Examine evolutionary bottlenecks to depict viral fitness
landscapes
An evolutionary bottleneck is the event that reduces the size of a
population, limiting the genetic diversity of the species. It occurs
when viruses transmit from one host to another, rendering the
functionally dominant populations remaining in the circulation among
hosts. Molecular barcodes thus become a powerful tool, with which we can
simply trace transmission paths of a population of the viruses over
different hosts at a single-virus level. Influenza virus is one of the
viruses that has subsisted in the human community over a long history.
The most remarkable pandemics caused by influenza virus is the so-called
Spanish flu, or the 1918 H1N1 pandemic, infecting ~30%
of the
population[112,113].
Influenza virus A is endemic in waterfowl and is usually nonpathogenic
in these
birds[114]until the emergence of H5N1 outbreaks in
Asia[115–117].
Soon afterwards H5N1 influenza virus is known to be zoonoses, which can
transmit from its natural host to
humans[118–122].
To date, in addition to avian influenza virus A(H5N1), several zoonotic
influenza viruses, such as avian influenza virus
A(H7N9)[123,124]and
A(H5N6)[125–127]as well as swine influenza virus
A(H1N1)[128–131]and
A(H3N2)[132,133]and its variant
(H3N2v)[134]have been reported. Rapid antigenic variation that enables the viruses
to escape from neutralizing
antibodies[135]is frequently observed in influenza viruses, rendering vaccines not
fully effective. It thus a requisite to understand which variations of
the viruses could go through the pressure of selection bottlenecks in
different cross-species transmission routes before developing a better
strategy against influenza virus infection.
With barcoded influenza A virus in hand, Varble and colleagues examined
viral transmission bottlenecks under the selection forces present in
four different experimental systems, including Madin-Darby canine kidney
cells, embryonated eggs, direct-contact transmission in guinea pigs and
ferrets and respiratory-droplet transmission in
ferrets[24].
In the context of population dynamics and evolution, the bottleneck
concept is often used in reference to events that limit population size:
only individuals which successfully pass through the bottleneck retrain
in a population in a new environment. The authors detected that
bottleneck selection occurred only when embryonated-chicken eggs were
infected with barcoded viruses: 5 - 13 viral clones harboring unique
barcodes were successfully amplified in each
egg[24].
Intriguingly, such bottlenecks observed in individual recipient animals
can be independent from viral genome sequences. Furthermore, the authors
observed that viral transmission routes affect bottleneck stringency:
survival of barcoded viruses transmitting via contact- and airborne
infection showed a dramatic decrease compared with direct
inoculation[24].
As such, the authors concluded that viruses like H5N1 have to overcome
two distinct bottlenecks before the emergence of pandemic. The first one
lies on the level of the viral genome sequence. Viruses acquire genetic
mutations and/or reassortments to maintain replication fitness in
recipient
hosts[136].
Another is dependent on viral transmission routes. This barcoded
influenza A virus has further been applied by Muñoz-Moreno and
colleagues to reveal the evolutionary relationship between influenza NS1
genotypic variants and host
tropism[137].
Zika virus is another example of zoonotic diseases that is through
mosquito-borne transmission. It was first discovered in a Rhesus monkey
and in Aedes africanus mosquitoes during a yellow fever study in
the Zika forest of Uganda in 1947 and
1948[138,139].
Through the past fifteen years several outbreaks of Zika virus were
seen, bringing this virus to the world’s attention. Even though the
World Health Organization declared the end of the Zika virus epidemic in
2016[140],
it still represents a highly significant and long-term problem. The
virus induces a mild flu-like disease in about one in five infected
individuals[141–144];
in other words, approximately 80% of Zika infections are asymptomatic.
Pathologically speaking, Zika virus can also infect the placenta,
transmitting from pregnant women to
fetuses[145]in addition to blood-brain barrier endothelial cells, neurons and neural
stem
cells[146,147].
Even though the frequency of vertical transmission is not clear, current
data suggest that it may be a very common case, especially if infection
occurs in the period of the first
trimester[148].
At least 5% of babies contaminated by Zika virus during maternal
pregnancy suffered a collection of neurological, visual, auditory, and
developmental birth defects, so called congenital Zika
syndrome[145].
It is now also known that Zika virus infection is closely associated
with diseases. In Brazil the outbreak of Zika virus correlated with an
increase in cases of infant
microcephaly[149,150],
and in other parts of the Amercias there has been a significant increase
in Guillain-Barré syndrome coinciding with Zika
infections[151].
In order to better understand the in vivo replication and
evolutionary dynamics of Zika virus infection, Aliota and
colleagues[26]employed barcoded Zika viruses to track and monitor individual viral
lineages during acute infection in pregnant and nonpregnant macaques.
The authors first confirmed that viral RNA from barcoded Zika virus was
detectable in placentae. Fetal histology also showed several
pathological symptoms relevant to Zika virus
infections[26],
meaning that this animal model with barcoded Zika virus infection can
most likely bring us the picture representing Zika virus infections in
humans. Although no significant changes in the frequency of barcode
distribution was observed in nonpregnant macaques, a bottleneck effect
appeared after seven dpi in pregnant
macaques[26]:
the prevalence of the dominant viral lineages identified by unique
barcodes changes mainly after day 8 post infection. Aliota and
colleagues further used mosquitos fed with Aedes aegypti vector
competence for barcoded Zika virus to infect the pregnant macaque. Only
one viral lineage, Zika_BC02, representing the second most dominant
barcode present in the early period of infection was successfully
transmitted via mosquitoes.