Zika virus infographics
Zika virus infographics

There is great urgency to understand Zika virus as it continues its spread throughout the Americas and in tropical regions around the globe. What do we actually know about its biology? And what basic research questions need to be
answered to counter its spread and effects?

The essentials are this: Zika falls in the category of positive single-strand RNA virus and has a genome of 10 kb, which
encodes three structural proteins

The essentials are this: Zika falls in the category of positive single-strand RNA virus and has a genome of 10 kb, which encodes three structural proteins (capsid, premembrane/ membrane and envelope) and seven nonstructural proteins. By sequence homology, Zika is similar to other recently emerging pathogens, West Nile, chikungunya, and dengue viruses, and like these, it is also spread by the Aedes mosquito. Although the virus was first noted in Uganda in 1947, the strains causing the current outbreak are part of the Asian

lineage, closely related to that which caused the 2007 epidemic in French Polynesia (Enfissi et al., 2016). This was the first outbreak outside of Asia and Africa and was characterised
by a significant incidence of neurological symptoms, including Guillain-Barre´ syndrome. It is unclear if the virus has undergone changes that have accelerated its spread or that contributed to its neurological sequelae, though one early report proposes that codon usage for the nonstructural 1 (NS1) gene in the Asian lineage may be better optimised for expression in humans (Freire et al., 2015). Although many cases of Zika are asymptomatic and the most common symptoms of infection are rash, fever, and joint pain, the
recent outbreak has caused alarm because it has been associated with a significant increase in microcephaly in newborns.

Let’s start with the basics—how does Zika virus get first
into human cells?

Hamel et al. (2015) recently explored this question by exposing Zika virus to human skin cells (from adult biopsies and neonatal foreskins) to simulate what happens after exposure to an infected mosquito. Similar to dengue virus, the authors show that Zika appears to use
the C-type lectin receptor DC-SIGN and members of the TIM and TAM families of phosphatidylserine receptors on host cell surface to gain access to the cytoplasm via receptor-mediated endocytosis. Their findings indicate that dermalfibroblast, keratinocytes, and immature dendritic cells can all be readily infected and support viral replication. Skin dendritic cells in particular look to be an important Zika target since they have also been proposed to facilitate the spread of dengue virus. Assessment of other vulnerable cell types
awaits further investigation. Hamel et al. also shed light on host-virus interactions that
shape the course of infection. In infected primary human fibroblasts, the virus triggers an innate immune response, including expression of interferons, and both type I and
type 2 interferons inhibit viral replication. At the molecular level TLR3, which recognizes double-stranded RNA appears to be particularly central to the innate immune response to
Zika infection. This is reminiscent of other flaviviruses that have been studied. At the cellular level the virus induces autophagosome formation to promote replication and may
trigger apoptosis to foster viral dissemination. In broad strokes, these cellular events appear similar to what is known about dengue infection. Future work will delineate the extent
to which the pathways targeted and involved in infection are the same, and whether these point to shared vulnerabilities that could be useful therapeutically to quell infection by flaviviruses more generally.

The incidence of neurological symptoms associated with Zika infection is a distinctive feature. While Guillain-Barre syndrome, a weakness or paralysis caused by immune
attack on the peripheral nervous system, is frequently associated with the aftermath of a variety of infections and so its association with Zika is perhaps not altogether surprising,
the incidence of microcephaly in newborns is more mysterious. In contrast to Guillain-Barre´ , microcephaly impacts the developing central nervous system and is likely due to
teratogenic effects of the virus, rather than the immune response, and microcephaly has not previously been considered a potential repercussion of infection with flaviviruses.
That said, it is not entirely without precedent, as other types of infection, such as toxoplasmosis and cytomegalovirus, are also implicated in microcephaly. It should be cautioned that a causal link between microcephaly and Zika virus has not yet
been firmly established (for a discussion of the growing evidence read Vogel, 2016).
As concern grows, so does the impetus for developing a Zika vaccine and for augmenting Aedes mosquito control strategies. Here, recent efforts for dengue may point the
way forward. Brazil, which has been hit hard by both dengue and Zika, recently approved for use the world’s first dengue vaccine, Dengvaxia (from Sanofi Pasteur), which has also
been approved in Mexico and the Philippines. It is a chimeric vaccine in which the envelope and pre-membrane genes of the four serotypes of dengue replace those of an attenuated
strain of yellow fever. Other vaccine candidates, which employ diverse approaches, are in phase I and II trials. No such vaccines for Zika are at this stage of development,
and basic research directed at this goal will be key. Exploring how neutralising antibodies from previously infected individuals block viral infection pinpoints potential targets for therapeutic development and provides insight into weak links in the viral life cycle. For instance, Jin et al. (2015) recently defined a critical epitope bound by neutralizing monoclonal antibodies for chikungunya that block both its entry and release. Additionally, new vaccine design strategies also offer promise, including the recent use of structure-based
engineering to create broadly-neutralizing antibodies for dengue (Robinson et al., 2015). Targeting the mosquitos that carry these diseases is another approach, bolstered by
the discovery that the wMel strain of Wolbachia, a genus of bacteria that infect insects, blocks dengue transmission (Walker et al., 2011). First tested in the lab, the wMel strain
of Wolbachia has since been introduced into natural mosquito populations with results showing promise (Hoffmann et al., 2011; Nguyen et al., 2015)

The expansion of mosquito-borne flaviviruses over the past twenty years, first dengue, then West Nile, and more recently chikungunya and Zika have followed similar patterns (discussed
by Fauci and Morens, 2016). This recurrence places them at the forefront of research on emerging pathogens. In light of this and the many open questions highlight the need
to accelerate research on their basic biology and vaccine development, in order to position the research community to rapidly respond to this and future epidemics

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