- Email: [email protected]
An Ecosystems Perspective on Virus Evolution and Emergence
Please cite this article in press as: French and Holmes, An Ecosystems Perspective on Virus Evolution and Emergence, Trends in Microbiology (2019), https://doi.org/10.1016/j.tim.2019.10.010
Trends in Microbiology
Opinion
An Ecosystems Perspective on Virus Evolution and Emergence Rebecca K. French1 and Edward C. Holmes1,* Understanding the emergence of pathogenic viruses has dominated studies of virus evolution. However, new metagenomic studies imply that relatively few of an immense number of viruses may lead to overt disease. This suggests a change in emphasis, from viruses as habitual pathogens to integral components of ecosystems. Here we show how viruses alter interactions between host individuals, populations, and ecosystems, impacting ecosystem health, resilience, and function, and how host ecology in turn impacts viral abundance and diversity. Moving to an ecosystems perspective will put virus evolution and disease emergence in its true context, and enhance our understanding of ecological processes.
Ecological Virology A central pillar of virology has been the idea that viruses are commonly pathogens responsible for diseases with potentially devastating consequences. Such a view is understandable as viral diseases have imposed a major disease burden on many host species, particularly following cross-species transmission (host jumping), and a vast array of strongly selected host genes are devoted to combating and evading viruses [1]. However, recent metagenomic studies of diverse host species are leading to a very different view of the virosphere, in which the total number of viruses is immense [2], hosts are commonly infected by multiple viruses and sometimes at high abundance, but where relatively few are clearly associated with disease [3,4]. In a few cases viruses have even been shown to be beneficial to their hosts [5]. Studies of virus ecology have traditionally been challenging, particularly as limitations to detection power meant that viruses were largely studied individually rather than in toto. Hence, the full diversity of viruses and their possible interactions could not easily be determined. This is changing with metagenomics, an approach that enables the entire virome of a sample to be sequenced and that is opening up an ecosystem-scale approach to studying viruses. Although viruses have sometimes been studied as part of ecological communities, for example, in plant, bacterial, and microscopic algae communities [5–8], to date metagenomics has been primarily used to identify the pathogens involved in disease outbreaks or associated with specific disease syndromes [9,10], revealing the structure of the virosphere [11–15], and understanding key aspects of virus evolution such as their antiquity and changing genome organizations [3,16]. What has largely been absent is an attempt to understand the ecological context to these evolutionary events. For example, although cross-species virus transmission is central to understanding disease emergence, it is not known how frequently a host jump results in a marked reduction in host fitness, particularly as these fitness costs may be difficult to measure in nature [4,17]. In addition, viruses may be ideally suited to the study of ecological events as their rapid evolution makes them powerful markers for tracking short-term processes [18]. The sheer abundance of viruses in nature and their ability to move between hosts suggests that we adopt a new perspective in virology: rather than considering viruses as likely disease-causing pathogens, we should instead regard them as integral components of ecosystems that may only rarely lead to emerging disease (Figure 1, Key Figure). Herein, we attempt to paint a backdrop for this ecological perspective on viruses, outlining how viruses can be better incorporated into the study of ecology and vice versa, particularly using metagenomic sequencing.
Virus Interactions in Ecosystems Virus ecology can be considered at scales spanning individuals to communities. An ecosystem is defined as a community of living organisms and their nonliving environment [19]. How organisms
Trends in Microbiology, --, Vol. --, No. --
Highlights The high abundance and diversity of viruses in nature, often in the apparent absence of disease, suggests that they are naturally embedded into global ecosystems at all ecological scales. Studies of virus ecology and evolution need to refocus to understand the role played by viruses in global ecosystems rather than only on pathogens that emerge following host jumping. Viruses alter interactions between host individuals, populations, and ecosystems, impacting ecosystem health, resilience, and function. Host ecology in turn impacts viral abundance and diversity. Viruses account for extensive biodiversity and have abundant links within ecosystems. An ecosystem with higher diversity has higher functional redundancy and is more resilient to change. The natural virome may therefore be beneficial to ecosystem function.
1Marie Bashir Institute for Infectious Diseases and Biosecurity, Charles Perkins Centre, School of Life and Environmental Sciences and Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia
*Correspondence: [email protected]
https://doi.org/10.1016/j.tim.2019.10.010 ª 2019 Elsevier Ltd. All rights reserved.
1
Please cite this article in press as: French and Holmes, An Ecosystems Perspective on Virus Evolution and Emergence, Trends in Microbiology (2019), https://doi.org/10.1016/j.tim.2019.10.010
Trends in Microbiology
Key Figure
Shifting the Focus from Studies of Disease Emergence to That of Ecosystems (A)
(B)
Trends in Microbiology
Figure 1. (A) A focus on disease emergence primarily considers viruses as pathogens that cause morbidity and mortality, particularly in humans or host species important to humans. (B) An ecosystem focus not only encompasses emerging and pathogenic viruses, but the entire virome in healthy and unhealthy hosts, as well as the complex interactions between viruses, hosts, and environments.
interact with each other and with the nonliving environment within a population, between populations, and between communities will affect the way an ecosystem is structured and functions [19]. Viruses are naturally embedded in ecosystems, and the interactions among them and with their hosts will not only impact their own abundance, diversity, and evolution, but also that of their host populations and communities [20,21]. Only through studying viruses in an ecosystem context at individual, population, and community scales can we understand these key processes: cross-species transmission, that underpins disease emergence, is one such process. Below, we outline some of the ways that viruses impact ecosystems, how the abundance and diversity of viruses is affected by host ecology, and how metagenomics might be used to study this.
Individuals The abundance and diversity of viruses within an individual host organism will be impacted by the behavior of that organism (Figure 2). For example, territorial males that have frequent contact with conspecifics (such as fighting and mating), and hence more opportunities for transmission, may have a greater prevalence and diversity of viruses than nonterritorial males. Experimentally increasing testosterone in the white-footed mouse (Peromyscus leucopus) increased the number of contacts between hosts and transmission potential ([22], Table 1). Similarly, some species show considerable individual and/or temporal variation in diet (e.g., [23,24]), which is also likely to impact the types of viruses they harbor (e.g., [25], Table 1). High contact rates and low genetic diversity may mean eusocial species have a high density and diversity of viruses [26]. Concurrently, viruses may impact host interactions by changing host behavior (Figure 3). In theory, behavioral modifications could be an adaptive strategy by a virus to increase transmission rates [8]. Although this is difficult to test empirically [27], there are examples of host behavioral modification
2
Trends in Microbiology, --, Vol. --, No. --
Please cite this article in press as: French and Holmes, An Ecosystems Perspective on Virus Evolution and Emergence, Trends in Microbiology (2019), https://doi.org/10.1016/j.tim.2019.10.010
Trends in Microbiology
Trends in Microbiology
Figure 2. The Different Ways in Which Host Ecology Might Impact Virus Diversity and Abundance. Host behavior, such as social hierarchy and individual foraging, affects the number and type of intra- and interspecific interactions. Host population dynamics will affect the density of hosts, and the number and type of interspecific interactions. The abiotic environment may directly impact the ability of the virus to spread to other hosts, as well as the geographic distribution of those hosts. Similarly, the host’s ecological niche will determine its geographic distribution, which also affects the number and type of interspecific interactions. All of these variables will affect the number of opportunities a virus has to jump from one host species to another, in turn shaping the diversity and abundance of viruses in populations.
that ‘appear’ to facilitate transmission (e.g., [28–30], Table 2). A case in point is the aphid Rhopalosiphum padi that, after acquiring barley yellow dwarf virus (BYDV), changed its feeding preferences to noninfected plants, enhancing spread [29]. Some host behavioral modifications could instead impact host interactions and hence virus transmission. A high viral load could increase energy requirements, in turn leading to behavioral changes ([30,31], Table 2). For example, Bewick’s swans (Cygnus columbianus bewickii) infected with low-pathogenic avian influenza (LPAI) A viruses changed their feeding rates and delayed their migration [31]. Conversely, behavioral modifications may be an adaptive strategy by the host to reduce viral load, such as seeking out temperatures unfavorable for replication (Table 2). Zebra fish (Danio rerio) experimentally infected with synthetic spring viremia of carp virus (SVCV) changed their thermal preference by 3 C, rapidly clearing the infection. Infected fish prevented from expressing behavioral fever showed decreased survival [32]. In eusocial animals, infection may also result in behavioral changes to protect their social group (e.g., [26], Table 2). As outlined below, changing an individual organism’s behavior has important flow-on effects on population dynamics and community food webs. Metagenomic studies of viromes within and among species that differ in behavior, diet, and social structure could help to reveal the impact of host ecology on the abundance and diversity of viruses, as well as the impact of virus abundance on host behavior.
Populations Virus diversity and abundance will be directly impacted by the number and extent of exposure events between and among host species, in turn shaped by host ecology and population dynamics (Figure 2). With density-dependent transmission, the probability that an infected individual has contact with a susceptible host increases with host population density. Accordingly, host density increases the number of new infections arising from an infected individual and the likelihood that a virus will successfully spread through a population [33]. Viruses with high transmission rates are better able to invade novel hosts at lower host population densities [33], and may be consistently present in a population with a continuous supply of susceptible hosts [34]. Conversely, viruses with lower transmission rates would only be able to invade at high host contact rates, and would only be present at high host densities (e.g., [35,36], Table 1). However, in some viruses, such as those that are sexually transmitted, transmission rate is independent of host density [33]. These viruses can therefore persist at very low host densities (frequency-dependent transmission) [33].
Trends in Microbiology, --, Vol. --, No. --
3
Please cite this article in press as: French and Holmes, An Ecosystems Perspective on Virus Evolution and Emergence, Trends in Microbiology (2019), https://doi.org/10.1016/j.tim.2019.10.010
Trends in Microbiology
Table 1. Examples of How Host Ecology Affects Virus Diversity and Abundance
Factor(s)
Effect
Host behavior
Intraspecific interactions
Host ecology affecting virus ecology Examples
Refs
Experimentally increasing
[22]
testosterone in the whitefooted mouse (Peromyscus leucopus) increased the number of contacts between hosts, in turn increasing transmission potential. Differences in behavior between sexes may therefore explain the malebiased infection rates commonly found in vertebrates. The cannibalistic behavior
[25]
displayed by some tiger salamander larvae (Ambystoma tigrinum) is thought to affect the transmission of Ambystoma tigrinum virus (ATV). Population dynamics
Population density
High densities of seals on
[35]
land were central to triggering the 1988 phocine distemper virus (PDV) epidemic in harbor seals (Phoca vitulina). The density of flying fox
[36]
species (Pteropus alecto and Pteropus conspicillatus) is strongly correlated with reported cases of Hendra virus in horses. Interspecific interactions
Simian foamy viruses (SFV)
[38]
are transmitted between wild chimpanzees (Pan troglodytes verus) and western red colobus monkeys (Piliocolobus badius) during predator– prey interactions. Abiotic factors
Viral dispersal
Red-necked avocets
[48]
(Recurvirostra novaehollandiae) from the arid interior in Australia had a
(Continued on next page)
4
Trends in Microbiology, --, Vol. --, No. --
Please cite this article in press as: French and Holmes, An Ecosystems Perspective on Virus Evolution and Emergence, Trends in Microbiology (2019), https://doi.org/10.1016/j.tim.2019.10.010
Trends in Microbiology
Table 1. Continued.
Factor(s)
Effect
Host ecology affecting virus ecology Examples
Refs
greater viral diversity and abundance than those from temperate Australia. This is likely because water sources in arid areas are visited by a higher diversity and density of species than in temperate areas. Abiotic factors/host
Virus geographic
The range of the hispid
ecological niche
distribution
cotton rat (Sigmodon
[53,54]
hispidus), host to hantaviruses and the Tamiami arenavirus, is severely limited by climate, but has expanded northward and to higher altitudes in the past few decades. Modeling suggests that the
[55,56]
Asian tiger mosquito (Stegomyia albopicta) will significantly increase its range due to warmer and wetter winters, as well as warmer and drier summers, in the Americas, Europe, and China. This mosquito is an important vector for dengue virus (DENV) and chikungunya virus (CHIKV). Modeling of environmental suitability also indicated that DENV susceptibility will increase in many regions, and 2.25 (1.27–2.80) billion more people will be at risk of infection in 2080 compared with 2015.
There has been considerable interest in understanding the interactions between predators and prey, and how this affects behavior, population trends, and geographical distributions [37]. Viral infection is likely to cause changes in host interactions and population dynamics, including mortality and reproductive rates (Figure 3), impacting key aspects of population ecology including predator–prey interactions and interspecific competition. These interactions also provide opportunities for cross-species transmission. The most frequent interactions among species in ecosystems occur in community food webs: every time a predator consumes prey it will also consume viruses, providing opportunities for viruses to jump hosts (Table 1). Although most food-associated viruses will likely not be able to replicate in a novel host, important examples exist. As a case in point, simian foamy viruses (SFV) are transmitted between wild chimpanzees (Pan troglodytes verus) and western red colobus monkeys
Trends in Microbiology, --, Vol. --, No. --
5
Please cite this article in press as: French and Holmes, An Ecosystems Perspective on Virus Evolution and Emergence, Trends in Microbiology (2019), https://doi.org/10.1016/j.tim.2019.10.010
Trends in Microbiology
Trends in Microbiology
Figure 3. Examples of the Ways in Which Viruses Might Affect Ecosystems. Examples of how viruses might affect ecosystems are given at different scales: within individual organisms, populations, communities, and ecosystems. Viruses can affect host behavior directly by replicating in specific cells, leading to behavioral changes that could increase transmission ability. Alternatively, the indirect effects of infection could lead to behavioral changes due to increased energy requirements. These behavioral changes could lead to changes in birth and death rates due to an increased risk of predation, or decreased investment in reproduction. Viruses can also directly affect host populations by altering birth and death rates in their hosts. Changes in host population dynamics can lead to top-down regulation, in which the virus regulates the size of the host population. It could also lead to changes in predator–prey interactions (such as hyperpredation) and interspecific competition, in which the virus prevents spatial overlap of host species with differing reactions to infection. This can have flow-on effects to host communities, leading to top-down or bottom-up trophic cascades and shifts in ecosystems to alternative stable states. The different colored circles represent viral diversity, some restricted to a single host species, others shared between species.
(Piliocolobus badius) during predator–prey interactions [38]. In this manner, virus ecology will be shaped by the frequency of predator–prey interactions between species, particularly when predator and prey species are phylogenetically close [39]. Interactions between hosts and eukaryotic parasites also likely shape viral abundance, and may facilitate transmission between hosts that do not otherwise interact. A key area for future research will be metagenomic studies of entire food webs. These may reveal the influence of phylogenetic relatedness and predator–prey interactions on the movement of viruses through ecosystems, and the existence of barriers to this process. As well as interactions between two species, higher order interactions, modulated by one or more additional species, also take place [40]. Viruses are likely to interact with other species in this manner by altering predator–prey interactions and interspecific competition (Figure 3). For example, viruses could influence predator–prey interactions by changing the behavior of infected individuals (see above), making prey more vulnerable to predators or predators less able to catch prey. Alternatively, viruses could cause a decline in a predator’s primary prey, resulting in hyperpredation of secondary prey. This occurred in Spain, where outbreaks of rabbit hemorrhagic disease (RHD) resulted in a large decrease in the European rabbit (Oryctolagus cuniculus) population and increased predation of the red-legged partridge (Alectoris rufa) ([41], Table 2). Interspecific competition is another important component of population ecology [42,43]. As viruses can only be transmitted between species that overlap in ecological niche and distribution, in theory they may reduce spatial overlap between competitors, perhaps even reinforcing host speciation (Figure 3, e.g., [44–46], Table 2). For example, red squirrels (Sciurus vulgaris) are, unlike gray squirrels
6
Trends in Microbiology, --, Vol. --, No. --
Please cite this article in press as: French and Holmes, An Ecosystems Perspective on Virus Evolution and Emergence, Trends in Microbiology (2019), https://doi.org/10.1016/j.tim.2019.10.010
Trends in Microbiology
Table 2. Examples of the Ways in Which Viruses Affect Ecosystems
Scale
Effect
Individual
Host behavioral changes
Viruses affecting ecosystems Example
Refs
After acquiring barley yellow dwarf virus (BYDV),
[29]
the aphid Rhopalosiphum padi changed its feeding preference to noninfected plants, enhancing spread. When infected with Leptopilina boulardi
[30]
filamentous virus (LbFV), female Drosophila parasitoids (Leptopilina boulardi) lay eggs in already parasitized hosts, unlike uninfected females. This allows horizontal transmission within Drosophila from infected embryos to uninfected embryos. Bewick’s swans (Cygnus columbianus bewickii)
[31]
infected with low-pathogenic avian influenza (LPAI) A viruses changed their feeding rates and delayed their migration by more than a month compared with noninfected individuals. Black garden ants (Lasius niger) changed their
[26]
behavior in response to pathogens, reducing individual contamination risk and helping contain disease. [32]
Zebra fish (Danio rerio), when experimentally infected with synthetic spring viremia carp virus (SVCV), changed their thermal preference by 3 C, and rapidly cleared the infection. Fish that were not able to express this behavioral fever (as they were not offered a choice of temperatures) showed decreased survival when infected. Population
Top-down regulation
/community
A pandemic of rinderpest (caused by a
[20]
paramyxovirus) in the 1890s in Tanzania suppressed populations of wildebeest (Connochaetes spp) and buffalo (Syncerus caffer). Virus-modulated predator–prey
Outbreaks of rabbit hemorrhagic disease (RHD) in
interactions
Spain resulted in a large decrease in the European
[41]
rabbit (Oryctolagus cuniculus) population and increased predation of the red-legged partridge (Alectoris rufa), a form of hyperpredation. Virus-mediated competition
The louping ill virus reduced red grouse (Lagopus
[44]
scoticus) populations through high virus-induced mortality, but did not affect red deer (Cervus elephus). The deer maintain a high sheep tick (Ixodes ricinus) population, facilitating virus persistence and transmission into grouse.
(Continued on next page)
Trends in Microbiology, --, Vol. --, No. --
7
Please cite this article in press as: French and Holmes, An Ecosystems Perspective on Virus Evolution and Emergence, Trends in Microbiology (2019), https://doi.org/10.1016/j.tim.2019.10.010
Trends in Microbiology
Table 2. Continued.
Scale
Effect
Viruses affecting ecosystems Example
Refs
Red squirrels (Sciurus vulgaris), unlike gray squirrels
[46]
(Sciurus carolinensis), are severely affected by squirrelpox. This has been implicated in their decline in the UK, and may have contributed to the gray squirrel’s ability to outcompete red squirrels. Ecosystem
Trophic cascade
A new variant of the rabbit hemorrhagic disease
[49]
virus (RHDV2 or RHDVb) caused a large reduction in the European rabbit, resulting in knock-on reductions in the rabbit’s natural predators, the Iberian Lynx (Lynx pardinus) and Spanish imperial Eagle (Aquila adalberti). Virus-mediated ecosystem shifts
The 1890 rinderpest pandemic in Tanzania led to a
[20]
reduction in wildebeest and buffalo populations, reducing grazing pressure. This led to increased fires, which suppressed the establishment of trees. This changed the ecosystem from a woodland state, to an alternative, stable, grassland state.
(Sciurus carolinensis), severely affected by squirrelpox. This has been implicated in their decline in the UK, and may have contributed to the gray squirrel’s ability to outcompete its relative [46]. Plant viruses have been shown to interact with plants and insects in complex ways, including mutualistic relationships, manipulating vector behavior, and ‘protecting’ vectors from plant defenses, suggesting that viruses frequently interact with multiple species in ecosystems [5,8].
Communities There is considerable interest in understanding how communities interact [37,47]. Differences in abiotic conditions between communities impact viruses by affecting host behavior and distribution (Figure 2). Metagenomic sequencing revealed that red-necked avocets (Recurvirostra novaehollandiae) from the arid Australian interior had a higher viral diversity and abundance than individuals sampled in temperate Australia, likely due to higher visitation of water sources in arid areas (e.g., [48], Table 1). Changes in the abundance of one species can lead to changes in entire communities. If an important prey species is suppressed in a community it can result in a top-down or bottom-up trophic cascade. Viruses may have far-reaching impacts on communities in this manner (Figure 3 and Table 2). For example, a new variant of rabbit hemorrhagic disease virus (RHDV2/RHDVb) in the Mediterranean impacted the entire food web by causing a large reduction in a keystone species, the European rabbit [49]. This caused similar reductions in the rabbit’s natural predators, the Iberian Lynx (Lynx pardinus) and Spanish imperial Eagle (Aquila adalberti) [49]. RHDV2 therefore influenced the dynamics of species interactions, changing the structure of the entire community. Indeed, RHDV2 may act as a keystone species itself, causing substantial changes in the ecosystem relative to its biomass [49].
Viral Ecological Niches The ecological niche of an organism is that set of biotic and abiotic conditions it requires to survive and reproduce [50]. For viruses, this would be the conditions within the host required for reproduction and dispersal. By defining the ecological niche of an organism we can predict the places where it will survive, and in turn the geographic course of dispersal into new environments [50,51]. Because of the intimate association between viruses and their hosts this has obvious implications for understanding the risk of specific viruses emerging in particular geographic areas.
8
Trends in Microbiology, --, Vol. --, No. --
Please cite this article in press as: French and Holmes, An Ecosystems Perspective on Virus Evolution and Emergence, Trends in Microbiology (2019), https://doi.org/10.1016/j.tim.2019.10.010
Trends in Microbiology
Changes in abiotic factors (such as increasing sea temperatures) can cause host range shifts, dispersal of organisms into new areas, and displacement [52]. Accordingly, these have the potential to have major impacts on both viral diversity and patterns of disease emergence. Changes in abiotic factors could directly impact viral transmission from one host to another: for example, increased temperatures could prolong survival outside the host [52]. Alternatively, changes in abiotic factors could indirectly impact viral dispersal by changing host/vector behavior, distribution, and interactions with other species [52]. Studying the natural ecological niches of viruses could lead to a better understanding of these processes, and hence improve our understanding of host jumping and disease emergence, as well as understanding the impact of climate change on virus spread. Increasing temperatures will likely allow the spread of arthropod vectors outside their previous range and change the distributions of many host species (e.g., [53–56], Table 1). Modeling suggests that the Asian tiger mosquito (Stegomyia albopicta), an important vector for dengue virus (DENV) and chikungunya virus (CHIKV), will significantly increase its range due to climate change in the Americas, Europe, and China [55]. Using metagenomics to monitor the virome of an ecological community through time could show the early effects of changing abiotic conditions, and allow for early warning of viruses moving into new areas. However, predicting virus invasions and dispersal into new habitats using ecological niches relies on the niche to remain stable and have little variation [50]: the high mutation rates of viruses may mean that their ecological niche is plastic, complicating predictions. For example, mutations in a bacteriophage with a narrow host range enabled it to broaden its niche through the evolution of new generalist morphs able to exploit new hosts [57]. When invading a new host species, a virus’s niche will also change on multiple scales. For example, bird-adapted influenza viruses primarily replicate in the intestinal tract, whereas human-adapted influenza viruses replicate in the respiratory tract [58]. Therefore, when the avian virus adapted to human replication, the niche of the virus changed at both the host species and tissue levels.
Viruses in Ecosystem Resilience and Health Metagenomic studies have shown that viruses account for substantial biodiversity, and with abundant links within ecosystems [59]. As obligate intracellular parasites, viruses are intimately embedded into the food web structure, probably account for a significant number of ecosystem interactions, and therefore may play an important role in ecosystem health. To our knowledge, however, the roles that viruses play in food-web interactions and stability have not been measured and are an important area for future research. Ecosystem functions, such as pollination and seed dispersal, are important processes that underpin the ecosystem structure [60]. The ability of an ecosystem to continue providing functions when changes occur (its ’resilience’) is affected by functional redundancy – the ability of multiple species to perform similar functions [60]. An ecosystem with higher diversity has higher functional redundancy and is more resilient to change. There is an increasing appreciation that parasite interactions have important influences on diversity, food web structure, and stability (e.g., [61,62]). Virus-mediated lysis of unicellular algae is thought to be a key mechanism for releasing cellular compounds, important for bacteria production and the marine food web [6]. As viruses probably account for significant diversity in ecosystems, it is possible that they also increase functional redundancy and ecosystem resilience. For example, by suppressing host populations and preventing species from overexploiting their environment, viruses may stabilize food webs (Figure 3). Viruses could also prevent local extinction by suppressing predator populations and stopping them from overexploiting their prey (e.g., [20], Table 2). Hence, viruses do not necessarily have negative impacts, and from a broad ecological perspective, the natural virome may actually be beneficial to ecosystem function. As a case in point, while eradicating wildlife diseases may reduce animal suffering and mortality, they may have unintended consequences for food-web structure, host– pathogen coevolution and ecosystem function [63–65]. Although the benefits of disease eradication may outweigh the costs in many cases, we contend that it is important that these costs are always considered.
Trends in Microbiology, --, Vol. --, No. --
9
Please cite this article in press as: French and Holmes, An Ecosystems Perspective on Virus Evolution and Emergence, Trends in Microbiology (2019), https://doi.org/10.1016/j.tim.2019.10.010
Trends in Microbiology
Alternative stable states are also important to ecosystems [19,66], reflecting when an ecosystem shifts from one stable community structure (a state) to another, sometimes irreversibly, due to perturbations or pressure on the ecosystem [19,60,66]. The emergence of new viruses has led to ecosystems shifting to alternative stable states (Figure 3). For example, a pandemic of rinderpest (caused by a paramyxovirus) in the 1890s in Tanzania led to a reduction in wildebeest and buffalo populations, which reduced grazing pressure (e.g., [20], Table 2). This led to increased fires, suppressing the establishment of trees, and changing the ecosystem from a woodland state, to an alternative, stable, grassland state [20]. When rinderpest was eradicated through vaccination, the ecosystem reverted back to a woodland state. This example therefore illustrates how viruses can significantly impact entire ecosystems [20]. Notably, this impact also extended to human health. The reduction in grazing mammals reduced the number of the carnivores that predated on them, in turn leading to tsetse flies (Glossina spp.) prey-switching from wildebeest and cattle to humans, and an epidemic of African trypanosomiasis (sleeping sickness) caused by protozoans Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense that use the flies as a vector [20]. Monitoring the virome of an ecological community using metagenomics could allow disease emergence to be observed in realtime, providing insights and early warning.
Concluding Remarks We suggest that the time is right for an appreciation of viruses at the scale of ecosystems, a task made possible by the new ability to study entire viromes from species assemblages using unbiased metagenomic sequencing (see Outstanding Questions). The high abundance and diversity of viruses in many organisms in nature, which are often shared among multiple species in the apparent absence of clearly associated disease, suggests that they are naturally embedded in ecosystems at all ecological scales. It is therefore necessary to move from an inherently anthropocentric focus on viruses in the context of disease emergence focus to a broader take on ecosystems as a whole. Not only will this place pathogenic viruses arising through host jumping in their true evolutionary and ecological context, but it will help explain virome composition in both healthy and diseased hosts, as well as the interactions among viruses, hosts, and their environments.
Acknowledgments E.C.H .is supported by an Australian Research Council (ARC) Australian Laureate Fellowship (FL170100022).
References 1. Enard, D. et al. (2016) Viruses are a dominant driver of protein adaptation in mammals. eLife 5, e12469 2. Geoghegan, J.L. and Holmes, E.C. (2017) Predicting virus emergence amid evolutionary noise. Open Biol. 7, 170189 3. Shi, M. et al. (2018) The evolutionary history of vertebrate RNA viruses. Nature 556, 197–202 4. Zhang, Y.-Z. et al. (2018) Using metagenomics to characterize an expanding virosphere. Cell 172, 1168–1172 5. Roossinck, M.J. (2015) Plants, viruses and the environment: ecology and mutualism. Virology 479, 271–277 6. Short, S.M. (2012) The ecology of viruses that infect eukaryotic algae. Environ. Microbiol. 14, 2253–2271 7. Brussard, C.P.D. et al. (2008) Global-scale processes with a nanoscale drive: the role of marine viruses. ISME J. 2, 575–578 8. Lefeuvre, P. et al. (2019) Evolution and ecology of plant viruses. Nat. Rev. Microbiol. 17, 632–644 9. Delwart, E. (2012) Animal virus discovery: improving animal health, understanding zoonoses, and opportunities for vaccine development. Curr. Opin. Virol. 2, 344–352
10
Trends in Microbiology, --, Vol. --, No. --
10. Kapoor, A. et al. (2008) A highly prevalent and genetically diversified Picornaviridae genus in South Asian children. Proc. Natl. Acad. Sci. U. S. A. 105, 20482–20487 11. Chow, C.-E.T. and Suttle, C.A. (2015) Biogeography of viruses in the sea. Annu. Rev. Virol. 2, 41–66 12. Koonin, E.V. and Dolja, V.V. (2018) Metaviromics: a tectonic shift in understanding virus evolution. Virus Res. 246, A1–A3 13. Paez-Espino, D. et al. (2016) Uncovering Earth’s virome. Nature 536, 425–430 14. Roossinck, M.J. et al. (2015) Plant virus metagenomics: advances in virus discovery. Phytopathol. 105, 716–727 15. Edwards, R.A. and Rohwer, F. (2005) Viral metagenomics. Nat. Rev. Microbiol. 3, 504–510 16. Li, C.-X. et al. (2015) Unprecedented genomic diversity of RNA viruses in arthropods reveals the ancestry of negative-sense RNA viruses. eLife 4, e05378 17. Shi, M. et al. (2018) Meta-transcriptomics and the evolutionary biology of RNA viruses. Virus Res. 243, 83–90 18. Duffy, S. et al. (2008) Rates of evolutionary change in viruses: patterns and determinants. Nat. Rev. Genet. 9, 267–276
Outstanding Questions How does host ecology (such as behavior, diet, trophic level, intra/ interspecific interactions, and population density) impact viral diversity and abundance? What impact do viruses (both pathogenic and nonpathogenic) have on hosts at individual, population, community, and ecosystem scales? How frequently does cross-species transmission result in overt disease? How will changes in abiotic conditions as a result of climate change, such as in average temperature and rainfall, impact viral diversity and abundance? What impact will this have on disease emergence? What role does the virome play in ecosystem resilience and health? How often are viruses beneficial to ecosystems?
Please cite this article in press as: French and Holmes, An Ecosystems Perspective on Virus Evolution and Emergence, Trends in Microbiology (2019), https://doi.org/10.1016/j.tim.2019.10.010
Trends in Microbiology
19. Folke, C. et al. (2004) Regime shifts, resilience, and biodiversity in ecosystem management. Annu. Rev. Ecol. Evol. Syst. 35, 557–581 20. Dobson, A. (2009) Food-web structure and ecosystem services: insights from the Serengeti. Phil. Trans. R. Soc. B. 364, 1665–1682 21. Dobson, A. (2004) Population dynamics of pathogens with multiple host species. Am. Nat. 164, S64–S78 22. Grear, D.A. et al. (2009) Does elevated testosterone result in increased exposure and transmission of parasites? Ecol. Lett. 12, 528–537 23. Arau´jo, M. et al. (2009) Individual-level diet variation in four species of Brazilian frogs. J. Animal Ecol. 78, 848–856 24. Molsher, R. et al. (2000) Temporal, spatial and individual variation in the diet of red foxes (Vulpes vulpes) in central New South Wales. Wildlife Res. 27, 593–601 25. Brunner, J. et al. (2007) Transmission dynamics of the amphibian ranavirus Ambystoma tigrinum virus. Dis. Aquatic Organ. 77, 87–95 26. Stroeymeyt, N. et al. (2018) Social network plasticity decreases disease transmission in a eusocial insect. Science 362, 941–945 27. Poulin, R. (1995) Adaptive’ changes in the behaviour of parasitized animals: a critical review. Int. J. Parasitol. 25, 1371–1383 28. van Houte, S. et al. (2013) Walking with insects: molecular mechanisms behind parasitic manipulation of host behaviour. Mol. Ecol. 22, 3458– 3475 29. Ingwell, L.L. et al. (2012) Plant viruses alter insect behavior to enhance their spread. Sci. Rep. 2, 578 30. Varaldi, J. et al. (2006) The virus infecting the parasitoid Leptopilina boulardi exerts a specific action on superparasitism behaviour. Parasitol. 132, 747–756 31. Van Gils, J.A. et al. (2007) Hampered foraging and migratory performance in swans infected with lowpathogenic avian influenza A virus. PLoS One 2, e184 32. Boltana, S. et al. (2013) Behavioural fever is a synergic signal amplifying the innate immune response. Proc. R. Soc. B. 280, 20131381 33. Anderson, R.M. and May, R.M. (1992) Infectious Diseases of Humans: Dynamics and Control, Oxford University Press 34. Hudson, P.J. et al. (2002) Ecology of Wildlife Diseases, Oxford University Press 35. Lavigne, D.M. and Schmitz, O.J. (1990) Global warming and increasing population densities: a prescription for seal plagues. Marine Pollut. Bull. 21, 280–284 36. Smith, C. et al. (2014) Flying-fox species density-a spatial risk factor for Hendra virus infection in horses in eastern Australia. PLoS One 9, e99965 37. Schmitz, O.J. et al. (2017) Toward a community ecology of landscapes: predicting multiple predator–prey interactions across geographic space. Ecology 98, 2281–2292 38. Leendertz, F.H. et al. (2008) Interspecies transmission of simian foamy virus in a natural predator–prey system. J. Virol. 82, 7741–7744 39. Holmes, E.C. (2009) The Evolution and Emergence of RNA Viruses, Oxford University Press 40. Bairey, E. et al. (2016) High-order species interactions shape ecosystem diversity. Nat. Commun. 7, 12285 41. Moleo´n, M. et al. (2008) An emerging infectious disease triggering large-scale hyperpredation. PLoS One 3, e2307 42. Tilman, D. (1987) The importance of the mechanisms of interspecific competition. Am. Nat. 129, 769–774 43. Aschehoug, E.T. et al. (2016) The mechanisms and consequences of interspecific competition
44.
45. 46. 47. 48. 49.
50. 51. 52. 53.
54.
55.
56. 57. 58.
59. 60. 61. 62. 63.
64. 65. 66.
among plants. Annu. Rev. Ecol. Evol. Syst. 47, 263–281 Gilbert, L. et al. (2001) Disease persistence and apparent competition in a three-host community: an empirical and analytical study of large-scale, wild populations. J. Anim. Ecol. 70, 1053–1061 Reid, H. (1975) Experimental infection of red grouse with louping-ill virus (Flavivirus group): I. The viraemia and antibody response. J. Comp. Pathol. 85, 223–229 Chantrey, J. et al. (2014) European red squirrel population dynamics driven by squirrelpox at a gray squirrel invasion interface. Ecol. Evol. 4, 3788–3799 Agrawal, A.A. et al. (2007) Filling key gaps in population and community ecology. Front. Ecol. Env. 5, 145–152 Wille, M. et al. (2018) Virus–virus interactions and host ecology are associated with RNA virome structure in wild birds. Mol. Ecol. 27, 5263–5278 Monterroso, P. et al. (2016) Disease-mediated bottom-up regulation: An emergent virus affects a keystone prey, and alters the dynamics of trophic webs. Sci. Rep. 6, 36072 Peterson, A.T. (2003) Predicting the geography of species’ invasions via ecological niche modeling. Quart. Rev. Biol. 78, 419–433 Escobar, L.E. and Craft, M.E. (2016) Advances and limitations of disease biogeography using ecological niche modeling. Front. Microbiol. 7, 1174 Harvell, C. et al. (1999) Emerging marine diseases climate links and anthropogenic factors. Science 285, 1505–1510 Mills, J.N. et al. (2010) Potential influence of climate change on vector-borne and zoonotic diseases: a review and proposed research plan. Environ. Health Perspect. 118, 1507–1514 Dunnum, J.L. et al. (2002) Elevational range extension for the hispid cotton rat, Sigmodon hispidus, (Rodentia: Muridae). Southwest. Naturalist 47, 637–639 Proestos, Y. et al. (2015) Present and future projections of habitat suitability of the Asian tiger mosquito, a vector of viral pathogens, from global climate simulation. Phil. Trans. R. Soc. B. 370, 20130554 Messina, J.P. et al. (2019) The current and future global distribution and population at risk of dengue. Nat. Microbiol. 4, 1508–1515 Bono, L.M. et al. (2013) Competition and the origins of novelty: experimental evolution of niche-width expansion in a virus. Biol. Lett. 9, 20120616 Baigent, S.J. and McCauley, J.W. (2003) Influenza type A in humans, mammals and birds: Determinants of virus virulence, host-range and interspecies transmission. Bioessays 25, 657–671 Shi, M. et al. (2016) Redefining the invertebrate RNA virosphere. Nature 540, 539–543 Oliver, T.H. et al. (2015) Biodiversity and resilience of ecosystem functions. Trends Ecol. Evol. 30, 673–684 Hudson, P.J. et al. (2006) Is a healthy ecosystem one that is rich in parasites? Trends Ecol. Evol. 21, 381–385 Jephcott, T.G. et al. (2016) Host–parasite interactions in food webs: diversity, stability, and coevolution. Food Webs 6, 1–8 Crozier, G.K.D. and Schulte-Hostedde, A.I. (2014) The ethical dimensions of wildlife disease management in an evolutionary context. Evol. App. 7, 788–798 Gandon, S. and Day, T. (2007) The evolutionary epidemiology of vaccination. J. R. Soc. Interface 4, 803–817 Go´mez, A. and Nichols, E. (2013) Neglected wild life: Parasitic biodiversity as a conservation target. Int. J. Parasitol. Parasit. Wildlife 2, 222–227 Beisner, B.E. et al. (2003) Alternative stable states in ecology. Front. Ecol. Env. 1, 376–382
Trends in Microbiology, --, Vol. --, No. --
11
Trends in Microbiology
Opinion
An Ecosystems Perspective on Virus Evolution and Emergence Rebecca K. French1 and Edward C. Holmes1,* Understanding the emergence of pathogenic viruses has dominated studies of virus evolution. However, new metagenomic studies imply that relatively few of an immense number of viruses may lead to overt disease. This suggests a change in emphasis, from viruses as habitual pathogens to integral components of ecosystems. Here we show how viruses alter interactions between host individuals, populations, and ecosystems, impacting ecosystem health, resilience, and function, and how host ecology in turn impacts viral abundance and diversity. Moving to an ecosystems perspective will put virus evolution and disease emergence in its true context, and enhance our understanding of ecological processes.
Ecological Virology A central pillar of virology has been the idea that viruses are commonly pathogens responsible for diseases with potentially devastating consequences. Such a view is understandable as viral diseases have imposed a major disease burden on many host species, particularly following cross-species transmission (host jumping), and a vast array of strongly selected host genes are devoted to combating and evading viruses [1]. However, recent metagenomic studies of diverse host species are leading to a very different view of the virosphere, in which the total number of viruses is immense [2], hosts are commonly infected by multiple viruses and sometimes at high abundance, but where relatively few are clearly associated with disease [3,4]. In a few cases viruses have even been shown to be beneficial to their hosts [5]. Studies of virus ecology have traditionally been challenging, particularly as limitations to detection power meant that viruses were largely studied individually rather than in toto. Hence, the full diversity of viruses and their possible interactions could not easily be determined. This is changing with metagenomics, an approach that enables the entire virome of a sample to be sequenced and that is opening up an ecosystem-scale approach to studying viruses. Although viruses have sometimes been studied as part of ecological communities, for example, in plant, bacterial, and microscopic algae communities [5–8], to date metagenomics has been primarily used to identify the pathogens involved in disease outbreaks or associated with specific disease syndromes [9,10], revealing the structure of the virosphere [11–15], and understanding key aspects of virus evolution such as their antiquity and changing genome organizations [3,16]. What has largely been absent is an attempt to understand the ecological context to these evolutionary events. For example, although cross-species virus transmission is central to understanding disease emergence, it is not known how frequently a host jump results in a marked reduction in host fitness, particularly as these fitness costs may be difficult to measure in nature [4,17]. In addition, viruses may be ideally suited to the study of ecological events as their rapid evolution makes them powerful markers for tracking short-term processes [18]. The sheer abundance of viruses in nature and their ability to move between hosts suggests that we adopt a new perspective in virology: rather than considering viruses as likely disease-causing pathogens, we should instead regard them as integral components of ecosystems that may only rarely lead to emerging disease (Figure 1, Key Figure). Herein, we attempt to paint a backdrop for this ecological perspective on viruses, outlining how viruses can be better incorporated into the study of ecology and vice versa, particularly using metagenomic sequencing.
Virus Interactions in Ecosystems Virus ecology can be considered at scales spanning individuals to communities. An ecosystem is defined as a community of living organisms and their nonliving environment [19]. How organisms
Trends in Microbiology, --, Vol. --, No. --
Highlights The high abundance and diversity of viruses in nature, often in the apparent absence of disease, suggests that they are naturally embedded into global ecosystems at all ecological scales. Studies of virus ecology and evolution need to refocus to understand the role played by viruses in global ecosystems rather than only on pathogens that emerge following host jumping. Viruses alter interactions between host individuals, populations, and ecosystems, impacting ecosystem health, resilience, and function. Host ecology in turn impacts viral abundance and diversity. Viruses account for extensive biodiversity and have abundant links within ecosystems. An ecosystem with higher diversity has higher functional redundancy and is more resilient to change. The natural virome may therefore be beneficial to ecosystem function.
1Marie Bashir Institute for Infectious Diseases and Biosecurity, Charles Perkins Centre, School of Life and Environmental Sciences and Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia
*Correspondence: [email protected]
https://doi.org/10.1016/j.tim.2019.10.010 ª 2019 Elsevier Ltd. All rights reserved.
1
Please cite this article in press as: French and Holmes, An Ecosystems Perspective on Virus Evolution and Emergence, Trends in Microbiology (2019), https://doi.org/10.1016/j.tim.2019.10.010
Trends in Microbiology
Key Figure
Shifting the Focus from Studies of Disease Emergence to That of Ecosystems (A)
(B)
Trends in Microbiology
Figure 1. (A) A focus on disease emergence primarily considers viruses as pathogens that cause morbidity and mortality, particularly in humans or host species important to humans. (B) An ecosystem focus not only encompasses emerging and pathogenic viruses, but the entire virome in healthy and unhealthy hosts, as well as the complex interactions between viruses, hosts, and environments.
interact with each other and with the nonliving environment within a population, between populations, and between communities will affect the way an ecosystem is structured and functions [19]. Viruses are naturally embedded in ecosystems, and the interactions among them and with their hosts will not only impact their own abundance, diversity, and evolution, but also that of their host populations and communities [20,21]. Only through studying viruses in an ecosystem context at individual, population, and community scales can we understand these key processes: cross-species transmission, that underpins disease emergence, is one such process. Below, we outline some of the ways that viruses impact ecosystems, how the abundance and diversity of viruses is affected by host ecology, and how metagenomics might be used to study this.
Individuals The abundance and diversity of viruses within an individual host organism will be impacted by the behavior of that organism (Figure 2). For example, territorial males that have frequent contact with conspecifics (such as fighting and mating), and hence more opportunities for transmission, may have a greater prevalence and diversity of viruses than nonterritorial males. Experimentally increasing testosterone in the white-footed mouse (Peromyscus leucopus) increased the number of contacts between hosts and transmission potential ([22], Table 1). Similarly, some species show considerable individual and/or temporal variation in diet (e.g., [23,24]), which is also likely to impact the types of viruses they harbor (e.g., [25], Table 1). High contact rates and low genetic diversity may mean eusocial species have a high density and diversity of viruses [26]. Concurrently, viruses may impact host interactions by changing host behavior (Figure 3). In theory, behavioral modifications could be an adaptive strategy by a virus to increase transmission rates [8]. Although this is difficult to test empirically [27], there are examples of host behavioral modification
2
Trends in Microbiology, --, Vol. --, No. --
Please cite this article in press as: French and Holmes, An Ecosystems Perspective on Virus Evolution and Emergence, Trends in Microbiology (2019), https://doi.org/10.1016/j.tim.2019.10.010
Trends in Microbiology
Trends in Microbiology
Figure 2. The Different Ways in Which Host Ecology Might Impact Virus Diversity and Abundance. Host behavior, such as social hierarchy and individual foraging, affects the number and type of intra- and interspecific interactions. Host population dynamics will affect the density of hosts, and the number and type of interspecific interactions. The abiotic environment may directly impact the ability of the virus to spread to other hosts, as well as the geographic distribution of those hosts. Similarly, the host’s ecological niche will determine its geographic distribution, which also affects the number and type of interspecific interactions. All of these variables will affect the number of opportunities a virus has to jump from one host species to another, in turn shaping the diversity and abundance of viruses in populations.
that ‘appear’ to facilitate transmission (e.g., [28–30], Table 2). A case in point is the aphid Rhopalosiphum padi that, after acquiring barley yellow dwarf virus (BYDV), changed its feeding preferences to noninfected plants, enhancing spread [29]. Some host behavioral modifications could instead impact host interactions and hence virus transmission. A high viral load could increase energy requirements, in turn leading to behavioral changes ([30,31], Table 2). For example, Bewick’s swans (Cygnus columbianus bewickii) infected with low-pathogenic avian influenza (LPAI) A viruses changed their feeding rates and delayed their migration [31]. Conversely, behavioral modifications may be an adaptive strategy by the host to reduce viral load, such as seeking out temperatures unfavorable for replication (Table 2). Zebra fish (Danio rerio) experimentally infected with synthetic spring viremia of carp virus (SVCV) changed their thermal preference by 3 C, rapidly clearing the infection. Infected fish prevented from expressing behavioral fever showed decreased survival [32]. In eusocial animals, infection may also result in behavioral changes to protect their social group (e.g., [26], Table 2). As outlined below, changing an individual organism’s behavior has important flow-on effects on population dynamics and community food webs. Metagenomic studies of viromes within and among species that differ in behavior, diet, and social structure could help to reveal the impact of host ecology on the abundance and diversity of viruses, as well as the impact of virus abundance on host behavior.
Populations Virus diversity and abundance will be directly impacted by the number and extent of exposure events between and among host species, in turn shaped by host ecology and population dynamics (Figure 2). With density-dependent transmission, the probability that an infected individual has contact with a susceptible host increases with host population density. Accordingly, host density increases the number of new infections arising from an infected individual and the likelihood that a virus will successfully spread through a population [33]. Viruses with high transmission rates are better able to invade novel hosts at lower host population densities [33], and may be consistently present in a population with a continuous supply of susceptible hosts [34]. Conversely, viruses with lower transmission rates would only be able to invade at high host contact rates, and would only be present at high host densities (e.g., [35,36], Table 1). However, in some viruses, such as those that are sexually transmitted, transmission rate is independent of host density [33]. These viruses can therefore persist at very low host densities (frequency-dependent transmission) [33].
Trends in Microbiology, --, Vol. --, No. --
3
Please cite this article in press as: French and Holmes, An Ecosystems Perspective on Virus Evolution and Emergence, Trends in Microbiology (2019), https://doi.org/10.1016/j.tim.2019.10.010
Trends in Microbiology
Table 1. Examples of How Host Ecology Affects Virus Diversity and Abundance
Factor(s)
Effect
Host behavior
Intraspecific interactions
Host ecology affecting virus ecology Examples
Refs
Experimentally increasing
[22]
testosterone in the whitefooted mouse (Peromyscus leucopus) increased the number of contacts between hosts, in turn increasing transmission potential. Differences in behavior between sexes may therefore explain the malebiased infection rates commonly found in vertebrates. The cannibalistic behavior
[25]
displayed by some tiger salamander larvae (Ambystoma tigrinum) is thought to affect the transmission of Ambystoma tigrinum virus (ATV). Population dynamics
Population density
High densities of seals on
[35]
land were central to triggering the 1988 phocine distemper virus (PDV) epidemic in harbor seals (Phoca vitulina). The density of flying fox
[36]
species (Pteropus alecto and Pteropus conspicillatus) is strongly correlated with reported cases of Hendra virus in horses. Interspecific interactions
Simian foamy viruses (SFV)
[38]
are transmitted between wild chimpanzees (Pan troglodytes verus) and western red colobus monkeys (Piliocolobus badius) during predator– prey interactions. Abiotic factors
Viral dispersal
Red-necked avocets
[48]
(Recurvirostra novaehollandiae) from the arid interior in Australia had a
(Continued on next page)
4
Trends in Microbiology, --, Vol. --, No. --
Please cite this article in press as: French and Holmes, An Ecosystems Perspective on Virus Evolution and Emergence, Trends in Microbiology (2019), https://doi.org/10.1016/j.tim.2019.10.010
Trends in Microbiology
Table 1. Continued.
Factor(s)
Effect
Host ecology affecting virus ecology Examples
Refs
greater viral diversity and abundance than those from temperate Australia. This is likely because water sources in arid areas are visited by a higher diversity and density of species than in temperate areas. Abiotic factors/host
Virus geographic
The range of the hispid
ecological niche
distribution
cotton rat (Sigmodon
[53,54]
hispidus), host to hantaviruses and the Tamiami arenavirus, is severely limited by climate, but has expanded northward and to higher altitudes in the past few decades. Modeling suggests that the
[55,56]
Asian tiger mosquito (Stegomyia albopicta) will significantly increase its range due to warmer and wetter winters, as well as warmer and drier summers, in the Americas, Europe, and China. This mosquito is an important vector for dengue virus (DENV) and chikungunya virus (CHIKV). Modeling of environmental suitability also indicated that DENV susceptibility will increase in many regions, and 2.25 (1.27–2.80) billion more people will be at risk of infection in 2080 compared with 2015.
There has been considerable interest in understanding the interactions between predators and prey, and how this affects behavior, population trends, and geographical distributions [37]. Viral infection is likely to cause changes in host interactions and population dynamics, including mortality and reproductive rates (Figure 3), impacting key aspects of population ecology including predator–prey interactions and interspecific competition. These interactions also provide opportunities for cross-species transmission. The most frequent interactions among species in ecosystems occur in community food webs: every time a predator consumes prey it will also consume viruses, providing opportunities for viruses to jump hosts (Table 1). Although most food-associated viruses will likely not be able to replicate in a novel host, important examples exist. As a case in point, simian foamy viruses (SFV) are transmitted between wild chimpanzees (Pan troglodytes verus) and western red colobus monkeys
Trends in Microbiology, --, Vol. --, No. --
5
Please cite this article in press as: French and Holmes, An Ecosystems Perspective on Virus Evolution and Emergence, Trends in Microbiology (2019), https://doi.org/10.1016/j.tim.2019.10.010
Trends in Microbiology
Trends in Microbiology
Figure 3. Examples of the Ways in Which Viruses Might Affect Ecosystems. Examples of how viruses might affect ecosystems are given at different scales: within individual organisms, populations, communities, and ecosystems. Viruses can affect host behavior directly by replicating in specific cells, leading to behavioral changes that could increase transmission ability. Alternatively, the indirect effects of infection could lead to behavioral changes due to increased energy requirements. These behavioral changes could lead to changes in birth and death rates due to an increased risk of predation, or decreased investment in reproduction. Viruses can also directly affect host populations by altering birth and death rates in their hosts. Changes in host population dynamics can lead to top-down regulation, in which the virus regulates the size of the host population. It could also lead to changes in predator–prey interactions (such as hyperpredation) and interspecific competition, in which the virus prevents spatial overlap of host species with differing reactions to infection. This can have flow-on effects to host communities, leading to top-down or bottom-up trophic cascades and shifts in ecosystems to alternative stable states. The different colored circles represent viral diversity, some restricted to a single host species, others shared between species.
(Piliocolobus badius) during predator–prey interactions [38]. In this manner, virus ecology will be shaped by the frequency of predator–prey interactions between species, particularly when predator and prey species are phylogenetically close [39]. Interactions between hosts and eukaryotic parasites also likely shape viral abundance, and may facilitate transmission between hosts that do not otherwise interact. A key area for future research will be metagenomic studies of entire food webs. These may reveal the influence of phylogenetic relatedness and predator–prey interactions on the movement of viruses through ecosystems, and the existence of barriers to this process. As well as interactions between two species, higher order interactions, modulated by one or more additional species, also take place [40]. Viruses are likely to interact with other species in this manner by altering predator–prey interactions and interspecific competition (Figure 3). For example, viruses could influence predator–prey interactions by changing the behavior of infected individuals (see above), making prey more vulnerable to predators or predators less able to catch prey. Alternatively, viruses could cause a decline in a predator’s primary prey, resulting in hyperpredation of secondary prey. This occurred in Spain, where outbreaks of rabbit hemorrhagic disease (RHD) resulted in a large decrease in the European rabbit (Oryctolagus cuniculus) population and increased predation of the red-legged partridge (Alectoris rufa) ([41], Table 2). Interspecific competition is another important component of population ecology [42,43]. As viruses can only be transmitted between species that overlap in ecological niche and distribution, in theory they may reduce spatial overlap between competitors, perhaps even reinforcing host speciation (Figure 3, e.g., [44–46], Table 2). For example, red squirrels (Sciurus vulgaris) are, unlike gray squirrels
6
Trends in Microbiology, --, Vol. --, No. --
Please cite this article in press as: French and Holmes, An Ecosystems Perspective on Virus Evolution and Emergence, Trends in Microbiology (2019), https://doi.org/10.1016/j.tim.2019.10.010
Trends in Microbiology
Table 2. Examples of the Ways in Which Viruses Affect Ecosystems
Scale
Effect
Individual
Host behavioral changes
Viruses affecting ecosystems Example
Refs
After acquiring barley yellow dwarf virus (BYDV),
[29]
the aphid Rhopalosiphum padi changed its feeding preference to noninfected plants, enhancing spread. When infected with Leptopilina boulardi
[30]
filamentous virus (LbFV), female Drosophila parasitoids (Leptopilina boulardi) lay eggs in already parasitized hosts, unlike uninfected females. This allows horizontal transmission within Drosophila from infected embryos to uninfected embryos. Bewick’s swans (Cygnus columbianus bewickii)
[31]
infected with low-pathogenic avian influenza (LPAI) A viruses changed their feeding rates and delayed their migration by more than a month compared with noninfected individuals. Black garden ants (Lasius niger) changed their
[26]
behavior in response to pathogens, reducing individual contamination risk and helping contain disease. [32]
Zebra fish (Danio rerio), when experimentally infected with synthetic spring viremia carp virus (SVCV), changed their thermal preference by 3 C, and rapidly cleared the infection. Fish that were not able to express this behavioral fever (as they were not offered a choice of temperatures) showed decreased survival when infected. Population
Top-down regulation
/community
A pandemic of rinderpest (caused by a
[20]
paramyxovirus) in the 1890s in Tanzania suppressed populations of wildebeest (Connochaetes spp) and buffalo (Syncerus caffer). Virus-modulated predator–prey
Outbreaks of rabbit hemorrhagic disease (RHD) in
interactions
Spain resulted in a large decrease in the European
[41]
rabbit (Oryctolagus cuniculus) population and increased predation of the red-legged partridge (Alectoris rufa), a form of hyperpredation. Virus-mediated competition
The louping ill virus reduced red grouse (Lagopus
[44]
scoticus) populations through high virus-induced mortality, but did not affect red deer (Cervus elephus). The deer maintain a high sheep tick (Ixodes ricinus) population, facilitating virus persistence and transmission into grouse.
(Continued on next page)
Trends in Microbiology, --, Vol. --, No. --
7
Please cite this article in press as: French and Holmes, An Ecosystems Perspective on Virus Evolution and Emergence, Trends in Microbiology (2019), https://doi.org/10.1016/j.tim.2019.10.010
Trends in Microbiology
Table 2. Continued.
Scale
Effect
Viruses affecting ecosystems Example
Refs
Red squirrels (Sciurus vulgaris), unlike gray squirrels
[46]
(Sciurus carolinensis), are severely affected by squirrelpox. This has been implicated in their decline in the UK, and may have contributed to the gray squirrel’s ability to outcompete red squirrels. Ecosystem
Trophic cascade
A new variant of the rabbit hemorrhagic disease
[49]
virus (RHDV2 or RHDVb) caused a large reduction in the European rabbit, resulting in knock-on reductions in the rabbit’s natural predators, the Iberian Lynx (Lynx pardinus) and Spanish imperial Eagle (Aquila adalberti). Virus-mediated ecosystem shifts
The 1890 rinderpest pandemic in Tanzania led to a
[20]
reduction in wildebeest and buffalo populations, reducing grazing pressure. This led to increased fires, which suppressed the establishment of trees. This changed the ecosystem from a woodland state, to an alternative, stable, grassland state.
(Sciurus carolinensis), severely affected by squirrelpox. This has been implicated in their decline in the UK, and may have contributed to the gray squirrel’s ability to outcompete its relative [46]. Plant viruses have been shown to interact with plants and insects in complex ways, including mutualistic relationships, manipulating vector behavior, and ‘protecting’ vectors from plant defenses, suggesting that viruses frequently interact with multiple species in ecosystems [5,8].
Communities There is considerable interest in understanding how communities interact [37,47]. Differences in abiotic conditions between communities impact viruses by affecting host behavior and distribution (Figure 2). Metagenomic sequencing revealed that red-necked avocets (Recurvirostra novaehollandiae) from the arid Australian interior had a higher viral diversity and abundance than individuals sampled in temperate Australia, likely due to higher visitation of water sources in arid areas (e.g., [48], Table 1). Changes in the abundance of one species can lead to changes in entire communities. If an important prey species is suppressed in a community it can result in a top-down or bottom-up trophic cascade. Viruses may have far-reaching impacts on communities in this manner (Figure 3 and Table 2). For example, a new variant of rabbit hemorrhagic disease virus (RHDV2/RHDVb) in the Mediterranean impacted the entire food web by causing a large reduction in a keystone species, the European rabbit [49]. This caused similar reductions in the rabbit’s natural predators, the Iberian Lynx (Lynx pardinus) and Spanish imperial Eagle (Aquila adalberti) [49]. RHDV2 therefore influenced the dynamics of species interactions, changing the structure of the entire community. Indeed, RHDV2 may act as a keystone species itself, causing substantial changes in the ecosystem relative to its biomass [49].
Viral Ecological Niches The ecological niche of an organism is that set of biotic and abiotic conditions it requires to survive and reproduce [50]. For viruses, this would be the conditions within the host required for reproduction and dispersal. By defining the ecological niche of an organism we can predict the places where it will survive, and in turn the geographic course of dispersal into new environments [50,51]. Because of the intimate association between viruses and their hosts this has obvious implications for understanding the risk of specific viruses emerging in particular geographic areas.
8
Trends in Microbiology, --, Vol. --, No. --
Please cite this article in press as: French and Holmes, An Ecosystems Perspective on Virus Evolution and Emergence, Trends in Microbiology (2019), https://doi.org/10.1016/j.tim.2019.10.010
Trends in Microbiology
Changes in abiotic factors (such as increasing sea temperatures) can cause host range shifts, dispersal of organisms into new areas, and displacement [52]. Accordingly, these have the potential to have major impacts on both viral diversity and patterns of disease emergence. Changes in abiotic factors could directly impact viral transmission from one host to another: for example, increased temperatures could prolong survival outside the host [52]. Alternatively, changes in abiotic factors could indirectly impact viral dispersal by changing host/vector behavior, distribution, and interactions with other species [52]. Studying the natural ecological niches of viruses could lead to a better understanding of these processes, and hence improve our understanding of host jumping and disease emergence, as well as understanding the impact of climate change on virus spread. Increasing temperatures will likely allow the spread of arthropod vectors outside their previous range and change the distributions of many host species (e.g., [53–56], Table 1). Modeling suggests that the Asian tiger mosquito (Stegomyia albopicta), an important vector for dengue virus (DENV) and chikungunya virus (CHIKV), will significantly increase its range due to climate change in the Americas, Europe, and China [55]. Using metagenomics to monitor the virome of an ecological community through time could show the early effects of changing abiotic conditions, and allow for early warning of viruses moving into new areas. However, predicting virus invasions and dispersal into new habitats using ecological niches relies on the niche to remain stable and have little variation [50]: the high mutation rates of viruses may mean that their ecological niche is plastic, complicating predictions. For example, mutations in a bacteriophage with a narrow host range enabled it to broaden its niche through the evolution of new generalist morphs able to exploit new hosts [57]. When invading a new host species, a virus’s niche will also change on multiple scales. For example, bird-adapted influenza viruses primarily replicate in the intestinal tract, whereas human-adapted influenza viruses replicate in the respiratory tract [58]. Therefore, when the avian virus adapted to human replication, the niche of the virus changed at both the host species and tissue levels.
Viruses in Ecosystem Resilience and Health Metagenomic studies have shown that viruses account for substantial biodiversity, and with abundant links within ecosystems [59]. As obligate intracellular parasites, viruses are intimately embedded into the food web structure, probably account for a significant number of ecosystem interactions, and therefore may play an important role in ecosystem health. To our knowledge, however, the roles that viruses play in food-web interactions and stability have not been measured and are an important area for future research. Ecosystem functions, such as pollination and seed dispersal, are important processes that underpin the ecosystem structure [60]. The ability of an ecosystem to continue providing functions when changes occur (its ’resilience’) is affected by functional redundancy – the ability of multiple species to perform similar functions [60]. An ecosystem with higher diversity has higher functional redundancy and is more resilient to change. There is an increasing appreciation that parasite interactions have important influences on diversity, food web structure, and stability (e.g., [61,62]). Virus-mediated lysis of unicellular algae is thought to be a key mechanism for releasing cellular compounds, important for bacteria production and the marine food web [6]. As viruses probably account for significant diversity in ecosystems, it is possible that they also increase functional redundancy and ecosystem resilience. For example, by suppressing host populations and preventing species from overexploiting their environment, viruses may stabilize food webs (Figure 3). Viruses could also prevent local extinction by suppressing predator populations and stopping them from overexploiting their prey (e.g., [20], Table 2). Hence, viruses do not necessarily have negative impacts, and from a broad ecological perspective, the natural virome may actually be beneficial to ecosystem function. As a case in point, while eradicating wildlife diseases may reduce animal suffering and mortality, they may have unintended consequences for food-web structure, host– pathogen coevolution and ecosystem function [63–65]. Although the benefits of disease eradication may outweigh the costs in many cases, we contend that it is important that these costs are always considered.
Trends in Microbiology, --, Vol. --, No. --
9
Please cite this article in press as: French and Holmes, An Ecosystems Perspective on Virus Evolution and Emergence, Trends in Microbiology (2019), https://doi.org/10.1016/j.tim.2019.10.010
Trends in Microbiology
Alternative stable states are also important to ecosystems [19,66], reflecting when an ecosystem shifts from one stable community structure (a state) to another, sometimes irreversibly, due to perturbations or pressure on the ecosystem [19,60,66]. The emergence of new viruses has led to ecosystems shifting to alternative stable states (Figure 3). For example, a pandemic of rinderpest (caused by a paramyxovirus) in the 1890s in Tanzania led to a reduction in wildebeest and buffalo populations, which reduced grazing pressure (e.g., [20], Table 2). This led to increased fires, suppressing the establishment of trees, and changing the ecosystem from a woodland state, to an alternative, stable, grassland state [20]. When rinderpest was eradicated through vaccination, the ecosystem reverted back to a woodland state. This example therefore illustrates how viruses can significantly impact entire ecosystems [20]. Notably, this impact also extended to human health. The reduction in grazing mammals reduced the number of the carnivores that predated on them, in turn leading to tsetse flies (Glossina spp.) prey-switching from wildebeest and cattle to humans, and an epidemic of African trypanosomiasis (sleeping sickness) caused by protozoans Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense that use the flies as a vector [20]. Monitoring the virome of an ecological community using metagenomics could allow disease emergence to be observed in realtime, providing insights and early warning.
Concluding Remarks We suggest that the time is right for an appreciation of viruses at the scale of ecosystems, a task made possible by the new ability to study entire viromes from species assemblages using unbiased metagenomic sequencing (see Outstanding Questions). The high abundance and diversity of viruses in many organisms in nature, which are often shared among multiple species in the apparent absence of clearly associated disease, suggests that they are naturally embedded in ecosystems at all ecological scales. It is therefore necessary to move from an inherently anthropocentric focus on viruses in the context of disease emergence focus to a broader take on ecosystems as a whole. Not only will this place pathogenic viruses arising through host jumping in their true evolutionary and ecological context, but it will help explain virome composition in both healthy and diseased hosts, as well as the interactions among viruses, hosts, and their environments.
Acknowledgments E.C.H .is supported by an Australian Research Council (ARC) Australian Laureate Fellowship (FL170100022).
References 1. Enard, D. et al. (2016) Viruses are a dominant driver of protein adaptation in mammals. eLife 5, e12469 2. Geoghegan, J.L. and Holmes, E.C. (2017) Predicting virus emergence amid evolutionary noise. Open Biol. 7, 170189 3. Shi, M. et al. (2018) The evolutionary history of vertebrate RNA viruses. Nature 556, 197–202 4. Zhang, Y.-Z. et al. (2018) Using metagenomics to characterize an expanding virosphere. Cell 172, 1168–1172 5. Roossinck, M.J. (2015) Plants, viruses and the environment: ecology and mutualism. Virology 479, 271–277 6. Short, S.M. (2012) The ecology of viruses that infect eukaryotic algae. Environ. Microbiol. 14, 2253–2271 7. Brussard, C.P.D. et al. (2008) Global-scale processes with a nanoscale drive: the role of marine viruses. ISME J. 2, 575–578 8. Lefeuvre, P. et al. (2019) Evolution and ecology of plant viruses. Nat. Rev. Microbiol. 17, 632–644 9. Delwart, E. (2012) Animal virus discovery: improving animal health, understanding zoonoses, and opportunities for vaccine development. Curr. Opin. Virol. 2, 344–352
10
Trends in Microbiology, --, Vol. --, No. --
10. Kapoor, A. et al. (2008) A highly prevalent and genetically diversified Picornaviridae genus in South Asian children. Proc. Natl. Acad. Sci. U. S. A. 105, 20482–20487 11. Chow, C.-E.T. and Suttle, C.A. (2015) Biogeography of viruses in the sea. Annu. Rev. Virol. 2, 41–66 12. Koonin, E.V. and Dolja, V.V. (2018) Metaviromics: a tectonic shift in understanding virus evolution. Virus Res. 246, A1–A3 13. Paez-Espino, D. et al. (2016) Uncovering Earth’s virome. Nature 536, 425–430 14. Roossinck, M.J. et al. (2015) Plant virus metagenomics: advances in virus discovery. Phytopathol. 105, 716–727 15. Edwards, R.A. and Rohwer, F. (2005) Viral metagenomics. Nat. Rev. Microbiol. 3, 504–510 16. Li, C.-X. et al. (2015) Unprecedented genomic diversity of RNA viruses in arthropods reveals the ancestry of negative-sense RNA viruses. eLife 4, e05378 17. Shi, M. et al. (2018) Meta-transcriptomics and the evolutionary biology of RNA viruses. Virus Res. 243, 83–90 18. Duffy, S. et al. (2008) Rates of evolutionary change in viruses: patterns and determinants. Nat. Rev. Genet. 9, 267–276
Outstanding Questions How does host ecology (such as behavior, diet, trophic level, intra/ interspecific interactions, and population density) impact viral diversity and abundance? What impact do viruses (both pathogenic and nonpathogenic) have on hosts at individual, population, community, and ecosystem scales? How frequently does cross-species transmission result in overt disease? How will changes in abiotic conditions as a result of climate change, such as in average temperature and rainfall, impact viral diversity and abundance? What impact will this have on disease emergence? What role does the virome play in ecosystem resilience and health? How often are viruses beneficial to ecosystems?
Please cite this article in press as: French and Holmes, An Ecosystems Perspective on Virus Evolution and Emergence, Trends in Microbiology (2019), https://doi.org/10.1016/j.tim.2019.10.010
Trends in Microbiology
19. Folke, C. et al. (2004) Regime shifts, resilience, and biodiversity in ecosystem management. Annu. Rev. Ecol. Evol. Syst. 35, 557–581 20. Dobson, A. (2009) Food-web structure and ecosystem services: insights from the Serengeti. Phil. Trans. R. Soc. B. 364, 1665–1682 21. Dobson, A. (2004) Population dynamics of pathogens with multiple host species. Am. Nat. 164, S64–S78 22. Grear, D.A. et al. (2009) Does elevated testosterone result in increased exposure and transmission of parasites? Ecol. Lett. 12, 528–537 23. Arau´jo, M. et al. (2009) Individual-level diet variation in four species of Brazilian frogs. J. Animal Ecol. 78, 848–856 24. Molsher, R. et al. (2000) Temporal, spatial and individual variation in the diet of red foxes (Vulpes vulpes) in central New South Wales. Wildlife Res. 27, 593–601 25. Brunner, J. et al. (2007) Transmission dynamics of the amphibian ranavirus Ambystoma tigrinum virus. Dis. Aquatic Organ. 77, 87–95 26. Stroeymeyt, N. et al. (2018) Social network plasticity decreases disease transmission in a eusocial insect. Science 362, 941–945 27. Poulin, R. (1995) Adaptive’ changes in the behaviour of parasitized animals: a critical review. Int. J. Parasitol. 25, 1371–1383 28. van Houte, S. et al. (2013) Walking with insects: molecular mechanisms behind parasitic manipulation of host behaviour. Mol. Ecol. 22, 3458– 3475 29. Ingwell, L.L. et al. (2012) Plant viruses alter insect behavior to enhance their spread. Sci. Rep. 2, 578 30. Varaldi, J. et al. (2006) The virus infecting the parasitoid Leptopilina boulardi exerts a specific action on superparasitism behaviour. Parasitol. 132, 747–756 31. Van Gils, J.A. et al. (2007) Hampered foraging and migratory performance in swans infected with lowpathogenic avian influenza A virus. PLoS One 2, e184 32. Boltana, S. et al. (2013) Behavioural fever is a synergic signal amplifying the innate immune response. Proc. R. Soc. B. 280, 20131381 33. Anderson, R.M. and May, R.M. (1992) Infectious Diseases of Humans: Dynamics and Control, Oxford University Press 34. Hudson, P.J. et al. (2002) Ecology of Wildlife Diseases, Oxford University Press 35. Lavigne, D.M. and Schmitz, O.J. (1990) Global warming and increasing population densities: a prescription for seal plagues. Marine Pollut. Bull. 21, 280–284 36. Smith, C. et al. (2014) Flying-fox species density-a spatial risk factor for Hendra virus infection in horses in eastern Australia. PLoS One 9, e99965 37. Schmitz, O.J. et al. (2017) Toward a community ecology of landscapes: predicting multiple predator–prey interactions across geographic space. Ecology 98, 2281–2292 38. Leendertz, F.H. et al. (2008) Interspecies transmission of simian foamy virus in a natural predator–prey system. J. Virol. 82, 7741–7744 39. Holmes, E.C. (2009) The Evolution and Emergence of RNA Viruses, Oxford University Press 40. Bairey, E. et al. (2016) High-order species interactions shape ecosystem diversity. Nat. Commun. 7, 12285 41. Moleo´n, M. et al. (2008) An emerging infectious disease triggering large-scale hyperpredation. PLoS One 3, e2307 42. Tilman, D. (1987) The importance of the mechanisms of interspecific competition. Am. Nat. 129, 769–774 43. Aschehoug, E.T. et al. (2016) The mechanisms and consequences of interspecific competition
44.
45. 46. 47. 48. 49.
50. 51. 52. 53.
54.
55.
56. 57. 58.
59. 60. 61. 62. 63.
64. 65. 66.
among plants. Annu. Rev. Ecol. Evol. Syst. 47, 263–281 Gilbert, L. et al. (2001) Disease persistence and apparent competition in a three-host community: an empirical and analytical study of large-scale, wild populations. J. Anim. Ecol. 70, 1053–1061 Reid, H. (1975) Experimental infection of red grouse with louping-ill virus (Flavivirus group): I. The viraemia and antibody response. J. Comp. Pathol. 85, 223–229 Chantrey, J. et al. (2014) European red squirrel population dynamics driven by squirrelpox at a gray squirrel invasion interface. Ecol. Evol. 4, 3788–3799 Agrawal, A.A. et al. (2007) Filling key gaps in population and community ecology. Front. Ecol. Env. 5, 145–152 Wille, M. et al. (2018) Virus–virus interactions and host ecology are associated with RNA virome structure in wild birds. Mol. Ecol. 27, 5263–5278 Monterroso, P. et al. (2016) Disease-mediated bottom-up regulation: An emergent virus affects a keystone prey, and alters the dynamics of trophic webs. Sci. Rep. 6, 36072 Peterson, A.T. (2003) Predicting the geography of species’ invasions via ecological niche modeling. Quart. Rev. Biol. 78, 419–433 Escobar, L.E. and Craft, M.E. (2016) Advances and limitations of disease biogeography using ecological niche modeling. Front. Microbiol. 7, 1174 Harvell, C. et al. (1999) Emerging marine diseases climate links and anthropogenic factors. Science 285, 1505–1510 Mills, J.N. et al. (2010) Potential influence of climate change on vector-borne and zoonotic diseases: a review and proposed research plan. Environ. Health Perspect. 118, 1507–1514 Dunnum, J.L. et al. (2002) Elevational range extension for the hispid cotton rat, Sigmodon hispidus, (Rodentia: Muridae). Southwest. Naturalist 47, 637–639 Proestos, Y. et al. (2015) Present and future projections of habitat suitability of the Asian tiger mosquito, a vector of viral pathogens, from global climate simulation. Phil. Trans. R. Soc. B. 370, 20130554 Messina, J.P. et al. (2019) The current and future global distribution and population at risk of dengue. Nat. Microbiol. 4, 1508–1515 Bono, L.M. et al. (2013) Competition and the origins of novelty: experimental evolution of niche-width expansion in a virus. Biol. Lett. 9, 20120616 Baigent, S.J. and McCauley, J.W. (2003) Influenza type A in humans, mammals and birds: Determinants of virus virulence, host-range and interspecies transmission. Bioessays 25, 657–671 Shi, M. et al. (2016) Redefining the invertebrate RNA virosphere. Nature 540, 539–543 Oliver, T.H. et al. (2015) Biodiversity and resilience of ecosystem functions. Trends Ecol. Evol. 30, 673–684 Hudson, P.J. et al. (2006) Is a healthy ecosystem one that is rich in parasites? Trends Ecol. Evol. 21, 381–385 Jephcott, T.G. et al. (2016) Host–parasite interactions in food webs: diversity, stability, and coevolution. Food Webs 6, 1–8 Crozier, G.K.D. and Schulte-Hostedde, A.I. (2014) The ethical dimensions of wildlife disease management in an evolutionary context. Evol. App. 7, 788–798 Gandon, S. and Day, T. (2007) The evolutionary epidemiology of vaccination. J. R. Soc. Interface 4, 803–817 Go´mez, A. and Nichols, E. (2013) Neglected wild life: Parasitic biodiversity as a conservation target. Int. J. Parasitol. Parasit. Wildlife 2, 222–227 Beisner, B.E. et al. (2003) Alternative stable states in ecology. Front. Ecol. Env. 1, 376–382
Trends in Microbiology, --, Vol. --, No. --
11