Zika virus: A newly emergent vector-borne public health
threat in the Americas
Sujit Pujhari, Jason Rasgon
Zika virus is a newly emergent mosquito-borne flavivirus. Once almost ignored
epidemiologically, recent major outbreaks and links to neurological birth defects have
focused attention on this neglected pathogen. We review the discovery, biology and
symptomatology of Zika virus, what is known and not known about the mosquitoes that
transmit the virus, conspiracy theories currently hampering control efforts, and potential
avenues of Zika control. It is likely that Zika virus is here to stay in the Americas, so a
thorough understanding of the complete epidemiological transmission cycle and potential
effects on the human population will be critical for managing this new disease in the
coming years.
PeerJ PrePrints | https://doi.org/10.7287/peerj.preprints.1781v1 | CC-BY 4.0 Open Access | rec: 23 Feb 2016, publ: 23 Feb 2016
1 Zika virus: A newly emergent vector-borne public health threat in the Americas
2 3 Sujit Pujhari and Jason L. Rasgon*
4 5 6 7 Department of Entomology, Pennsylvania State University, the Center for Infectious
Disease Dynamics, and the Huck Institutes of the Life Sciences, Pennsylvania State
University, University Park PA, USA
8 9 10 *To whom correspondence should be addressed: Email jlr54@psu.edu Tel: 1-814-8633668
11 12 13 14 15 16 17 18 19 20 21 22 23 1 PeerJ PrePrints | https://doi.org/10.7287/peerj.preprints.1781v1 | CC-BY 4.0 Open Access | rec: 23 Feb 2016, publ: 23 Feb 2016
24 25 Abstract
26 Zika virus is a newly emergent mosquito-borne flavivirus. Once almost ignored
27 epidemiologically, recent major outbreaks and links to neurological birth defects have
28 focused attention on this neglected pathogen. We review the discovery, biology and
29 symptomatology of Zika virus, what is known and not known about the mosquitoes that
30 transmit the virus, conspiracy theories currently hampering control efforts, and potential
31 avenues of Zika control. It is likely that Zika virus is here to stay in the Americas, so a
32 thorough understanding of the complete epidemiological transmission cycle and
33 potential effects on the human population will be critical for managing this new disease
34 in the coming years.
35 36 37 38 39 40 41 42 43 44 45 46 2 PeerJ PrePrints | https://doi.org/10.7287/peerj.preprints.1781v1 | CC-BY 4.0 Open Access | rec: 23 Feb 2016, publ: 23 Feb 2016
47 What is Zika virus? Zika virus is a mosquito-borne flavivirus first isolated in the Zika
48 forest
49 http://www.atcc.org/products/all/VR-84.aspx]. The main vertebrate hosts for Zika virus
50 are humans, and to a lesser extent non-human primates [McCrae and Kirya, 1982]. In
51 addition to transmission through the bite of an infected mosquito, Zika virus has other
52 possible modes of transmission including mother to child, sexual and blood transfusion
53 [Foy et al., 2011, Musso et al., 2015]. For many decades, Zika virus was of no major
54 epidemiological concern, causing occasional small outbreaks in Africa and Southeast
55 Asia with only a handful of human cases recorded. This changed in 2007, when the first
56 outbreak outside of Africa or Asia occurred on the island of Yap in Micronesia. The Yap
57 outbreak ended with approximately 100-200 confirmed or suspected cases, and
58 resulted in no hospitalizations or deaths [Duffy et al., 2009]. Zika virus is no longer a
59 mild infection limited to Africa and Asia; autochthonous Zika transmission has been
60 documented in Brazil since May 2015, in other countries in central and south America,
61 and multiple imported cases in the United States [Hennessey et al., 2016] (Figure 1).
62 The World Health Organization (WHO) has declared Zika a global emergency and is
63 estimating approximately 3-4 million cases by the end of 2016 [Gulland, 2016].
of
what
is
now
Uganda
in
1947
[ATCC
product
sheet
VR-84;
64 65 Symptoms: Symptoms of classical Zika virus infection are generally mild and self-
66 limiting, and include a characteristic rash, fever, pain and headache, and are similar to
67 those caused by other co-circulating vector-borne pathogens such as dengue and
68 Chikungunya viruses, likely contributing to under-diagnosis in endemic areas. Usually,
69 symptoms resolve in about a week without medical treatment [Hayes, 2009]. However,
70 more recently Zika infection has been associated with the occurrence of severe
71 symptoms such as Guillain-Barré syndrome (an auto-immune disorder triggered by an
72 infection that leads to muscle weakness, paralysis and potentially death if breathing is
73 sufficiently impaired [Oehler et al., 2009]). In the recent Brazilian outbreak,
74 epidemiologists have observed a strong correlation between Zika virus infection in
75 pregnant women and the development of microcephaly, as well as miscarriage and
76 other birth defects in their newborns [Schuler-Faccini et al., 2016]. The US Centers for
3 PeerJ PrePrints | https://doi.org/10.7287/peerj.preprints.1781v1 | CC-BY 4.0 Open Access | rec: 23 Feb 2016, publ: 23 Feb 2016
77 Disease Control (CDC) has recommended that pregnant women avoid travelling to
78 Zika-affected regions, and El Salvador has made the recommendation that women
79 avoid getting pregnant until 2018. The link between Zika virus and microcephaly is not
80 fully resolved at this point, as it had never been observed in other outbreaks prior to
81 Brazil. However, this may be explained by the magnitude of the Brazilian outbreak,
82 coupled with the complete lack of herd immunity in the human population.
83 84 Mosquito vectors: Similar to dengue and Chikungunya viruses, the mosquito Aedes
85 aegypti is thought to be the primary vector for Zika virus. Aedes albopictus (the Asian
86 tiger mosquito) has also been demonstrated to be a highly competent vector in
87 laboratory studies [Wong et al. 2013]. However, there has been a surprising lack of
88 experimental study into the range of mosquitoes that can potentially become infected
89 with and transmit Zika virus. In surveys, Zika virus has been detected in over 25 species
90 of mosquitoes from 5 genera [Diallo et al., 2014, Ledermann et al., 2014, Marcondes et
91 al., 2015] (Table 1). Even more troubling, there are news reports from Brazil that Zika
92 virus has been detected in Culex quinquefasciatus, which is widespread and has the
93 potential to act as a major bridging vector into the urban environment. Although merely
94 detecting virus in a mosquito is not proof of transmission, these studies emphasize our
95 lack of knowledge about the transmission biology of this emergent pathogen. Some
96 identified vector species (Aedes albopictus and Aedes aegypti) are present in the
97 United States, opening the possibility of outbreaks and even local transmission in parts
98 of the USA. If some native mosquito species are competent to transmit Zika, the virus
99 could potentially move into the USA beyond areas currently colonized by aegypti and
100 albopictus, similar to what was observed with the invasion of West Nile virus in the early
101 2000’s [Venkatesan and Rasgon, 2010].
102 103 Control: While the Brazilian Zika outbreak has stimulated research into the
104 development of a vaccine, it will likely be several years before a vaccine becomes
105 available (if at all). At the moment, the only way to control Zika virus is to control the
4 PeerJ PrePrints | https://doi.org/10.7287/peerj.preprints.1781v1 | CC-BY 4.0 Open Access | rec: 23 Feb 2016, publ: 23 Feb 2016
106 mosquitoes that transmit it. There are already significant Aedes aegypti control efforts
107 ongoing (based primarily on insecticides) in Zika-affected areas to suppress dengue
108 virus transmission, and due to similar epidemiology these efforts will likely have an
109 affect on Zika virus. However, novel vector control strategies based on mosquito genetic
110 modification and heritable bacterial symbionts are taking center-stage in Brazil. The
111 British/American Company Oxitec has been releasing genetically modified sterile Aedes
112 aegypti mosquitoes in Brazil for several years [Carvalho et al. 2015]. These releases
113 suppress the mosquito populations, reducing their ability to sustain dengue virus
114 transmission. Oxitec is now preparing releases for Zika control, and all indications are
115 that properly conducted releases will reduce Zika virus transmission in a similar manner
116 to what has been observed for dengue virus. An alternative strategy relies on the
117 bacterial endosymbiont Wolbachia. When mosquitoes are artificially infected with
118 Wolbachia, they often become resistant to infection and transmission of pathogens
119 [Moreira et al. 2009, Hughes et al., 2011]. The EliminateDengue program has initiated
120 field releases of Wolbachia-infected Aedes aegypti for dengue virus control in 5
121 countries, including Brazil (Eliminatedengue.org). While the effects of Wolbachia on
122 mosquito pathogen transmission can be variable [Dodson et al., 2014, Hughes et al.,
123 2014], the strain being released in Brazil to block dengue virus transmission seems to
124 block Zika virus to a similar extent (S. O’Neill, personal communication).
125 126 Conspiracy theories: With the public panicking about the speed and magnitude of the
127 current multi-country Zika outbreak, conspiracy theories about the “real” cause of Zika
128 emergence and microcephaly have become widely disseminated. There are two major
129 conspiracy theories. The first is that release of genetically modified mosquitoes has
130 resulted in the emergence of a highly virulent Zika virus strain or was the cause of
131 microcephaly. This theory originated on an Internet message board specializing in
132 conspiracy theories, and was further developed by an article in the online publication
133 “The Ecologist”, which proposed that the piggyBac transposon used to genetically
134 modify the mosquitoes was transferred into the Zika virus genome, which was then
135 transferred to the developing fetal brain during gestation. This theory ignores the fact
5 PeerJ PrePrints | https://doi.org/10.7287/peerj.preprints.1781v1 | CC-BY 4.0 Open Access | rec: 23 Feb 2016, publ: 23 Feb 2016
136 that piggyBac is a DNA transposon (which can only transpose into DNA) while Zika has
137 an RNA genome, as well as the fact that the size of the transposon construct was a
138 significant fraction of the size of the Zika genome. In addition, the genetically modified
139 mosquitoes were not released in the same area of the initial Zika outbreak, but rather in
140 a different city of the same name.
141 The second conspiracy theory is that treatment of drinking water with the insect juvenile
142 hormone analogue pyriproxyfen is the true cause of microcephaly. This theory was put
143 forth by an Argentinian group calling themselves “Physicians in Crop Sprayed Towns”,
144 which seems to be an environmentalist group opposed to pesticide usage. There is no
145 plausible rational for this theory. Pyriproxyfen is an analogue of insect juvenile hormone
146 and has been widely used across the globe for over 20 years. It is poorly absorbed by
147 vertebrates, and what is quickly degraded. At exposure levels from treated drinking
148 water, a person would have to consume hundreds of gallons per day to even approach
149 toxic levels (which are > 1g/kg body weight in lab studies) [WHO, 2006]. Despite this,
150 some states in Brazil have suspended water treatment with this insecticide, which will
151 undoubtedly result in the outbreak getting worse.
152 153 Conclusion: The speed and extent of the Zika outbreak has taken scientists, public
154 health officials and medical practitioners by surprise. The upcoming summer Olympics
155 and the carnival in Brazil could greatly exacerbate the epidemic by allowing Zika to
156 move broadly across the globe. Controlling this emergent pathogen will rely on a rapid
157 public health response in affected countries, as well as proactive preparation in
158 countries likely to see virus introductions. With a vaccine several years off (at best),
159 vector control remains the only way to control the virus. Research risk assessment
160 priorities should focus on defining the mosquito vector range both in areas currently
161 experiencing outbreak and in areas where the virus is likely to be introduced, and the
162 refinement of strategies (both traditional and novel) to suppress or control the mosquito
163 vectors. Epidemiological research needs to confirm or refute the link between Zika virus
164 infection and birth defects, and if confirmed, family planning recommendations for those
165 in affected areas need to be addressed. Conspiracy theories that ultimately hamper
6 PeerJ PrePrints | https://doi.org/10.7287/peerj.preprints.1781v1 | CC-BY 4.0 Open Access | rec: 23 Feb 2016, publ: 23 Feb 2016
166 control efforts need to be addressed through education campaigns. Ultimately, it is likely
167 that Zika virus is here to stay in the Americas, so a thorough understanding of the
168 complete epidemiological transmission cycle and potential effects on the human
169 population will be critical for managing this new disease in the coming years.
170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 References
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256 257 Table 1. Mosquito taxa from which Zika virus has been isolated.
Genus
Aedes
Anopheles
Culex
Eretmapodites
Mansonia
*"suspected
258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 species
aegypti
africanus
albopictus
apicoargenteus
dalzielii
fowleri
furcifer
grahami
hensilli
hirsutus
jamoti
luteocephalus
metallicus
minutus
neoafricanus
opok
taylori
unilineatus
vittatus
coustani
gambiae
perfuscus
quinquefasciatus*
inornatus
quinquevittatus
uniformis
9 PeerJ PrePrints | https://doi.org/10.7287/peerj.preprints.1781v1 | CC-BY 4.0 Open Access | rec: 23 Feb 2016, publ: 23 Feb 2016
273 274 275 276 277 278 Figure legends
Figure 1. Worldwide distribution of Zika virus detection, isolation, and outbreaks.
Information is current as of February 22, 2016.
USA&
82&imported&Cases&
1947%
Uganda&
2015%
Brazil&
(~&1.5&million&cases)&
2007%
Yap&Island&
&
&&&&(180&cases)&
2014%
2013%
Tahi#&
&
(19,000&Cases)&
2014%
Ester&Island,&Chile&
&
&
(51&Cases)&
Ac#ve&&Zika&transmission&&
New&Caledonia&&&Cook&Island&
(8633&cases)&&(175&&cases)&
&
Imported&Zika&cases&
Serological&evidence&of&&Zika&&
Isola#on&of&&Zika&&
10 PeerJ PrePrints | https://doi.org/10.7287/peerj.preprints.1781v1 | CC-BY 4.0 Open Access | rec: 23 Feb 2016, publ: 23 Feb 2016