The ecoimmunology of invasive species - Wiley Online Library

Functional Ecology 2012, 26, 1313–1323

doi: 10.1111/1365-2435.12012

INVASIONS AND INFECTIONS

The ecoimmunology of invasive species Thomas A. White1,2 and Sarah E. Perkins*,3 1

Department of Ecology and Evolutionary Biology, Cornell University, Corson Hall, Ithaca, New York, 14853-2701 USA; 2CMPG Lab, Institute of Ecology and Evolution, University of Bern, Baltzerstrasse 6, CH-3012, Bern, Switzerland; and 3Cardiff School of Biosciences, Biomedical Sciences Building, Museum Avenue, Cardiff, CF10 3AX UK

Summary 1. Invasive populations frequently harbour a reduced parasite community compared with their native counterparts. The loss of regulating enemies may result in re-allocation of resources away from costly defences, effects that may be particularly pronounced at the wave-front of the invasion during the range expansion stage. Bottlenecking and increased genetic drift is also expected to result in a loss of immunogenetic diversity. As the invasive species expands its range, selection will strongly favour increased growth and reproduction, traits that may tradeoff against immune function. 2. Relaxed parasite-mediated selection is expected to alter the trade-offs between immune response and immunopathology. Hence, we might expect that a combination of necessity (i.e. loss of specific alleles at immune loci) and natural selection away from immunity towards other fitness traits should result in invasive populations having reduced resistance to parasites but greater potential for demographic growth in the invaded range. 3. Following this argument to its logical conclusion would suggest that invasive species could also be more vulnerable to novel parasites, or to parasites to which the invasive population has lost immunity arriving from the native range. Despite this attractive narrative, there is currently little empirical evidence on the ecoimmunology and immunogenetics of invasions. 4. In this article, we review the evidence for changes in the immune response of invasive species. We also examine the likely effects of range expansions and population genetic processes on the immune systems of invasive species. We conclude that much more empirical research is necessary in this field before general patterns and predictions can emerge. Key-words: ecoimmunology, enemy release hypothesis, fitness trade-offs, immunity, immunogenetics, infection, invasion, range expansion Introduction Successful invasion by a non-native species progresses through three stages: (i) inoculation, (ii) establishment (often including a lag period) and (iii) range expansion (Williamson 1996). Understanding how invasive species establish and spread has been a long-term focus for conservation and management bodies as invaders can disrupt ecosystem function, cause native biota loss and significant economic damage (Davis 2009). Success of invasive species may be explained, in part, by the enemy release hypothesis: the liberation of the invader from its co-evolved natural enemies resulting in fitness trade-offs, for example increased demographic growth (Keane & Crawley 2002). *Correspondence author. E-mail: perkinss@cardiff.ac.uk

Enemies have typically been thought of as predators, but parasites are also known to have strong regulatory effects on their host populations, altering host density, fecundity and/or growth (Hudson, Dobson & Newborn 1998; Tompkins & Begon 1999). During all three stages of invasion, multiple parasite species are expected to be ‘lost’ from the invading population due to low host densities and founder effects. Biogeographical comparisons have indeed found, on average, parasite diversity to be lower in hosts in the invaded range for both animals and plants, respectively (53% fewer helminths in invaded range, Torchin et al. 2003; 77% fewer pathogens in invaded range, Mitchell & Power 2003). Furthermore, during range expansion, those individuals at the wave-front have been found to be additionally lacking in parasites, compared to core range individuals (Phillips et al. 2010). Invaders, in the absence

© 2012 The Authors. Functional Ecology © 2012 British Ecological Society

1314 T. A. White & S. E. Perkins of parasites, are expected to reallocate energetic resources away from unnecessary defence mechanisms into fitness and growth, potentially leading to a mechanism explaining invader success and the evolution of increased competitive ability (Blossey & No¨tzold 1995). On an evolutionary scale, the relaxed parasite selection experienced by invaders is expected to lead to changes in the immune system (Horrocks, Matson & Tieleman 2011). As such, we predict the reduced parasite-mediated selection acting on invasive species to alter the immune phenotype of invaders with consequences for the invasion process. Here, we take a fresh look at ‘Invasions and Infections’ by first reviewing the empirical evidence for fitness tradeoffs between host immunity, immunopathology and lifehistory traits in invasion ecology. Examples are reviewed from the ecoimmunological literature, a burgeoning field that aims to understand the links between host fitness and variation in immune phenotypes in natural systems (Martin, Hawley & Ardia 2010; Pedersen & Babayan 2011). Despite advances in immune assays and molecular techniques, however (Pedersen & Babayan 2011), the role of immunity in invasion ecology is a relatively recent area of investigation (Lee & Klasing 2004). As such, empirical studies are often lacking, and therefore rather than providing a synthesis here we provide a perspective on the potential pathways of host–parasite evolution during invasion. Fitness trade-offs are considered in more detail in the third stage of successful invasion, the range expansion phase. This is because spatial sorting of phenotypes and differential selection between the core and the expansion front of an establishing invader become important at this stage, processes that have recently attracted considerable attention in the invasion biology literature (e.g. Burton, Phillips & Travis 2010; Shine, Brown & Phillips 2011). We also review the population genetic processes that influence and constrain the evolution of immune responses, in particular the loss of genetic diversity during founder events and subsequent range expansion.

Invasions and investment in immunity: tradeoffs and immunopathology In the absence of parasitism (used here to describe both parasites and pathogens), or with reduced parasitic pressure, we may expect invasive species to reallocate resources from host immunity into host reproductive fitness (Zuk & Stoehr 2002). Evidence of host fitness trade-offs is plentiful in the immunological literature (Sheldon & Verhulst 1996; Knowles, Nakagawa & Sheldon 2009; Graham et al. 2010; van der Most et al. 2011). In an invasion context, however, reallocation of resources away from immune defence may present problems over the longer term. Re-allocation of resources away from immunity may lead to loss of parasite resistance, leaving invaders especially susceptible to re-infection and novel infections (Emblidge Fromme & Dybdahl 2006; Hasu, Benesh & Valtonen 2009; Duncan, Fellous & Kaltz 2011). Investment in immunity, however,

may not be reduced across the board, but rather reallocations may be targeted towards specific elements of the immune response. For example, experimental removal of helminths has been shown to switch the immune phenotype from a T-helper type 2 (Th2) response that promotes immune effector mechanisms directed against helminth infection to enhancement of a Th1 response, immune effector mechanisms directed against intracellular microparasites, to the extent that, in the Buffalo-Bovine tuberculosis (TB) system TB failed to invade the helminth-free hosts (Ezenwa et al. 2010). Invasive species will encounter novel parasites in their new range, although in general the diversity of new parasites acquired does not appear to compensate for those lost on introduction, at least in the short term (Torchin et al. 2003; Mitchell & Power 2003). Novel parasites lack the adaptations that enable more co-evolved pathogens to avoid eliciting a strong immune response (Lee & Klasing 2004). They may therefore induce disproportionately vigorous inflammatory responses in invasive species (Sears et al. 2011), which can lead to severe or even mortal immunopathology (defined as inappropriate immune responses having a detrimental effect on the fitness of the host, for example cytokine storm; Graham, Allen & Read 2005). If parasite pressure from the recipient community is high, then a systemic inflammatory response from the invader could induce immunopathology, causing more harm than protection. As a consequence, Lee & Klasing (2004) suggest that invasive vertebrate hosts should dampen Th1-inflammatory responses, which may then upregulate Th2 responses. In support of this, Sakanari & Moser (1990) experimentally demonstrated that over time populations of introduced striped bass reduced the severity of immunological reaction to a highly pathogenic native tapeworm. Wilson-Rich & Starks (2010) found a reduced cellular and humoral innate immune response of the invasive wasp, Polistes dominulus, compared to a sympatric native species, P. fuscatus. Although the invasive wasp shows reduced systemic immunity, this is in comparison with a native wasp, and so this does not constitute a true biogeographical comparison. Similarly, Lee, Martin & Wikelski (2005) found a highly invasive house sparrow to have a reduced inflammatory response to antigen-challenge assays when compared to a less successful invader, the tree sparrow. Both studies are consistent with the idea that invaders avoid strong systemic immune responses, but clearly more empirical work is required in this area to draw any strong conclusions. It has been suggested that invasive species might lose protection against specialist parasites but instead shift resources into defences against generalist natural enemies (Joshi & Vrieling 2005), leading to few realized benefits in the form of increased performance in the new range, but no net declines in parasite resistance over time. Another suggested adaptation to invasion is that hosts should be generally parasite tolerant, meaning that instead of active removal of parasites, tolerant hosts mitigate the negative

© 2012 The Authors. Functional Ecology © 2012 British Ecological Society, Functional Ecology, 26, 1313–1323

Ecoimmunology of invasive species 1315 fitness consequences of infection, for example by removal of parasite-emitted toxins or by tissue repair after infection-associated damage (Ra˚berg, Graham & Read 2009). Tolerant hosts also do not have to endure the sickness behaviours associated with resistance responses (e.g. lethargy, decreased libido; Hart 1988), so they are free to engage in pro-invasive, fitness-maximizing behaviours (i.e. dispersal, reproduction). Whilst benefitting invasive species, a highly tolerant host can have important, negative downstream effects on native species in the form of parasite spillover and spillback (Kelly et al. 2009). From the above arguments, it might seem that, in terms of immunopathology, invasive species benefit from the reduction in parasite diversity in the invaded range. However, immunopathology can be triggered not only by parasites but, in the case of allergic reactions and autoimmunity, also by antigens present on innocuous substances, such as food, or on the host’s own cells (Graham, Allen & Read 2005). There are parallels between invasive species and humans in modern post-industrial society; both have a depauperate parasite community. Modern sanitation has resulted in ‘biome depletion’ and given rise to the ‘hygiene hypothesis’, whereby non-pathogenic particles, for example pollen and dust, induce strong auto- and hyper-immune responses with far-reaching consequences for human health (Bilbo et al. 2011). Again, this is an analogy that has not been studied empirically in invasion biology, but could yield interesting parallels. Of course, rather than differences in immune responses between invaders and non-invaders being due to adaptive evolution post-invasion, it may be due to pre-selection.

Invasions and immunogenetics The arguments in the previous section suggest that we expect the immune system of invasive species to show a good deal of plasticity, and that it will tend to adapt to conditions of parasitic enemy release in somewhat predictable ways. To a certain extent we can predict which parasites will be lost, for example, those with complex life cycles that rely on the presence of intermediate hosts, but parasite species loss is also partly stochastic as it is a function of which individuals established and their associated parasite community (Perkins et al. 2008). As such, the parasitic environment or ‘immunobiome’ (Horrocks, Matson & Tieleman 2011) in the invaded range may vary from one invasion to another leading to unpredictable changes in host immunity. Moreover, there are factors additional to changes in antigenic diversity and pressure that can constrain or limit flexibility in the immune system (Ardia, Parmentier & Vogel 2011). One of these is immunogenetics, the genetic factors controlling an individual’s immune response and the transmission of those factors from one generation to the next. The influence of genetics on immunity remains under-explored in biological invasions (Handley et al. 2011). However, we may be able to draw general lessons and hypotheses from processes operating in

analogous situations such as populations undergoing demographic cycles (analogous because invasive populations also undergo rapid changes in population size). When an invading species establishes, it generally passes through a population bottleneck, losing genetic diversity. The extent to which diversity is lost appears to be highly variable (Bossdorf et al. 2005) and depends strongly on the number of founders (Uller & Leimu 2011) and whether or not there have been multiple introductions (Dlugosch & Parker 2008). High genetic diversity is thought generally to be beneficial, to avoid inbreeding depression and to allow populations to respond to selection (Frankham, Ballou & Briscoe 2002; White & Searle 2008). Genome-wide diversity may be important for parasite resistance (Rijks et al. 2008; Voegeli et al. 2012), either because individuals in good condition (i.e. not showing inbreeding depression) should be better able to resist parasites (Beldomenico et al. 2008) or because a large percentage of all genes are involved in defence against infection and some of these genes exhibit overdominance (Pemberton et al. 2011; Webster et al. 2011; Charbonnel & Cosson 2012). The issue of low genetic diversity is more commonly raised in the context of agricultural systems (e.g. Elton 1958) or species of conservation concern (Frankham, Ballou & Briscoe 2002). However, similar problems could apply to populations of invasive species with low genetic diversity, as has been suggested for the unusually high susceptibility of invasive house finches in eastern N. America to ongoing outbreaks of mycoplasmal conjunctivitis (Dhondt et al. 2005). In some cases, repeated introductions from multiple native sites could actually cause blending of alleles from different geographic locations in the new habitat, leading to greater genetic variation – rather than less – in the introduced range (as has been demonstrated with brown anole lizards; Kolbe et al. 2004). Hybridization in the new range could also lead to hosts with novel gene combinations that are highly resistant to parasite infections (Sakai et al. 2001). In vertebrates, diversity at the major histocompatibility complex (MHC) loci may be particularly important for invasive populations, as this diversity provides the basis for rapid adaptive immunity (Eizaguirre et al. 2012). There has been much debate concerning the processes maintaining the extraordinary allelic diversity we see at the MHC loci (Piertney & Oliver 2006). The overdominance hypothesis states that MHC heterozygotes should have higher fitness, as two variant alleles will identify a broader range of pathogens (Oliver et al. 2009). Conversely, many studies suggest that specific alleles are more effective against specific parasites and that the high allelic diversity is maintained by opposing directional selection working at different spatio-temporal scales, or by negative frequencydependent selection (Tollenaere et al. 2008; Oliver, Telfer & Piertney 2009; Charbonnel et al. 2010; Kloch et al. 2010). The various hypotheses are difficult to untangle because rare alleles will tend to be present only in


1316 T. A. White & S. E. Perkins heterozygotes (Apanius et al. 1997). As population bottlenecks and genetic drift have a greater impact on allelic diversity than heterozygosity (Allendorf 1986), the details of the mechanism connecting MHC diversity and parasite resistance are likely to be important for invasive species. If specific alleles are necessary for a successful immune response, bottlenecks could reduce the resistance in the invader, whereas if heterozygosity is the most important factor bottlenecks should have less impact. The importance of bottlenecks will also be reduced if any functional diversity lost during a bottleneck is regenerated quickly. For example, Spurgin et al. (2011) found that only 11–15 MHC haplotypes were retained when Berthelot’s pipit (Anthus berthelotii) spread across its island range. Since then, at least 26 new haplotypes have been generated in situ by gene conversion. However, as these changes have taken place at some point over the last c. 75 000 years, it is unknown whether this mechanism will be important over the shorter time-scales relevant for invasive species. Loss of parasites during invasions may, to some extent, negate the impact of founder events on the loss of MHC diversity, as certain alleles may be unnecessary for an immune response to the invaders accompanying parasites. Sampling bias associated with which individuals constitute the invading population may be important in this regard, as successful invasions may be those where the particular combination of retained alleles and parasites has not presented a serious problem in the native range, and we simply may not observe those occasions where it has. MHC diversity is also linked to auto-immunity (Maizels 2009), as too much diversity is thought to increase the likelihood of self-reactivity (Wucherpfennig & Strominger 1995). A loss of parasites may therefore shift the trade-off between pathogen recognition and immunopathology, resulting in selection for individuals with reduced MHC diversity. Loss of MHC diversity in invasive species is therefore predicted due to a combination of drift, relaxed selection and directional selection. To date, MHC diversity has attracted the most interest for researchers studying immunogenetics of populations in the wild. However, this variation only accounts for a fraction of the variation in infectious disease susceptibility (Acevedo-Whitehouse & Cunningham 2006; Tonteri et al. 2010; Bollmer et al. 2011; Turner et al. 2011, 2012). Indeed, a high proportion of all genes are involved in defence against infection (Pemberton et al. 2011). However, a few immune genes in particular stand out as being worthy of study. These include cytokines, signalling molecules with a role in many immunological processes including inflammation and regulation of the Th1/Th2 response, and Toll-like receptors (TLR), membrane-bound receptors that recognize structurally conserved ligands derived from microbes (Roach et al. 2005; Turner et al. 2011). In the few studies that have examined immune genes other than MHC, selection has been clearly observed. For example, in a study of a natural population of field voles (Microtus agrestis), Turner et al. (2012)

found that diversity at cytokine loci had strong effects on host immunology and resistance to multiple pathogens. Part of the need to move beyond MHC is that, in terms of gene 9 environment interactions, the MHC loci are predicted to behave very differently from other immune genes. Due to the high functional diversity of receptors, MHC variation is likely to have qualitative effects on the host immune response with little scope for plasticity, because the gain/loss of a particular receptor may render a population resistant/susceptible to a specific parasite. MHC function may therefore be particularly sensitive to genetic drift and the loss of specific alleles during inoculation and establishment of an invasion. Conversely, other immune gene systems, such as TLR, have much less variation in the molecular structure of their gene products, as they interact with more conserved ligands (Roach et al. 2005). Such variation as there is in these systems is mostly due to quantity and distribution of receptor molecules (Schmaußer et al. 2004). Genes such as TLR are therefore likely to influence immunity quantitatively and may show greater plasticity of response. As there is known to be a great deal of plasticity in the immune response, there also needs to be a greater consideration of expression levels of immune genes. Despite recent progress in these areas (Guivier et al. 2010; Jackson et al. 2011; Pemberton et al. 2011; Webster et al. 2011; Turner et al. 2012), so far no studies have addressed these issues with regard to invasive species.

Evolution of immunity during the range expansion stage of an invasion The range expansion stage of an invasion is expected to generate a new set of selective pressures and population genetic effects that are likely to have profound impacts on the immunity of invasive species. Spatial sorting of dispersing individuals will naturally lead to the expansion front having a higher proportion of individuals that have a genetic predisposition to disperse longer distances (Shine, Brown & Phillips 2011). Higher dispersal may also be favoured by natural selection, as it will allow those dispersing individuals at the expansion front to exploit new resources and avoid overcrowding. Evidence for this phenomenon has been found in a wide variety of taxa, including cane toads (Phillips et al. 2006), butterflies (Hughes, Dytham & Hill 2007) and wind-dispersed plants (Monty & Mahy 2010). At the edge of an expanding population, selection will favour reproduction early and often (Moreau et al. 2011). Being at the expanding wave-front increases the fitness of individuals over multiple generations, as the offspring of these individuals (and so on) will tend to contribute more genetic material to the expanding population (Phillips 2009). Where trade-offs exist, individuals should therefore invest more in dispersal, growth and reproduction, and less in competition and immunity (Burton, Phillips & Travis 2010).


Ecoimmunology of invasive species 1317 At the expansion front, parasites may be lost stochastically and/or the population may fall below the critical community size required to support parasite persistence (Bar-David, Lloyd-Smith & Getz 2006). Therefore, we might expect a preponderance of uninfected hosts at the expansion front, evidence for which has been found in cane toads, Bufo marinus (Phillips et al. 2010), the brown argus butterfly, Aricia agestis (Meneńdez et al. 2008) and the American beech, Fagus grandifolia (Tsai & Manos 2010). Therefore, at the expansion front in particular, we might expect both an increased need to invest in other traits and a reduced need to invest in immunity. Here, hosts should divert fewer resources to maintaining their immune systems. Reduced investments may be targeted at particular aspects of the immune response, due to different development and use costs (Lee 2006). For example, if selection at the expansion front favours rapid growth, trade-offs may favour reduced investment in immune components with particularly high development costs (van der Most et al. 2011), such as induced cell-mediated and antibody responses (Tschirren, Fitze & Richner 2003). Such ‘pace-of-life’ trade-offs have been studied at the interspecific level (Martin, Weil & Nelson 2007; Johnson et al. 2012) but less frequently at the intra-specific level (Sparkman & Palacios 2009). Within invasion ecology, empirical tests of expansion front adaptations are only just starting to appear in the literature. Llewellyn et al. 2012, for example, compared the metabolic rate response of the invasive cane toad in established and wave-front populations finding a significantly lower response to lipopolysaccharide challenge than in older populations. Whilst this provides evidence for changes in immune investment over a short period of time, to establish a causal link between immunity and any given trait, traits must be manipulated. In addition, empirical experiments should consider that trade-offs at the expansion front are likely to be transient. As densities increase and parasites arrive, selection pressures will favour increased investment in immunity, although this may still be reduced compared to immune investment in the native range (see above). The individuals that disperse are likely to be a non-random subset of those in the natal population. Additional complications arise if we consider the nature of this nonrandomness, that is, ‘did they jump or were they pushed?’ Where the cost of dispersal is higher than the cost of staying put, individuals should compete to remain in their natal site. The social dominance hypothesis states that stronger individuals that dominate socially and suppress weaker individuals (by, for example, defeating them in fights or denying them access to resources) force the weaker individuals to leave the local territory. Evidence for dispersal of weaker individuals has been found across taxa, for example in shrews (Hanski, Peltonen & Kaski 1991), dragonflies (McCauley 2010) and woodpeckers (Pasinelli & Walters 2002). If subordinate individuals are those with poor body condition, they may be more heavily parasitized than dominant individuals due to immunosup-

pression (Beldomenico et al. 2008). Alternatively, infection status may determine social rank. Whilst some studies report evidence for such associations (Rau 1983; Weatherhead et al. 1995), others have found subordinate individuals to have lower parasite burdens due to possible trade-offs between testosterone levels and immune function (Muehlenbein & Watts 2010). Parasites as well as hosts experience strong selection pressures during range expansions (Bull et al. 2006). For example, Kelehear, Brown & Shine (2012) conducted a common-garden experiment comparing life-history traits of the nematode lungworm (Rhabdias psuedophaerocephala) infecting invasive cane toads in Australia. Nematodes from nearer the expansion front had larger eggs, free-living adults and infective larvae and reduced age at maturity, traits that could serve to maximize transmission in the low host density environment of the expansion front. Such adaptations in parasites may be due to enemy release of the particular parasite species, due to a reduction in competition from ‘lost’ parasites within the host infracommunity. To summarize, in comparison with old-established populations, hosts at the wave-front of a range expansion may be less parasitized, due to stochastic parasite loss and low population densities. Conversely, they may be equally as parasitized, if parasites adapt to low-density environments at the wave-front, or they may be more parasitized, depending on the characteristics of those individuals that disperse. Unfortunately, due to the lack of studies in this area, we cannot say which result is likely to be more general, nor for which specific reasons. We hope, however, that this may spur further research in this area.

Immunogenetics during the range expansion stage of an invasion In species range expansions, decreasing allelic richness and heterozygosity are generally associated with increasing distance from the source populations (Handley et al. 2007; Parisod & Bonvin 2008; Estoup et al. 2010), which again may have negative consequences for fitness and the ability to fight parasite infections. The last 10 years have seen a surge of interest in the genetic effects of range expansions (Excoffier, Foll & Petit 2009), particularly the phenomenon of ‘allele surfing’. Edmonds, Lillie & Cavalli-Sforza (2004) and Klopfstein, Currat & Excoffier (2006) demonstrated that new alleles arising (by mutation) on the edge of a range expansion can sometimes ‘surf’ on the wave of the advance and reach higher densities than would be expected in a population at equilibrium. Travis et al. (2007) later showed that deleterious mutations can also surf to high frequencies at expanding range margins, including mutations having a negative effect on reproductive rate and juvenile competitive ability. Whilst beneficial mutations are expected to spread in any case, deleterious mutations are very unlikely to spread unless by surfing. Lohmueller et al. (2008) found that non-African human populations


1318 T. A. White & S. E. Perkins had significantly more deleterious mutations than Africans, consistent with the above predictions. Therefore, individuals on the edge of a range expansion may generally have lower fitness and thus be more susceptible to parasites than those at the core or in the native range (Beldomenico et al. 2008). Few studies have explicitly considered the impacts of range expansions on immune gene diversity (Charbonnel & Cosson 2012). However, we may be able to make inferences by considering humans as an example of a species having undergone a range expansion. Prugnolle et al. (2005) found that human leucocyte antigen diversity (HLA; called MHC in other vertebrate species), assessed in 61 populations, declined with distance from Africa. This suggests a strong influence of founder events and genetic drift as humans colonized the other continents. HLA diversity was also positively correlated with local pathogen (particularly virus) diversity, suggesting that diversifying selection mediated by pathogen resistance has been somewhat effective in the face of genetic drift. However, this study is a snapshot of the population thousands of years after the initial expansion, and it is likely that the pathogen and genetic landscape has changed significantly over that interval, particularly if pathogens tend to lag behind the expansion front (Phillips et al. 2010). We need also to consider the impact on immunogenetics of moving from low population density to high population density at the expansion front of the invasion. Bryja et al. (2007) studied fluctuating populations of water voles (Arvicola scherman) and compared genetic differentiation at MHC class II genes (DQA1, DRB) to putatively neutral microsatellite markers. During the low-abundance phase, there was little migration between populations. Simulation-based outlier tests suggested that the DQA1 locus was under directional selection in one of the population fragments. During the high-abundance year, when migration between demes was much higher, DQA1 displayed significantly lower levels of differentiation than the microsatellite markers, suggesting the action of balancing selection. This pattern was interpreted as representing spatial and temporal fluctuations in parasite pressure. We might expect a similar phenomenon in spatially expanding populations. At the expansion front, parasites may be lost stochastically and particular alleles of those parasites that are retained may surf to high frequency during the subsequent range expansion (Biek et al. 2007). Immune genes may evolve neutrally or under local selection depending on population densities and the particular combinations of host alleles, parasites and parasite alleles retained. Older-established populations may carry a higher diversity of parasites and hence experience stronger balancing selection, leading to a higher diversity of MHC alleles in these populations. When populations undergo spatial expansions, genetic drift and ‘allele surfing’ (Edmonds, Lillie & Cavalli-Sforza 2004) at the expansion front can generate signals very similar to those expected under directional selection (Hofer et al. 2009). It may therefore be very difficult to determine

whether specific alleles at immune genes are favoured by selection, for instance MHC alleles that are particularly effective against the remaining parasitic fauna, or alleles involved in down-regulation of specific arms of the immune system. Drift and surfing are unlikely to homogenize allele frequencies between populations, so we may have greater confidence in signals of balancing selection of invasive species if detected using outlier methods or using partial correlations of allelic diversity with local parasite diversity (Prugnolle et al. 2005). However, other tests for balancing selection based on dN : dS ratios are unlikely to be useful for detecting contemporary selection, as elevated ratios due to past selection may take many thousands of generations to return to equivalence (Garrigan & Hedrick 2003). New outlier methods have been developed to detect selection whilst accounting for demographic structure (Foll & Gaggiotti 2008; Excoffier, Hofer & Foll 2009; Coop et al. 2010). Of particular interest in this context is the approach of Coop and co-workers, which correlates allele frequencies with environmental variables (e.g. pathogen load or diversity). This method may have more power than alternatives for detecting selection (soft sweeps) from standing variation (Novembre & Han 2012). This is likely to be the most common type of selection in invasive populations given that, in general, there has not been much time for novel mutations to arise. Nevertheless, false-positive signals of directional selection in range expansions are likely to be a concern for the foreseeable future. In general, the nature of range expansions, with their concomitant loss of both genetic and parasite diversity, means that the separate effects of these phenomena will be difficult to disentangle using snapshots of wild populations. Longitudinal studies may help to distinguish cause from effect in many cases, but, as ever, the most robust results will likely come from experimental approaches.

Parasites and waves of invasion As we have described in previous sections, biological invasions and subsequent range expansions almost invariably generate asymmetries between the invasive population and populations of that species in the native range, particularly in terms of genetic and parasite diversity and natural selection operating on the invasive population. We predict these asymmetries might drive subsequent invasions, with new propagules tending to displace older invasive populations, whether they are populations of the same species or of a closely related species with a similar parasite fauna. This is perhaps best illustrated by a simple model (Fig. 1). A species expands out of its native range to become an invader and undergoes spatial expansion in the invaded range (Fig. 1a). As explained above, the invader may experience parasitic release and drift or pass through a genetic bottleneck due to the small number of founders, so that in their new range, the invaders have only a subset of the parasites found in the native range and may also have reduced immunogenetic diversity (e.g. fewer MHC alleles). The


Ecoimmunology of invasive species 1319

(a)

(b)

(c)

Fig. 1. (a) A species with two parasites invades a new territory. In the native range, not all host individuals possess all parasites. Due to random sampling, individuals in the invaded range possess only a subset of the parasites (stars) in the native range. (b) Over time individuals in the invaded range lose resistance to the parasites they have lost. (c) At some later time, there is a dispersal event between the native range and the invaded range, by an individual (or individuals) carrying the lost parasites. The invaded range individuals are highly susceptible to these parasites now, and their population declines. Depending on the number of parasites infecting the species in the native range, there is potential for this cycle to repeat many times.

invading population may develop reduced immunity to the parasites it has lost (see above sections; Fig. 1b). The loss of resistance may be immediate, if mediated via loss of particular resistance alleles during founder events. The relevant time-scale for evolved lack of resistance (due to trade-offs or relaxed selection, for example) is, however, likely to be of the order of hundreds of generations (Duncan, Fellous & Kaltz 2011), although other evidence from the literature is scarce and to the best of our knowledge has only been examined experimentally with single parasite scenarios, rather than the multi-parasite scenario expected for invaders. Eventually, there is likely to be a new arrival from the native range, particularly if the invasion was due to human-mediated transport – on a regular shipping route for example (Davis 2009). The new set of migrants

(population 2) may also only carry a subset of the parasites present in the native range (Fig. 1c). We predict the new invaders (population 2) to have immunity to the parasite community of established invasive population 1; they are likely to have a similar parasite community and, importantly, will not yet have evolved reduced resistance to those parasite species that have been lost. If population 2 has lost important resistance alleles to the parasites it carries, it is unlikely to establish and become invasive in any case. Conversely, it may be the case that the invading population 2 is carrying a parasite to which the established invasive population 1 has lost resistance. The parasite community associated with population 2 can then be transmitted to the now naı¨ ve population 1. As these parasites are invading a naı¨ ve population, they too will be under r-selection for increased transmission (Bull 1994). The rate of transmission is often positively correlated with virulence (de Roode, Yates & Altizer 2008), so parasitism experienced by the naı¨ ve population 1 may be unusually virulent (Bull 1994). As the parasite is introduced by individuals of the same or closely related host species, these new arrivals in population 2 will provide a reservoir for the parasite. This will increase the impact of the parasite on the naı¨ ve population 1; parasite transmission will not decline as the density of the naı¨ ve population drops (as would normally be the case; Bull 1994), and as local extinction of the parasite will be prevented, there will be reduced selection pressure on the parasite to become less virulent (Lafferty et al. 2005). This spill-over may result in the extinction of population 1 or generate sublethal effects in population 1 that tip the balance of competition to favour population 2 over population 1. If the two populations can interbreed, selection should favour recombination of resistant alleles into population 1. However, in the case of a more severe disease outbreak, the wave of disease may spread ahead of the invasion front (Bell et al. 2009), reducing the density of population 1 before interbreeding between populations 1 and 2 can take place. As population 2 still does not have all the parasites present in the core of the range, it too may lose resistance to some parasites and will itself be vulnerable to further invasions. Hence, we might expect to see a series of invasions by hosts, until an approximate equilibrium is reached between the parasite diversity and intensity in the invaded range/wave-front and the core or native range. If the diversity of parasites increases in invaders, this could have implications for population dynamics in the invasive species (Hilker 2010), which may gradually become more and more regulated by their co-evolved parasite fauna. This could be part of an explanation for the enigmatic collapse of some previously successful invaders (Simberloff & Gibbons 2004). There are some tantalizing clues that such parasitedriven invasion waves may be occurring in certain circumstances. The long-established Christmas island rats populations, Rattus macleari and R. nativitatis, were driven to extinction between 1899 and 1908 by Trypanosoma


1320 T. A. White & S. E. Perkins lewisi, a parasite introduced to the island with the invasive ship rat R. rattus (Wyatt et al. 2008). As T. lewisi is endemic in many species of the Rattini tribe (Dobigny et al. 2011), loss of this particular parasite and/or its flea vector during invasion seems to be a likely cause for the lack of T. lewisi in the Christmas Island species prior to R. rattus invasion. A similar ‘wave’ of invasion could have occurred in mainland Europe. Throughout the medieval period, R. rattus was the common house rat in Europe. It was replaced by the brown rat (Rattus norvegicus), which arrived in the 18th century (Simberloff & Gibbons 2004). It has been suggested that this replacement may have been facilitated by bubonic plague, a disease endemic to Asia, and to which R. norvegicus is more resistant than R. rattus (Loosjes 1956; Monecke, Monecke & Monecke 2009). Waves of invasion appear to be the norm in well-studied species, such as rodents. In New Zealand, there have been three documented waves of rat invasions. Polynesian colonists introduced R. exulans, which was then decimated by the arrival of R. norvegicus with European settlers. In turn, both species were decimated by the latest arrival, R. rattus, with R. exulans driven to extinction on the North Island. Again, disease-mediated extinction has been suggested as contributing factor (King 1990). It is interesting that in these invasions, the newest arrival has always been favoured, despite the switching in order of arrival of R. rattus and R. norvegicus between Europe and New Zealand. In addition, R. exulans survives on several offshore islands in New Zealand where R. rattus and R. norvegicus are also found. These considerations suggest that competition alone cannot explain the observed waves of invasion. For the within-species case, invasion waves moving from the species core range to the periphery could interrupt local adaptation in peripheral populations. This could place a limit on species range sizes (Bridle & Vines 2007). Parasite-mediated invasions could prevent secondary sympatry and hence slow down the process of species radiation (Ricklefs & Bermingham 2007; Ricklefs 2010). As rates of speciation and the evolution of range sizes have a bearing on a wide range of biogeographic patterns, we suggest that parasite-mediated invasion could be a fruitful area for further empirical research.

Conclusions and future directions There are gaps in the literature regarding the ecoimmunology of invasions, and whilst there is a good deal of theory, there is a need for more empirical studies of invasive species. These studies should combine field assays (e.g. Graham, Shuker & Pollitt 2011; Turner et al. 2012) and both longitudinal and experimental studies on host– parasite interactions. The immune response of hosts depends heavily on available genetic variants, which in invasive species is likely to be influenced by founder events and genetic drift. Studies should therefore integrate population genetics. Moreover, these studies should consider demographic history and spatially explicit genetic

processes such as allele surfing and the potential for spatial sorting during a range expansion. It is vital to move beyond the population genetics of MHC loci to study other genes involved in innate immunity and to consider gene expression. With recent advances in genomics (Hohenlohe et al. 2010), genome-wide studies are likely to soon become the norm. Due to the stochastic loss of both parasites and perhaps more so immune gene alleles, the outcomes of individual invasions may be idiosyncratic, with strong taxonomic biases (Uller & Leimu 2011). Therefore, there is a need for greater synthesis of empirical data and hypothesis testing in a structured way. Immunity has the potential to influence strongly the course of an invasion. As new technologies come online, we expect this to be a growth area for research in the coming years.

Acknowledgements TAW is supported by a FP7 Outgoing Fellowship. SEP is supported by an FP7 Intra-European Fellowship. Thanks are due to C. van Oosterhout and J. Lello for useful comments on an early draft of the manuscript.

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