The Zika virus disease, caused by a virus transmitted primarily by Aedes mosquitoes, can have symptoms including mild fever, skin rash, conjunctivitis, muscle and joint pain, malaise or headache. It has been linked to serious birth defects such as microcephaly and Guillain-Barré Syndrome (GBS).
Isolated from macaque monkeys in
the Ziika Forest in Uganda in 1947, the Zika virus still remains a mystery. The virus was shown to infect humans
not long after, but it was identified as a benign disease, with mild
‘Zika may have deep ancestry in Asia that has been under-recorded, suggested a new study.’
For this reason, it was not heavily studied until almost 70
years later when it appeared to be associated with an unusual cluster of
cases of microcephalic birth defects and Guillain-Barré Syndrome (GBS)
paralysis in Brazil in 2015 and 2016.
If the at-least-70-year-old virus is responsible for the recently
reported neurological diseases, why were the first serious effects not
noticed until recently? And, why were these effects first in Brazil,
very distant from its continent of apparent origin, Africa? The
mysterious history of the virus matters because its details might tell
us the backstory of how it came to be what it is where it is and from
that, why it is doing so much damage.
But, how do you know the history of an invisible virus, which leaves
no physical record? It is especially hard to know the history of Zika
because the seemingly benign disease has been under-the-radar for most
of its known time in human hosts.
This is where genetics can help, since single-strand RNA viruses
like Zika tend to change rapidly over time and, with bioinformatics,
researchers can deduce what the ancestral relationships are between
different viruses collected at different places in different times from
different hosts. While the first noted occurrence of the virus was in
Africa, it was detected only a few years later in Asia, and separate
lineages of the disease are known from both areas - a clue that the
history hidden in the genes may be complicated.
"But sequence data on Zika is limited," notes University of North
Carolina at Charlotte Bioinformatics and Genomics Professor Daniel
Janies. "People have made the assumption that it came out of Africa
because that's where it was discovered. However, it has not been easy
to reconstruct the history of Zika with the data we have," he said.
Janies heads a team of researchers who have recently completed a
phylogenetic and geographic analysis of the available collection of
Zika's genetic sequences. The analysis provides the most complete study
of the virus's history to date and reveals specific genetic changes
that occurred as the virus crossed the Pacific Ocean on its way to the
Americas. An analysis of the genes involved also suggests new hypotheses
to explain the virus's association with microcephaly and GBS.
A report by Janies, Adriano de Bernardi Schneider, Jun-tao Guo,
Gregorio Linchangco, Zachary Witter, Dylan Vinesett and Lambodhar
Damodaran from the department of Bioinformatics and Genomics at UNC
Charlotte, Robert Malone from Atheric Pharmaceutical, and Jane Homan
from IoGenetics LLC appears in the current issue of Cladistics
"Our results indicate that Zika may have deep ancestry in Asia that
has been under-recorded," Janies said. "For example, not all the recent
global outbreaks of Zika appear to result from a simple linear
chronology of travel from the most recent past outbreak."
"Recently there has been an outbreak of Zika in Singapore in
parallel to the one in the Americas. We have updated our analyses and
the Singapore Zika virus is distantly related to the viral lineage in
the Americas. This lends support for the hypothesis that there are
yet-to-be discovered reservoirs of Zika virus in Asia," Janies said.
The Cladistics report traces Zika's phylogenetic tree through
analysis of genetic sequences, combining it with the chronology and
geographic information from the samples, and allows the researchers to
detail the virus' probable historical path as well as specific genetic
and structural changes in the virus as it traveled to the Americas.
The researchers noted in particular some new mutations that began
appearing in the virus as it traveled from island to island across the
Pacific. Not long after these mutations appear, there are records in
French Polynesia of an increase in both microcephaly and GBS. The
specific nature of the new mutations in the virus also suggest to the
team some possible relationships between viral infection and the severe
symptoms associated with the virus in the Americas.
"We looked at the viral changes that correspond to the first reports
of microcephaly and we saw the origins of these changes in the Pacific
lineages," Janies noted. "There are mutations that occurred in the part
of the viral genome that codes the viral envelope protein and the ends
of the viral genome that are called 'untranslated regions.' We focused
on the envelope protein because that's the part responsible for the
entry of the virus to host's cells. We studied the untranslated regions
since they mediate the types of tissues the virus attacks and viral
Both sets of mutations suggested potential relationships to the
virus's new association with neurological and developmental problems in
adults and infants.
"Members of our team found that Zika has recently started making its
envelope proteins with features, called epitopes, that are similar to
human proteins, which could cause a human host immune response to the
virus to be diluted," Janies said. "The theory underlying this idea is
called 'epitope mimicry.' The similarity is advantageous to the virus
because it confuses the host's immune system and blunts the immune
reaction to the virus."
However, the researchers suspect that the human proteins being
mimicked may be significant for reasons besides providing immune system
"cover" for the attacking virus.
An important element of the envelope protein mutation, Janies points
out, is not only in the mimicry itself, but also, in the specific genes
being mimicked: "Our team members found that two of the human proteins
that Zika is mimicking are involved in the signaling that goes on when
the sensory organs are being formed in the fetus. These genes are called
'Neuron Navigator Protein 2' and 'Human Neurogenic Differentiation
Factor 4'," he said.
"Because these are the proteins are being mimicked, a hypothesis is
that the developmental pathways that rely on the proteins may be being
disrupted by the immune system," Janies said.
The other mutations, on the untranslated regions, suggest other
possible effects that might change where Zika virus infects in the body.
"Although epitope mimicry hypothesis helps clarify the
protein-immune interaction, the mutations in the untranslated regions
may explain the types of tissues Zika attacks" UNC Charlotte
Bioinformatics and Genomics graduate student Adriano de Bernardi
Schneider said. "The presence of specific binding regions on
untranslated regions of the Zika viral genome, called "Musashi Binding
Elements" provides bases for the study of changes in tissue preference
of the virus."
In this part of the study, the authors evaluated the changes in the
virus' Musashi Binding Elements and found that they increased the
efficiency of the Zika virus that is circulating in the Americas in
hijacking human cells.
Musashi is a family of RNA-binding proteins in the host cells that
control gene expression and the development of stem cells. The finding
that Zika has mutated to be better at binding to human Musashi proteins,
leads to the hypothesis that Zika is adapting to be more efficient at
attacking human cells. Moreover, the role of Musashi proteins in stem
cells provides another possible target for the study of developmental
defects in the fetus associated with Zika infection in pregnancy.
Both the autoimmune effect and changes in the virus' tissue
specificity are working hypotheses suggested by computational models and
will require further study to verify.
In contrast, the information gained from studying Zika's
phylogenetic history is of immediate importance to medicine and public
health response, as this work puts the mutations in specific time and
place context, at a time when the virus has nearly circled the planet,
changing from place to place in its travels and leaving different
variants. Many versions of the virus currently exist globally and these
variants have different capabilities and effects.
"We're tracing the lineages and the geographic links in a very
rigorous way and pulling it all together, pin-pointing Zika's molecular
changes in time and space - showing what actually is going on in
different places," Janies said.
"Why does it matter? Well, when Zika arrives someplace is it going
to be benign or dangerous? It has been both - it depends on where it is