Rapid Response to Selection,Competitive Release and Increased Transmission Potential of Artesunate-Selected Plasmodium chabaudi Malaria Parasites

The evolution of drug resistance, a key challenge for our ability to treat and control infections, depends on two processes: de-novo resistance mutations, and the selection for and spread of resistant mutants within a population. Understanding the factors influencing the rates of these two processes is essential for maximizing the useful lifespan of drugs and, therefore, effective disease control. For malaria parasites, artemisinin-based drugs are the frontline weapons in the fight against disease, but reports from the field of slower parasite clearance rates during drug treatment are generating concern that the useful lifespan of these drugs may be limited. Whether slower clearance rates represent true resistance, and how this provides a selective advantage for parasites is uncertain. Here, we show that Plasmodium chabaudi malaria parasites selected for resistance to artesunate (an artemisinin derivative) through a step-wise increase in drug dose evolved slower clearance rates extremely rapidly. In single infections, these slower clearance rates, similar to those seen in the field, provided fitness advantages to the parasite through increased overall density, recrudescence after treatment and increased transmission potential. In mixed infections, removal of susceptible parasites by drug treatment led to substantial increases in the densities and transmission potential of resistant parasites (competitive release). Our results demonstrate the double-edged sword for resistance management: in our initial selection experiments, no parasites survived aggressive chemotherapy, but after selection, the fitness advantage for resistant parasites was greatest at high drug doses. Aggressive treatment of mixed infections resulted in resistant parasites dominating the pool of gametocytes, without providing additional health benefits to hosts. Slower clearance rates can evolve rapidly and can provide a strong fitness advantage during drug treatment in both single and mixed strain infections.     

Quantifying Adaptive Evolution in the Drosophila Immune System

It is estimated that a large proportion of amino acid substitutions in Drosophila have been fixed by natural selection, and as organisms are faced with an ever-changing array of pathogens and parasites to which they must adapt, we have investigated the role of parasite-mediated selection as a likely cause. To quantify the effect, and to identify which genes and pathways are most likely to be involved in the host–parasite arms race, we have re-sequenced population samples of 136 immunity and 287 position-matched non-immunity genes in two species of Drosophila. Using these data, and a new extension of the McDonald-Kreitman approach, we estimate that natural selection fixes advantageous amino acid changes in immunity genes at nearly double the rate of other genes. We find the rate of adaptive evolution in immunity genes is also more variable than other genes, with a small subset of immune genes evolving under intense selection. These genes, which are likely to represent hotspots of host–parasite coevolution, tend to share similar functions or belong to the same pathways, such as the antiviral RNAi pathway and the IMD signalling pathway. These patterns appear to be general features of immune system evolution in both species, as rates of adaptive evolution are correlated between the D. melanogaster and D. simulans lineages. In summary, our data provide quantitative estimates of the elevated rate of adaptive evolution in immune system genes relative to the rest of the genome, and they suggest that adaptation to parasites is an important force driving molecular evolution.     

A model for the coevolution of immunity and immune evasion in vector-borne diseases with implications for the epidemiology of malaria

We describe a model of host-parasite coevolution, where the interaction depends on the investments by the host in its immune response and by the parasite in its ability to suppress (or evade) its host's immune response. We base our model on the interaction between malaria parasites and their mosquito hosts and thus describe the epidemiological dynamics with the Macdonald-Ross equation of malaria epidemiology. The qualitative predictions of the model are most sensitive to the cost of the immune response and to the intensity of transmission. If transmission is weak or the cost of immunity is low, the system evolves to a coevolutionarily stable equilibrium at intermediate levels of investment (and, generally, at a low frequency of resistance). At a higher cost of immunity and as transmission intensifies, the system is not evolutionarily stable but rather cycles around intermediate levels of investment. At more intense transmission, neither host nor parasite invests any resources in dominating its partner so that no resistance is observed in the population. These results may help to explain the lack of encapsulated malaria parasites generally observed in natural populations of mosquito vectors, despite strong selection pressure for resistance in areas of very intense transmission.     

An analytical model for genetic hitchhiking in the evolution of antimalarial drug resistance

We analytically study a deterministic model for the spread of drug resistance among human malaria parasites. The model incorporates all major characteristics of the complex malaria transmission cycle and accounts for the fact that only a fraction α of infected hosts receive drug treatment. Furthermore, the model incorporates that hosts can be co-infected. The number m of parasites co-infecting a host is either a constant or, more generally, follows a given frequency distribution.Although the model is formulated in a multilocus setup, for our results we assume that drug resistance is caused by a single locus with two alleles — a sensitive one and a resistant one. We assume that the resistant allele has a selective advantage only in treated hosts and pays metabolic costs, which causes this allele to be deleterious in untreated hosts. We provide necessary and sufficient conditions for the fixation of the resistant allele. Moreover, provided the resistant allele will sweep through the population, we derive a formula for the time until it reaches a given frequency and in particular for the time until quasi-fixation.Furthermore, we establish an analytical solution for allele frequency changes at a linked neutral biallelic locus due to the rapid increase in frequency of the resistant allele. Our solution describes a local reduction in heterozygosity among parasite chromosomes around the resistant allele, the effect commonly referred to as the hitchhiking effect, as a function of α and m. The result therefore allows the investigation of selective sweep patterns under specific demographic settings. We find that the hitchhiking effect is similar but different from the standard model of genetic hitchhiking that assumes random mating and homogeneous selection. In particular, the process of recombination and selection cannot be decoupled. We further explain why standard hitchhiking theory cannot be applied to drug resistance in malaria. Furthermore, we will show that a genome-wide reduction in relative heterozygosity can occur provided a fraction of hosts is infected by a single parasite haplotype.Finally, we show how to incorporate host heterogeneity, and generalize our results to this biologically more realistic case.     

Host lifespan and the evolution of resistance to multiple parasites

Hosts are typically challenged by multiple parasites, but to date theory on the evolution of resistance has mainly focused on single infections. We develop a series of models that examine the impact of multiple parasites on the evolution of resistance under the assumption that parasites coexist at the host population scale as a consequence of superinfection. In this way, we are able to explicitly examine the impact of ecological dynamics on the evolutionary outcome. We use our models to address a key question of how host lifespan affects investment in resistance to multiple parasites. We show that investment in costly resistance depends on the specificity of the immune response and on whether or not the focal parasite leads to more acute infection than the co‐circulating parasite. A key finding is that investment in resistance always increases as the immune response becomes more general independently of whether it is the focal or the co‐circulating parasite that exploits the host most aggressively. Long‐lived hosts always invest more than short‐lived hosts in both general resistance and resistance that is specific to relatively acute focal parasites. However, for specific resistance to parasites that are less acute than co‐circulating parasites it is the short‐lived hosts that are predicted to invest most. We show that these results apply whatever the mode of defence, that is whether it is through avoidance or through increased recovery, with or without acquired immunity, or through acquired immunity itself. As a whole, our results emphasize the importance of considering multiple parasites in determining optimal immune investment in eco‐evolutionary systems.     

Do Parasitic Trematode Cercariae Demonstrate a Preference for Susceptible Host Species?

Many parasites are motile and exhibit behavioural preferences for certain host species. Because hosts can vary in their susceptibility to infections, parasites might benefit from preferentially detecting and infecting the most susceptible host, but this mechanistic hypothesis for host-choice has rarely been tested. We evaluated whether cercariae (larval trematode parasites) prefer the most susceptible host species by simultaneously presenting cercariae with four species of tadpole hosts. Cercariae consistently preferred hosts in the following order: Anaxyrus ( = Bufo) terrestris (southern toad), Hyla squirella (squirrel tree frog), Lithobates ( = Rana) sphenocephala (southern leopard frog), and Osteopilus septentrionalis (Cuban tree frog). These host species varied in susceptibility to cercariae in an order similar to their attractiveness with a correlation that approached significance. Host attractiveness to parasites also varied consistently and significantly among individuals within a host species. If heritable, this individual-level host variation would represent the raw material upon which selection could act, which could promote a Red Queen “arms race” between host cues and parasite detection of those cues. If, in general, motile parasites prefer to infect the most susceptible host species, this phenomenon could explain aggregated distributions of parasites among hosts and contribute to parasite transmission rates and the evolution of virulence. Parasite preferences for hosts belie the common assumption of disease models that parasites seek and infect hosts at random.     

The immunoepidemiology of nematode parasites of farmed animals: a mathematical approach.

The population dynamics of farmed animals are controlled by humans, and often involve high host densities, which encourage higher parasite burdens than would be usual in wild animals. As a result, the immunity to reinfection acquired by the host is an important determinant of parasite population dynamics. For example, lambs are highly susceptible to gastrointestinal nematodes as they begin to graze, but develop an immunity that accounts for the observed within-year variation in parasite load and pasture contamination. In the longer term, control measures are compromised by the development of parasite strains resistant to chemotherapy, focusing attention on the development of 'natural' measures, including the selection for resistant hosts and the development of antiparasite vaccines. Mick Roberts here considers the immunoepidemiology of parasites of farmed animals on three levels: the interaction between the parasite and the host's immune system determining the individual's level of protection; the development of acquired immunity determining the within-year parasite population dynamics; and the long-term effects of control measures on the between-year parasite population dynamics.     

The costs of evolving resistance in heterogeneous parasite environments

The evolution of host resistance to parasites, shaped by associated fitness costs, is crucial for epidemiology and maintenance of genetic diversity. Selection imposed by multiple parasites could be a particularly strong constraint, as hosts either accumulate costs of multiple specific resistances or evolve a more costly general resistance mechanism. We used experimental evolution to test how parasite heterogeneity influences the evolution of host resistance. We show that bacterial host populations evolved specific resistance to local bacteriophage parasites, regardless of whether they were in single or multiple-phage environments, and that hosts evolving with multiple phages were no more resistant to novel phages than those evolving with single phages. However, hosts from multiple-phage environments paid a higher cost, in terms of population growth in the absence of phage, for their evolved specific resistances than those from single-phage environments. Given that in nature host populations face selection pressures from multiple parasite strains and species, our results suggest that costs may be even more critical in shaping the evolution of resistance than previously thought. Furthermore, our results highlight that a better understanding of resistance costs under combined control strategies could lead to a more 'evolution-resistant' treatment of disease.     

Host resistance and coevolution in spatially structured populations

Natural, agricultural and human populations are structured, with a proportion of interactions occurring locally or within social groups rather than at random. This within-population spatial and social structure is important to the evolution of parasites but little attention has been paid to how spatial structure affects the evolution of host resistance, and as a consequence the coevolutionary outcome. We examine the evolution of resistance across a range of mixing patterns using an approximate mathematical model and stochastic simulations. As reproduction becomes increasingly local, hosts are always selected to increase resistance. More localized transmission also selects for higher resistance, but only if reproduction is also predominantly local. If the hosts disperse, lower resistance evolves as transmission becomes more local. These effects can be understood as a combination of genetic (kin) and ecological structuring on individual fitness. When hosts and parasites coevolve, local interactions select for hosts with high defence and parasites with low transmissibility and virulence. Crucially, this means that more population mixing may lead to the evolution of both fast-transmitting highly virulent parasites and reduced resistance in the host.     

Studies of delayed hypersensitivity to L. Monocytogenes in mice: nature of cells involved in passive transfers

C3Hf/Umc mice were immunized by an intravenous injection of a sublethal dose of live Listeria monocytogenes. The animals developed delayed-type hypersensitivity (DH) concomitant with infectious immunity to this organism. Delayed hypersensitivity could be transferred to normal lethally irradiated mice with spleen cells from immune animals. The immune cells cells responsible for transfer of adoptive immunity were susceptible to in vitro cytolytic action of anti-theta iso-antibody and complement, since such treatment rendered these cells incapable of further passive transfer of specific immunity to Listeria. The acquired DH to Listeria persisted in mice after 900 R lethal irradiation, provided normal syngeneic bone marrow cells were also administered, thus indicating the persistance of a cell population in the immune irradiated mice, resistant to effects of radiation. The radio resistant nature of this immune cell population was further demonstrated by passive transfer with spleen cells, derived from preimmunized lethally irradiated mice to normal syngeneic mice or to lethally irradiated nonimmunized hosts reconstituted with normal bone marrow which then responded to antigenic challenge with DH.Treatment of the immune radio resistant spleen cells in vitro with anti-theta and complement eliminated passive transfers of DH by these cells; however, this effect was less obvious than similar treatment of the immune, nonirradiated, spleen cells.     

How parasite interaction strategies alter virulence evolution in multi‐parasite communities

The majority of organisms host multiple parasite species, each of which can interact with hosts and competitors through a diverse range of direct and indirect mechanisms. These within‐host interactions can directly alter the mortality rate of coinfected hosts and alter the evolution of virulence (parasite‐induced host mortality). Yet we still know little about how within‐host interactions affect the evolution of parasite virulence in multi‐parasite communities. Here, we modeled the virulence evolution of two coinfecting parasites in a host population in which parasites interacted through cross immunity, immune suppression, immunopathology, or spite. We show (1) that these within‐host interactions have different effects on virulence evolution when all parasites interact with each other in the same way versus when coinfecting parasites have unique interaction strategies, (2) that these interactions cause the evolution of lower virulence in some hosts, and higher virulence in other hosts, depending on the hosts infection status, and (3) that for cross immunity and spite, whether parasites increase or decrease the evolutionarily stable virulence in coinfected hosts depended on interaction strength. These results improve our understanding of virulence evolution in complex parasite communities, and show that virulence evolution must be understood at the community scale.     

MHC-I Affects Infection Intensity but Not Infection Status with a Frequent Avian Malaria Parasite in Blue Tits

Host resistance against parasites depends on three aspects: the ability to prevent, control and clear infections. In vertebrates the immune system consists of innate and adaptive immunity. Innate immunity is particularly important for preventing infection and eradicating established infections at an early stage while adaptive immunity is slow, but powerful, and essential for controlling infection intensities and eventually clearing infections. Major Histocompatibility Complex (MHC) molecules are central in adaptive immunity, and studies on parasite resistance and MHC in wild animals have found effects on both infection intensity (parasite load) and infection status (infected or not). It seems MHC can affect both the ability to control infection intensities and the ability to clear infections. However, these two aspects have rarely been considered simultaneously, and their relative importance in natural populations is therefore unclear. Here we investigate if MHC class I genotype affects infection intensity and infection status with a frequent avian malaria infection Haemoproteus majoris in a natural population of blue tits Cyanistes caeruleus. We found a significant negative association between a single MHC allele and infection intensity but no association with infection status. Blue tits that carry a specific MHC allele seem able to suppress H. majoris infection intensity, while we have no evidence that this allele also has an effect on clearance of the H. majoris infection, a result that is in contrast with some previous studies of MHC and avian malaria. A likely explanation could be that the clearance rate of avian malaria parasites differs between avian malaria lineages and/or between avian hosts.     

Enhanced transmission of drug-resistant parasites to mosquitoes following drug treatment in rodent malaria

The evolution of drug resistant Plasmodium parasites is a major challenge to effective malaria control. In theory, competitive interactions between sensitive parasites and resistant parasites within infections are a major determinant of the rate at which parasite evolution undermines drug efficacy. Competitive suppression of resistant parasites in untreated hosts slows the spread of resistance; competitive release following treatment enhances it. Here we report that for the murine model Plasmodium chabaudi, co-infection with drug-sensitive parasites can prevent the transmission of initially rare resistant parasites to mosquitoes. Removal of drug-sensitive parasites following chemotherapy enabled resistant parasites to transmit to mosquitoes as successfully as sensitive parasites in the absence of treatment. We also show that the genetic composition of gametocyte populations in host venous blood accurately reflects the genetic composition of gametocytes taken up by mosquitoes. Our data demonstrate that, at least for this mouse model, aggressive chemotherapy leads to very effective transmission of highly resistant parasites that are present in an infection, the very parasites which undermine the long term efficacy of front-line drugs.     

Individual patterns of habitat and nest-site use by hosts promote transgenerational transmission of avian brood parasitism status

Brood parasitic birds impose variable fitness costs upon their hosts by causing the partial or complete loss of the hosts' own brood. Growing evidence from multiple avian host-parasite taxa indicates that exposure of individual hosts to parasitism is not necessarily random and varies with habitat use, nest-site selection, age or other phenotypic attributes. For instance, nonrandom patterns of brood parasitism had similar evolutionary consequences to those of limited horizontal transmission of parasites and pathogens across space and time and altered the dynamics of both population productivity and co-evolutionary interactions of hosts and parasites. We report that brood parasitism status of hosts of brown-headed cowbirds Molothrus ater is also transmitted across generations in individually colour-banded female prothonotary warblers Protonotaria citrea. Warbler daughters were more likely to share their mothers' parasitism status when showing natal philopatry at the scale of habitat patch. Females never bred in their natal nestboxes but daughters of parasitized mothers had shorter natal dispersal distances than daughters of nonparasitized mothers. Daughters of parasitized mothers were more likely to use nestboxes that had been parasitized by cowbirds in both the previous and current years. Although difficult to document in avian systems, different propensities of vertical transmission of parasitism status within host lineages will have critical implications both for the evolution of parasite tolerance in hosts and, if found to be mediated by lineages of parasites themselves, for the difference in virulence between such extremes as the nestmate-tolerant and nestmate-eliminator strategies of different avian brood parasite species.     

Coevolution of recovery ability and virulence.

Most models for coevolution of hosts and parasites are based on the assumption that resistance of hosts to parasites is an all-or-nothing effect. In many cases, for example where parasites require an appropriate receptor on host cells, this is a reasonable assumption. However, in many other cases, for example where hosts mount an immune response, this picture may be too simple. An immune system is expensive to maintain, which poses a question as to how much of its resources a host should allocate to resist parasites: if the risk of infection is low, natural selection may favour hosts with less effective immune systems. As optimal allocation to defence will depend on the force of infection, and the force of infection, in turn, depends on the level of defence in the rest of the host population, a game-theoretic approach is necessary. Here I analyse a simple model for the evolution of the ability to recover from infection. If parasites are not allowed to coevolve, the outcome is a single evolutionarily stable strategy (ESS). If the parasites coevolve, multiple evolutionary outcomes are possible, one in which the parasites are relatively avirulent and common and the hosts invest little in recovery ability, and another (the escalated arms race) where parasites are rare but virulent and the hosts invest heavily in defence.     

Obligate Brood Parasites Show More Functionally Effective Innate Immune Responses: An Eco-immunological Hypothesis

Immune adaptations of obligate brood parasites attracted interest when three New World cowbird species (Passeriformes, Icteridae, genus Molothrus) proved unusually resistant to West Nile virus. We have used cowbirds as models to investigate the eco-immunological hypothesis that species in parasite-rich environments characteristically have enhanced immunity as a life history adaptation. As part of an ongoing program to understand the cowbird immune system, in this study we measured degranulation and oxidative burst, two fundamental responses of the innate immune system. Innate immunity provides non-specific, fast-acting defenses against a variety of invading pathogens, and we hypothesized that innate immunity experiences particularly strong selection in cowbirds, because their life history strategy exposes them to diverse novel and unpredictable parasites. We compared the relative effectiveness of degranulation and oxidative burst responses in two cowbird species and one related, non-parasitic species. Both innate immune defenses were significantly more functionally efficient in the two parasitic cowbird species than in the non-parasitic red-winged blackbird (Icteridae, Agelaius phoeniceus). Additionally, both immune defenses were more functionally efficient in the brown-headed cowbird (M. ater), an extreme host-generalist brood parasite, than in the bronzed cowbird (M. aeneus), a moderate host-specialist with lower exposure to other species and their parasites. Thus the relative effectiveness of these two innate immune responses corresponds to the diversity of parasites in the niche of each species and to their relative resistance to WNV. This study is the first use of these two specialized assays in a comparative immunology study of wild avian species.     

Antagonistic coevolution between a bacterium and a bacteriophage

Antagonistic coevolution between hosts and parasites is believed to play a pivotal role in host and parasite population dynamics, the evolutionary maintenance of sex and the evolution of parasite virulence. Furthermore, antagonistic coevolution is believed to be responsible for rapid differentiation of both hosts and parasites between geographically structured populations. Yet empirical evidence for host-parasite antagonistic coevolution, and its impact on between-population genetic divergence, is limited. Here we demonstrate a long-term arms race between the infectivity of a viral parasite (bacteriophage; phage) and the resistance of its bacterial host. Coevolution was largely driven by directional selection, with hosts becoming resistant to a wider range of parasite genotypes and parasites infective to a wider range of host genotypes. Coevolution followed divergent trajectories between replicate communities despite establishment with isogenic bacteria and phage, and resulted in bacteria adapted to their own, compared with other, phage populations.     

Determination of the processes driving the acquisition of immunity to malaria using a mathematical transmission model

Acquisition of partially protective immunity is a dominant feature of the epidemiology of malaria among exposed individuals. The processes that determine the acquisition of immunity to clinical disease and to asymptomatic carriage of malaria parasites are poorly understood, in part because of a lack of validated immunological markers of protection. Using mathematical models, we seek to better understand the processes that determine observed epidemiological patterns. We have developed an age-structured mathematical model of malaria transmission in which acquired immunity can act in three ways (“immunity functions”): reducing the probability of clinical disease, speeding the clearance of parasites, and increasing tolerance to subpatent infections. Each immunity function was allowed to vary in efficacy depending on both age and malaria transmission intensity. The results were compared to age patterns of parasite prevalence and clinical disease in endemic settings in northeastern Tanzania and The Gambia. Two types of immune function were required to reproduce the epidemiological age-prevalence curves seen in the empirical data; a form of clinical immunity that reduces susceptibility to clinical disease and develops with age and exposure (with half-life of the order of five years or more) and a form of anti-parasite immunity which results in more rapid clearance of parasitaemia, is acquired later in life and is longer lasting (half-life of >20 y). The development of anti-parasite immunity better reproduced observed epidemiological patterns if it was dominated by age-dependent physiological processes rather than by the magnitude of exposure (provided some exposure occurs). Tolerance to subpatent infections was not required to explain the empirical data. The model comprising immunity to clinical disease which develops early in life and is exposure-dependent, and anti-parasite immunity which develops later in life and is not dependent on the magnitude of exposure, appears to best reproduce the pattern of parasite prevalence and clinical disease by age in different malaria transmission settings. Understanding the effector mechanisms underlying these two immune functions will assist in the design of transmission-reducing interventions against malaria.     

The joint evolution of the Myxozoa and their alternate hosts: A cnidarian recipe for success and vast biodiversity

The relationships between parasites and their hosts are intimate, dynamic and complex; the evolution of one is inevitably linked to the other. Despite multiple origins of parasitism in the Cnidaria, only parasites belonging to the Myxozoa are characterized by a complex life cycle, alternating between fish and invertebrate hosts, as well as by high species diversity. This inspired us to examine the history of adaptive radiations in myxozoans and their hosts by determining the degree of congruence between their phylogenies and by timing the emergence of myxozoan lineages in relation to their hosts. Recent genomic analyses suggested a common origin of Polypodium hydriforme, a cnidarian parasite of acipenseriform fishes, and the Myxozoa, and proposed fish as original hosts for both sister lineages. We demonstrate that the Myxozoa emerged long before fish populated Earth and that phylogenetic congruence with their invertebrate hosts is evident down to the most basal branches of the tree, indicating bryozoans and annelids as original hosts and challenging previous evolutionary hypotheses. We provide evidence that, following invertebrate invasion, fish hosts were acquired multiple times, leading to parallel cospeciation patterns in all major phylogenetic lineages. We identify the acquisition of vertebrate hosts that facilitate alternative transmission and dispersion strategies as reason for the distinct success of the Myxozoa, and identify massive host specification‐linked parasite diversification events. The results of this study transform our understanding of the origins and evolution of parasitism in the most basal metazoan parasites known.     

Controlled Chaos of Polymorphic Mucins in a Metazoan Parasite (Schistosoma mansoni) Interacting with Its Invertebrate Host (Biomphalaria glabrata)

Invertebrates were long thought to possess only a simple, effective and hence non-adaptive defence system against microbial and parasitic attacks. However, recent studies have shown that invertebrate immunity also relies on immune receptors that diversify (e.g. in echinoderms, insects and mollusks (Biomphalaria glabrata)). Apparently, individual or population-based polymorphism-generating mechanisms exists that permit the survival of invertebrate species exposed to parasites. Consequently, the generally accepted arms race hypothesis predicts that molecular diversity and polymorphism also exist in parasites of invertebrates. We investigated the diversity and polymorphism of parasite molecules (Schistosoma mansoni Polymorphic Mucins, SmPoMucs) that are key factors for the compatibility of schistosomes interacting with their host, the mollusc Biomphalaria glabrata. We have elucidated the complex cascade of mechanisms acting both at the genomic level and during expression that confer polymorphism to SmPoMuc. We show that SmPoMuc is coded by a multi-gene family whose members frequently recombine. We show that these genes are transcribed in an individual-specific manner, and that for each gene, multiple splice variants exist. Finally, we reveal the impact of this polymorphism on the SmPoMuc glycosylation status. Our data support the view that S. mansoni has evolved a complex hierarchical system that efficiently generates a high degree of polymorphism—a “controlled chaos”—based on a relatively low number of genes. This contrasts with protozoan parasites that generate antigenic variation from large sets of genes such as Trypanosoma cruzi, Trypanosoma brucei and Plasmodium falciparum. Our data support the view that the interaction between parasites and their invertebrate hosts are far more complex than previously thought. While most studies in this matter have focused on invertebrate host diversification, we clearly show that diversifying mechanisms also exist on the parasite side of the interaction. Our findings shed new light on how and why invertebrate immunity develops.