Flavivirus

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Zika and microcephaly: the answer is…..

The structure of Zikavirus has been published [1]. The work was done by a well known virus structure group at Purdue University and follows their previous structures of similar viruses, notably Dengue virus. Pleasingly the paper is open access so anyone can read the details and see how the virus is. It looks, well, like any other flavivirus.

zik

Zikavirus. The outside surface of the virus shows the classic “herringbone” arrangement of the major glycoprotein (the yellow), the protein that gets the virus into a cell. The virus is symmetrical and the 2-fold (oval), 3-fold (triangle) and 5-fold (pentangle) axis of symmetry are shown.  

Ordinarily, a virus structure might resolve unknowns concerning virus entry into the cell, especially if the resolution of the structure, the level of detail that can be seen, is sufficient to make out the surface detail, as the authors have managed here. So the Zika structure was awaited in the hope it might cast some light on how Zika could(still could, not proven yet) cause microcephaly.

Viruses have notable affinities for some cells more than others, termed tropism, and this is most usually governed by the virus interaction with the cell surface via a virus “receptor”. If the receptor is present the virus can enter, if it is absent it cannot. The question for Zika prior to the structure was whether the detail of the virus surface could help resolve this question. That is, what is the receptor used for foetal infection and could this explain the supposed link with microcephaly – alas it does not.

As is the case for all other arboviruses (viruses transmitted from insects) the identity of a receptor that could explain virus tropism remains unknown. There are really none that can be stated as “the” entry gate for the virus. At best all that can be said is that the position of a sugar chain on the surface of the virus, attached to the envelope (E) protein, is consistent with initial binding to a cell surface lectin (a sugar binding protein). The position is largely conserved with Dengue virus, as is most of the E structure. The position does vary a bit among related viruses so it could be part of the tropism picture but if it is the first contact with a cell then it will be a point of contact also for neutralizing antibodies produced during an infection and that, in turn, will drive change in the region through the everyday forces of evolution. In other words, the fact that this site varies is not surprising and it may have nothing to do with cell specificity.

zik2

A model for the interaction of Zika with the host cell. It’s very likely but it does not explain any specificity for foetal tissue 

The outcomes attributed to Zika have continued to grow. Soon after the first reports of microcephaly, Guillain–Barré Syndrome (GBS) was added to the Zika list of possible outcomes and in neighbouring Colombia it has been linked to a creeping paralysis[2]. Could one relatively simple virus cause all of these outcomes? In the case of GBS, the underlying cause is an autoimmunity syndrome triggered by a number of different infections. It is difficult to see why Zika should be any more associated with it than any other of the previously listed causes and given that many other infections circulate with Zika proving Zika is a direct cause, let alone the only cause, will be very difficult.

A alternate view to the current sensation based reporting is that once the immediate epidemic is over[3] the immunity left in the population will naturally control subsequent infections so that the longer term outlook is not as bad as it might first seem.

[1] http://science.sciencemag.org/content/early/2016/03/30/science.aaf5316.full

[2] http://www.bbc.co.uk/news/health-35552340

[3] http://www.independent.co.uk/news/world/americas/zika-infections-decline-in-parts-of-latin-america-a6967026.html

 

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Zika and Microcephaly – all aboard the speculation express

My last post ended “We must wait for the next year to see … whether or not the El Nino effect that is giving the unseasonal weather will perturb virus dynamics (those transmitted by insect pests for example) later in the year” (Another Year). Well, we didn’t have to wait long.

No one would wish to underplay the possible role of a new infection in something as sensitive as birth defects but the assumption that the current Zika outbreak is THE cause of a reported surge in cases of microcephaly among new-borns is premature. There is no doubt that a Zika epidemic is in progress in South America, fuelled by mosquito infestation, and several independent reports suggest a rise in the number of cases of microcephaly. But whether these observations are linked is much less sure. It’s not unreasonable to make the assumption, especially as not to do so would risk making light of personal tragedies, but the hard data is yet to be presented. Is it Zika and only Zika (many other viruses are transmitted by the same mosquitoes) and if so why should this virus do it and why was it not seen before (other Zika outbreaks have occurred as it moved across the Pacific albeit not on the scale now being witnessed in countries like Brazil)? In the absence of reliable data here are some virus related points that might be considered.

That Zika could be linked to microcephaly

  • The virus has been reportedly fund at autopsy of affected new-borns
  • It is circulating and will obviously infect pregnant women (~4% of the population at any one time)
  • Some viruses of this family (flaviviruses) cause encephalitis in adults
  • Other viruses like Rubella and CMV, long known to be able to transfer across the placenta and infect the foetus, cause foetal abnormalities including microcephaly
  • It is a new infection so previous experience limited, nothing should be ruled out

That Zika is unlikely to be linked to microcephaly

  • Tests for Zika are often confused by cross reaction with other flaviviruses
  • Previous Zika epidemics, in Africa, Southeast Asia, and the Pacific Islands have not noted the link with microcephaly despite detailed follow up
  • Why only microcephaly? Rubella and CMV infection result in a range of birth defects resulting from damage of many foetal tissues. Generally the earlier in the pregnancy the infection, the greater the damage. No such range reported for Zika
  • Specific brain cell infection would require a tropism for that tissue. No such tropism has been shown in adult Zika infections. In fact arboviruses (insect transmitted viruses) are known for their wide host range, infecting many cell types

From a virology perspective the case for Zika being a “microcephaly virus” is not at all clear. It is reasonable to err on the side of caution, e.g. the travel advice for pregnant women, but no-one knows the real risk assessment and we must wait for much more comprehensive follow-ups to know if the presumed association is real. It seems too widespread to be mass hysteria but with a world sensitised to virus outbreaks by the Ebola and Swine/avian flu experiences it is also prudent to question whether there isn’t a hint of scaremongering in the coverage to date.