See how Zika infection changes a human cell

February 28, 2017, Cell Press
This visual abstract depicts the findings of Cortese et al., who show that Zika virus infection in both human hepatoma and neuronal progenitor cells induces drastic structural modification of the cellular architecture. Microtubules and intermediate filaments surround the viral replication factory composed of vesicles corresponding to ER membrane invagination toward the ER lumen. Importantly, alteration of microtubule flexibility impairs Zika replication. Credit: Cortese et al./Cell Reports 2017

The Zika virus taking hold of the inner organelles of human liver and neural stem cells has been captured via light and electron microscopy. In Cell Reports on February 28, researchers in Germany show how the African and Asian strains of Zika rearrange the endoplasmic reticulum and cytoskeletal architecture of host cells so that they can build factories where they make daughter viruses. The study reveals that targeting cytoskeleton dynamics could be a previously unexplored strategy to suppress Zika replication.

"Cytoskeleton elements control cellular shape, growth, and movement, provide mechanical support and stress-resilience, and coordinate organelle anchoring and vesicular transport," says senior author Ralf Bartenschlager, a virologist at Heidelberg University. "Zika infections cause a drastic perturbation of the cytoskeletal network, re-organizing both intermediate filaments and microtubules into a cage-like structure that surrounds the replication machinery."

His group, led by first author and Heidelberg postdoctoral fellow Mirko Cortese, also found that Zika and dengue, both flaviviruses, use similar strategies to infect host cells. Once inside of a cell, latch onto the rough endoplasmic reticulum—the ribosome-rich membranes outside the nucleus where RNA is translated into proteins. The viruses then remodel the to form a protective cage with small holes where RNA and newly made viral particles can travel in or out.

The difference with Zika is that it has unique ways of rearranging structures within the cell. For example, there are an abundance of microtubules—proteins that build the cellular cytoskeleton—surrounding its protective cage. There were also slight variations between how Zika establishes itself in human liver cells versus , where it is more physiologically relevant. This suggests there are yet-unknown cell-type-specific factors that affect how the virus replicates.

This video shows a three dimensional rendering of ZIKV-induced membranes in hNPCs. Intermediate filaments are shown in red, virus particles in gold, ER membranes in blue and virus-induced vesicles in dark blue. Credit: Cortese et al./Cell Reports 2017

"The cytoskeleton has a crucial role in neurogenesis," Cortese says. "Thus, it is tempting to speculate that the alterations induced by Zika virus on the host cytoskeleton might be connected to the underlying physio-pathological mechanisms that link congenital Zika virus infections to microcephaly and neurodegenerative disorders."

Seeing Zika's reliance on the microtubules for its replication, the researchers now want to explore whether these drugs, including taxanes routinely used during chemotherapy, can have potential anti-viral activity against Zika in animal models. These, and similar drugs, have been declared safe to use during the second and third trimester of pregnancy, as well as during breastfeeding.

"Having identified a link between cytoskeleton dynamics and Zika virus replication, together with the plethora of available cytoskeleton-targeting compounds, might contribute to gain mechanistic insight into the ZIKV replication cycle and identify new avenues for treatment," Bartenschlager says.

This video shows a three-dimensional reconstruction of cytoskeletal filaments and ZIKV-induced convoluted membranesand vesicle packets in infected Huh7 YFP-Sec61β reporter cells. Cytoskeletal filaments are shown in red, the nucleus in blue, the microtubules organizing center in pink, convoluted membranes in green and packets of virus-induced vesicles in yellow. Note the distribution of cytoskeletal filaments surrounding the vesicle packets in the perinuclear region. Credit: Cortese et al./Cell Reports 2017

Explore further: More evidence that Zika mRNA vaccines can stop viral replication in mice

More information: Cell Reports, Cortese et al.: "Ultrastructural characterization of Zika virus replication factories" http://www.cell.com/cell-reports/fulltext/S2211-1247(17)30179-1 , DOI: 10.1016/j.celrep.2017.02.014

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