Wolbachia versus dengue Evolutionary forecasts

A novel form of biological control is being applied to the dengue virus. The agent is the maternally transmitted bacterium Wolbachia, naturally absent from the main dengue vector, the mosquito Aedes aegypti. Three Wolbachia-based control strategies have been proposed. One is suppression of mosquito populations by large-scale releases of males incompatible with native females; this intervention requires ongoing releases. The other interventions transform wild mosquito populations with Wolbachia that spread via the frequency-dependent fitness advantage of Wolbachia-infected females; those interventions potentially require just a single, local release for area-wide disease control. One of these latter strategies uses Wolbachia that shortens mosquito life, indirectly preventing viral maturation/transmission. The other strategy uses Wolbachia that block viral transmission. All interventions can be undermined by viral, bacterial or mosquito evolution; viral virulence in humans may also evolve. We examine existing theory, experiments and comparative evidence to motivate predictions about evolutionary outcomes. (i) The life-shortening strategy seems the most likely to be thwarted by evolution. (ii) Mosquito suppression has a reasonable chance of working locally, at least in the short term, but longterm success over large areas is challenging. (iii) Dengue blocking faces strong selection for viral resistance but may well persist indefinitely at some level. Virulence evolution is not mathematically predictable, but comparative data provide no precedent for Wolbachia increasing dengue virulence. On balance, our analysis suggests that the considerable possible benefits of these technologies outweigh the known negatives, but the actual risk is largely unknown. K E Y W O R D S : intervention; biological control; cytoplasmic incompatibility; population suppression Wolbachia is a maternally transmitted bacterial symbiont of many insects [1, 2] and has several unusual properties that make it suitable for novel approaches to biological control of vector-borne diseases [3–5]. First, when introduced into an uninfected species, Wolbachia often increases the relative fitness of infected females so that the infection spreads to virtual fixation (hence it is frequently called ‘selfish’). Second, Wolbachia is compatible with a broad range of hosts, whereby a strain isolated from one species can often be successfully introduced to another species, even one distantly related [6–8]. Third, Wolbachia produces a range of effects that can be exploited for disease control: it can inhibit the commentary 197 The Author(s) 2013. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. D ow naded rom http/academ ic.p.com em ph/article-ab2013/1/197/1862923 by gest on 18 M arch 2019 growth of many other microbes in its hosts [9], it can shorten the life of its hosts [10, 11], and it can be used to potentially eliminate uninfected populations or populations whose Wolbachia is incompatible with the one being released [12, 13]. Despite these myriad effects, relatively little is known about the underlying mechanisms [14–16], in part because Wolbachia cannot be cultured in vitro. The most ambitious application yet proposed for disease control using Wolbachia is dengue ‘elimination’. Dengue is a viral disease of humans, now endemic on three continents, affecting approximately one-third of the human population [17, 18]. The main vector of dengue virus (DENV) is the mosquito Aedes aegypti, which has no native Wolbachia infection. Wolbachia were introduced into Ae. aegypti with the hope of controlling DENV transmission by shortening the life of female mosquitoes [8]. Although life-shortening was projected to have only a small impact on mosquito demography, it could potentially have a major effect on disease transmission by greatly reducing the number of females old enough to transmit the virus [19, 20]. The life-shortening Wolbachia, denoted wMelPop, was initially found in a laboratory population of Drosophila melanogaster [21]. Initial tests of wMelPop in Ae. aegypti raised doubts about the feasibility of successful introductions in nature because wMelPop severely reduced both viability and fecundity [11, 22], making spread beyond isolated populations unlikely [23–25]. Fortuitously, it was discovered almost concurrently that some Wolbachia interfere with viruses and other microbes in the same host [26, 27]. The Wolbachia variant wMel, originally found in natural D. melanogaster populations [28], partially blocks DENV transmission without greatly impacting Ae. aegypti [22, 29]. Field releases in isolated towns in northern Queensland, Australia, where DENV is not endemic but Ae. aegypti is, have successfully transformed the local Ae. aegypti populations, producing virtual fixation of DENV-blocking Wolbachia. Releases are underway to spread this infection in nearby urban areas, aiming for area-wide dengue control (S. L. O’Neill, personal communication). All else equal, decreasing DENV transmission even slightly throughout an entire Ae. aegypti population might have a meaningful impact on human health due to the large number of infections [18, 30, 31]. Yet this optimism is justified only to the extent that evolution does not reverse the Wolbachia effect. What can we expect or predict about evolutionary responses to such a wide-scale intervention? Will dengue virus evolve to dodge the suppression? Will the virus evolve in ways that affect disease severity? How might Wolbachia be expected to evolve in this new host and how will the host evolve in response to this novel infection? The choice of which Wolbachia strains to release is based on beneficial effects the strains exhibit at present. Yet these effects will likely change—evolve—after the release, and that evolution may alter the diseasecontrol effectiveness of the released Wolbachia for decades to come. Successful Wolbachia introduction is nearly irreversible; additional Wolbachia infections might be used to displace the initial ones [4, 32, 33], but elimination of an infection, once established, is likely to be difficult. Hence, anticipating evolutionary changes of dengue–Wolbachia–mosquito interactions is important—and comparable to anticipating the evolution of resistance to pesticides and antibiotics. FRAMEWORK Our goal is to suggest plausible paths of evolutionary change as it affects Wolbachia-based control of DENV: how likely is evolution to overturn an otherwise successful strategy? We also consider evolution of dengue virulence in response to these interventions. Beyond these, other possible effects of releases abound, spanning Ae. aegypti ecology [34], impacts on the larger insect community interacting with Ae. aegypti and impacts on non-dengue microbes found within this mosquito. We neglect these latter topics for lack of evidence on which to base predictions. Our primary concern is whether we can anticipate success or failure of attempted dengue reduction and whether dengue disease incidence and effects can be predicted to change. Furthermore, we consider only the evolutionary implications of these interventions, not practical, ethical, economic or efficacy issues related to them. THE BASES OF PREDICTION: NATURAL PATTERNS AND MODELS OF SELECTION Evolutionary predictions can be founded on two types of evidence, and our predictions will rely on both. The most straightforward predictions are derived from actual observed evolution—experimental evolution or natural evolution (‘comparative’ evidence). In this case, the prediction is merely an extrapolation of evolution observed in one context to a new context. The second basis for prediction comes from models of natural selection, such as 198 | Bull and Turelli Evolution, Medicine, and Public Health D ow naded rom http/academ ic.p.com em ph/article-ab2013/1/197/1862923 by gest on 18 M arch 2019 those that infer the fitnesses of alternative phenotypes in the context of specific ecologies [35]. Yet even when a phenotypic state has clear fitness benefits and the model has captured the relevant biology, evolutionary progress remains hostage to genetic variation. Thus, predictions of this second type require both an understanding of selection and knowledge of or assumptions about available genetic variation. Predictions about evolution in this Wolbachia– DENV interaction are necessarily based on fragmentary evidence at this early state. Apart from simple cases like the evolution of insecticide resistance, evolution is often so sensitive to details that the only well-founded predictions are post hoc. If evolution in this system is highly sensitive to details—if our current predictions prove wrong or even prove right for the wrong reasons—our study will clarify the difficulty of making such predictions. The main hopes for successful prediction here, despite our ignorance of details, are ‘natural experiments’ that have been underway for decades if not millennia and interventions, analogous to pesticide applications, that impose such strong selection on the virus or Wolbachia that predictable evolution is expected except in the complete absence of relevant genetic variation. We will focus on these seemingly simple cases, offering predictions in advance of observed evolutionary outcomes. EXPECTED RESPONSES TO INTERVENTIONS Evolutionary responses to life-shortening: a clear expectation of reduced impact Selection in response to a life-shortening maternal symbiont is aligned for both the symbiont and its host (Table 1). Under maternal transmission, Wolbachia should evolve to increase fitness of its female carriers [36]. On the basis of sel