Ultra-HD Map of Zika Virus Reveals Important Structural Secrets

An up-close and personal view of the notorious virus has opened up possibilities for future studies and treatment options for the Zika-prone.

A representation of the surface of the Zika virus with protruding envelope glycoproteins (red) shown. Credit: Kuhn and Rossmann research groups, Purdue University

A representation of the surface of the Zika virus with protruding envelope glycoproteins (red) shown. Credit: Kuhn and Rossmann research groups, Purdue University

As research teams around the world scramble to make sense of the ongoing Zika outbreak, scientists from Purdue University in the US have made a significant announcement: they have successfully determined a near-atomic level structure of the mature Zika virus.

Their visualisations, described in a paper published on March 31 in the journal Science, reveal that the virus is built similar to other flaviviruses, like that of dengue, but an important difference lies at a site that plays a role in choosing which cells to infect and affects host immune response. “The structure provides a framework for answering both basic questions about virus biology as well as providing a useful tool to developing antivirals and future vaccine studies,” virologist Richard Kuhn, one of the authors of the study, told this correspondent.

Parts of a flavivirus

The viruses that cause Zika fever, dengue fever, yellow fever and West Nile fever all belong to a family called flaviviruses and are transmitted by arthropods like mosquitos and tics. All flaviviruses have genomes that consist of single-stranded RNA molecules (as opposed to human genomes that are made of double-stranded DNA molecules) that encode about 10 proteins.

The RNA strands are about 11,000 nucleotides long and of the positive-sense type, meaning they can skip a step in protein production and so can infect the host faster and more easily. The genome lies in the centre, protected by a layer of capsid proteins. Around the capsid, there is a lipid membrane called the envelope on which float a layer of glycoproteins arranged as an icosahedral shell. A 3D animation of the parts of a dengue virus is available here.

Kuhn and team wanted to examine the structure of the Zika virus closely enough to be able to spot the ways in which it was identical to that of dengue and the ways in which it was not. The latter might explain some of the standout aspects of Zika infection, like why it seems to specially target neurons.

Spotting the differences

For this, they employed a highly advanced technology called cryo-electron microscopy (cryoEM). Here, the viruses are frozen and bombarded with a stream of high-energy electrons. Thousands of resultant 2D images are combined to create high-resolution 3D one. Unlike the powerful X-ray crystallography method, cryoEM is able to image the virus in a liquid solution rather than in crystals, Kuhn pointed out, an important advantage since membrane viruses such as Zika are extremely difficult to crystallise.

The image or ‘map’ that the scientists produced after the process showed that many of the features in Zika were similar to dengue and West Nile viruses – but not all. The most notable difference was observed in the Zika virus’s envelope glycoprotein E. “This region is on a loop on the envelope protein (the very outermost region of the virus) and thus sticks out. This ‘sticking out’ may make it easy to capture hooks that exist on target cells,” said Kuhn, explaining how this may control the virus’s entry.

This is important because the tropism, or the range of host cell types that the Zika virus targets, is still largely a mystery. Understanding such sensitive parts of the viral structure can help figure out if brain cells are especially susceptible as they seem in the light of the growing links between Zika, Guillain-Barré Syndrome and microcephaly.

A worthy approach

“Knowing the structure of the virus and the structure of the proteins that are coded by the viral genome is the best way to design therapeutic molecules against viruses,” said S. Ramaswamy, from the Institute for Stem Cell Biology and Regenerative Medicine, Bengaluru, about this development. He wasn’t involved in the study. He added that antiviral drugs against the HIV virus had resulted from structure-based strategies.

Ramaswamy also commented on the need for India to quickly invest in cryoEM, a technology he called a ‘game-changer’. “It is important that India be part of the first wave of adaptors of this technology, else we will significantly lag behind in structural biology, an area India has traditionally been strong,” he warned.  “What better example of the importance than the quick determination of the structure by this technique of an emerging viral epidemic.”