulltext/S2211-1247(17)30179-1 DOI: 10.1016/j.celrep.2017.02.014