Two distinct host-parasite associations mediate seasonal ecosystem linkages.

Nematomorph parasites manipulate terrestrial arthropods to enter streams where the parasites reproduce. These manipulated arthropods become a substantial prey subsidy for stream salmonids, causing cross-ecosystem energy flow. Diverse nematomorph-arthropod associations underlie the energy flow, but it remains unknown whether they can mediate the magnitude and temporal attributes of the energy flow. Here, we investigated whether distinct phylogenetic groups of nematomorphs manipulate different arthropod hosts and mediate seasonal prey subsidy for stream salmonids. The results of our molecular-based diagnoses show that Gordionus and Gordius nematomorphs infected ground beetle and orthopteran hosts, respectively. The presumable ground beetle hosts subsidized salmonid individuals in spring, whereas the presumable orthopteran hosts did so in autumn. Maintaining the two distinct nematomorph-arthropod associations thus resulted in the parasite-mediated prey subsidy in both spring and autumn in the study streams. Manipulative parasites are common, and often associated with a range of host lineages, suggesting that similar effects of phylogenetic variation in host-parasite associations on energy flow might be widespread in nature.

Does the body size, sex, and reproductive modes of leaf litter anurans affect the diversity of parasites?

We describe the composition of endoparasites associated with leaf litter anurans from an Atlantic Forest area, in southeastern Brazil. We tested if body size, sex, and reproductive modes of anuran hosts influence endoparasite abundance and richness. We sampled 583 individuals from 11 anuran species and recorded 1,600 helminths from 14 taxa. The helminths that infected the greatest number of anuran host species were the nematodes Cosmocerca parva (8 spp.), Physaloptera sp. (8 spp.), and Cosmocerca brasiliense (7 spp.), and the most abundant helminth species were Physaloptera sp. (14.6%), Cosmocerca brasiliense (13.7%) and Cosmocerca parva (12.6%). Both helminth abundance and richness were positively affected by anuran body size and dependence on water for reproduction. Larger hosts can contain a higher abundance of parasites because they may provide more physical space than smaller ones, or it can simply be a function of age. Besides, parasite species richness can be highly correlated with the amount of time a host spends in association with aquatic habitats, a conservative aspect of both parasite and host natural history. Within host species, there was a positive and significant influence of body size on helminth abundance. Haddadus binotatus females had greater helminth abundance than males, probably due to sex-related differences in behavior and/or in physiology. Our data suggest that reproductive modes could also influence helminth infection parameters in other anuran communities and should be considered in detail in future analyses.

Using our understanding of interactions between helminth metabolism and host immunity to target worm survival.

Helminths can adapt to environmental conditions in the host, utilising anaerobic processes like fermentation and malate dismutation to produce energy from carbohydrate. Although targeting carbohydrate metabolism is an established therapeutic strategy to combat helminth infection, questions remain over the metabolic pathways they employ as adults to survive and evade host immunity. Helminths also use amino acid, polyunsaturated fatty acid (PUFA), and cholesterol metabolism, a possible strategy favouring the production of immunomodulatory compounds that may influence survival in the host. Here, we discuss the significance of these differing metabolic pathways and whether targeting of helminth metabolic pathways may allow for the development of novel anthelmintics.

Worming into infancy: Exploring helminth-microbiome interactions in early life.

There is rapidly growing awareness of microbiome assembly and function in early-life gut health. Although many factors, such as antibiotic use and highly processed diets, impinge on this process, most research has focused on people residing in high-income countries. However, much of the world's population lives in low- and middle-income countries (LMICs), where, in addition to erratic antibiotic use and suboptimal diets, these groups experience unique challenges. Indeed, many children in LMICs are infected with intestinal helminths. Although helminth infections are strongly associated with diverse developmental co-morbidities and induce profound microbiome changes, few studies have directly examined whether intersecting pathways between these components of the holobiont shape health outcomes in early life. Here, we summarize microbial colonization within the first years of human life, how helminth-mediated changes to the gut microbiome may affect postnatal growth, and why more research on this relationship may improve health across the lifespan.

Glyphosate-environmental variables interaction: How does it affect the parasite Chordodes nobilii?

The worldwide used herbicide Glyphosate can interact with environmental variables, but there is limited information on the influence of environmental stressors on its toxicity. Environmental changes could modify glyphosate effects on non-target organisms, including parasites such as gordiids. The freshwater microscopic larvae of the gordiid Chordodes nobilii are sensitive to several pollutants and environmental variables, but their combined effect has not been evaluated yet. The aim of this study was to evaluate the impact of temperature, pH and exposure time on the toxicity of Glyphosate to C. nobilii larvae. A protocol was followed to evaluate the infectivity of larvae treated with factorial combinations of concentration (0 and 0.067 mg/L), exposure time (24 and 48 h), temperature (18, 23 and 28 °C), and pH (7, 8 and 9). The reference values were 23 °C, pH 8 and 48 h. The interaction effect on the infectivity of gordiid larvae was assessed post-exposure using Aedes aegyptii larvae as host. Results were evaluated using GLMM, which does not require data transformation. The modeling results revealed three highly significant triple interactions. Glyphosate toxicity varied depending on the combination of variables, with a decrease being observed after 24 h-exposure at pH 7 and 23 °C. Glyphosate and 28 °C combination led to slightly reduced infectivity compared to temperature alone. This study is the first to report the combined effects of glyphosate, temperature, pH and time on a freshwater animal. It demonstrates that a specific combination of factors determines the effect of glyphosate on a non-target organism. The potential use of C. nobilli as a bioindicator is discussed. In the context of global warming and considering that the behavioral manipulation of terrestrial hosts by gordiids can shape community structure and the energy flow through food webs, our results raise concerns about possible negative effects of climate change on host-parasite dynamics.

Searching for common patterns in parasite ecology: species and host contributions to beta-diversity in helminths of South African ungulates and fleas of South American rodents.

We searched for common patterns in parasite ecology by investigating species and host contributions to the beta-diversity of infracommunities (=assemblages of parasites harboured by a host individual) in helminths of three species of South African ungulates and fleas of 11 species of South American rodents, assuming that a comparison of patterns in distinctly different parasites and hosts would allow us to judge the generality or, at least, commonness of these patterns. We used data on species' composition and numbers of parasites and asked whether (i) parasite species' attributes (life cycle, transmission mode, and host specificity in helminths; possession of sclerotized combs, microhabitat preference, and host specificity in fleas) or their population structure (mean abundance and/or prevalence) and (ii) host characteristics (sex and age) affect parasite and host species' contributions to parasite beta-diversity (SCBD and HCBD, respectively). We found that parasite species' morphological and ecological attributes were mostly not associated with their SCBD. In contrast, parasite SCBD, in both ungulates and rodents, significantly increased with either parasite mean abundance or prevalence or both. The effect of host characteristics on HCBD was detected in a few hosts only. In general, parasite infracommunities' beta-diversity appeared to be driven by variation in parasite species rather than the uniqueness of the assemblages harboured by individual hosts. We conclude that some ecological patterns (such as the relationships between SCBD and parasite abundance/prevalence) appear to be common and do not differ between different host-parasite associations in different geographic regions, whereas other patterns (the relationships between SCBD and parasite species' attributes) are contingent and depend on parasite and host identities.

Regulation of host metabolic health by parasitic helminths.

Obesity is a worldwide pandemic and major risk factor for the development of metabolic syndrome (MetS) and type 2 diabetes (T2D). T2D requires lifelong medical support to limit complications and is defined by impaired glucose tolerance, insulin resistance (IR), and chronic low-level systemic inflammation initiating from adipose tissue. The current preventative strategies include a healthy diet, controlled physical activity, and medication targeting hyperglycemia, with underexplored underlying inflammation. Studies suggest a protective role for helminth infection in the prevention of T2D. The mechanisms may involve induction of modified type 2 and regulatory immune responses that suppress inflammation and promote insulin sensitivity. In this review, the roles of helminths in counteracting MetS, and prospects for harnessing these protective mechanisms for the development of novel anti-diabetes drugs are discussed.

Effects of food supplementation and helminth removal on space use and spatial overlap in wild rodent populations.

Animal space use and spatial overlap can have important consequences for population-level processes such as social interactions and pathogen transmission. Identifying how environmental variability and inter-individual variation affect spatial patterns and in turn influence interactions in animal populations is a priority for the study of animal behaviour and disease ecology. Environmental food availability and macroparasite infection are common drivers of variation, but there are few experimental studies investigating how they affect spatial patterns of wildlife. Bank voles (Clethrionomys glareolus) are a tractable study system to investigate spatial patterns of wildlife and are amenable to experimental manipulations. We conducted a replicated, factorial field experiment in which we provided supplementary food and removed helminths in vole populations in natural forest habitat and monitored vole space use and spatial overlap using capture-mark-recapture methods. Using network analysis, we quantified vole space use and spatial overlap. We compared the effects of food supplementation and helminth removal and investigated the impacts of season, sex and reproductive status on space use and spatial overlap. We found that food supplementation decreased vole space use while helminth removal increased space use. Space use also varied by sex, reproductive status and season. Spatial overlap was similar between treatments despite up to threefold differences in population size. By quantifying the spatial effects of food availability and macroparasite infection on wildlife populations, we demonstrate the potential for space use and population density to trade-off and maintain consistent spatial overlap in wildlife populations. This has important implications for spatial processes in wildlife including pathogen transmission.

Biomechanics of parasite migration within hosts.

The dissemination of protozoan and metazoan parasites through host tissues is hindered by cellular barriers, dense extracellular matrices, and fluid forces in the bloodstream. To overcome these diverse biophysical impediments, parasites implement versatile migratory strategies. Parasite-exerted mechanical forces and upregulation of the host's cellular contractile machinery are the motors for these strategies, and these are comparably better characterized for protozoa than for helminths. Using the examples of the protozoans, Toxoplasma gondii and Plasmodium, and the metazoan, Schistosoma mansoni, we highlight how quantitative tools such as traction force and reflection interference contrast microscopies have improved our understanding of how parasites alter host mechanobiology to promote their migration.

The impact of helminth-induced immunity on infection with bacteria or viruses.

Different human and animal pathogens trigger distinct immune responses in their hosts. The infection of bacteria or viruses can trigger type I pro-inflammatory immune responses (e.g., IFN-γ, TNF-α, TH1 cells), whereas infection by helminths typically elicits a type II host resistance and tolerizing immune response (e.g., IL-4, IL-5, IL-13, TH2 cells). In some respects, the type I and II immune responses induced by these different classes of pathogens are antagonistic. Indeed, recent studies indicate that infection by helminths differentially shapes the response and outcome of subsequent infection by viruses and bacteria. In this review, we summarize the current knowledge on how helminth infections influence concurrent or subsequent microbial infections and also discuss the implications for helminth-mediated immunity on the outcome of SARS-CoV-2 disease.

Soil-transmitted helminths: A critical review of the impact of co-infections and implications for control and elimination.

Researchers have raised the possibility that soil-transmitted helminth (STH) infections might modify the host's immune response against other systemic infections. STH infections can alter the immune response towards type 2 immunity that could then affect the likelihood and severity of other illnesses. However, the importance of co-infections is not completely understood, and the impact and direction of their effects vary considerably by infection. This review synthesizes evidence regarding the relevance of STH co-infections, the potential mechanisms that explain their effects, and how they might affect control and elimination efforts. According to the literature reviewed, there are both positive and negative effects associated with STH infections on other diseases such as malaria, human immunodeficiency virus (HIV), tuberculosis, gestational anemia, pediatric anemia, neglected tropical diseases (NTDs) like lymphatic filariasis, onchocerciasis, schistosomiasis, and trachoma, as well as Coronavirus Disease 2019 (COVID-19) and human papillomavirus (HPV). Studies typically describe how STHs can affect the immune system and promote increased susceptibility, survival, and persistence of the infection in the host by causing a TH2-dominated immune response. The co-infection of STH with other diseases has important implications for the development of treatment and control strategies. Eliminating parasites from a human host can be more challenging because the TH2-dominated immune response induced by STH infection can suppress the TH1 immune response required to control other infections, resulting in an increased pathogen load and more severe disease. Preventive chemotherapy and treatment are currently the most common approaches used for the control of STH infections, but these approaches alone may not be adequate to achieve elimination goals. Based on the conclusions drawn from this review, integrated approaches that combine drug administration with water, sanitation and hygiene (WASH) interventions, hygiene education, community engagement, and vaccines are most likely to succeed in interrupting the transmission of STH co-infections. Gaining a better understanding of the behavior and relevance of STH co-infections in the context of elimination efforts is an important intermediate step toward reducing the associated burden of disease.

Helminth-host-environment interactions: Looking down from the tip of the iceberg.

In 1978, the theory behind helminth parasites having the potential to regulate the abundance of their host populations was formalized based on the understanding that those helminth macroparasites that reduce survival or fecundity of the infected host population would be among the forces limiting unregulated host population growth. Now, 45 years later, a phenomenal breadth of factors that directly or indirectly affect the host-helminth interaction has emerged. Based largely on publications from the past 5 years, this review explores the host-helminth interaction from three lenses: the perspective of the helminth, the host, and the environment. What biotic and abiotic as well as social and intrinsic host factors affect helminths? What are the negative, and positive, implications for host populations and communities? What are the larger-scale implications of the host-helminth dynamic on the environment, and what evidence do we have that human-induced environmental change will modify this dynamic? The overwhelming message is that context is everything. Our understanding of second-, third-, and fourth-level interactions is extremely limited, and we are far from drawing generalizations about the myriad of microbe-helminth-host interactions.Yet the intricate, co-evolved balance and complexity of these interactions may provide a level of resilience in the face of global environmental change. Hopefully, this albeit limited compilation of recent research will spark new interdisciplinary studies, and application of the One Health approach to all helminth systems will generate new and testable conceptual frameworks that encompass our understanding of the host-helminth-environment triad.

Top-down and bottom-up effects and relationships with local environmental factors in the water frog-helminth systems in Latvia.

Semi-aquatic European water frogs (Pelophylax spp.) harbour rich helminth infra-communities, whose effects on host population size in nature are poorly known. To study top-down and bottom-up effects, we conducted calling male water frog counts and parasitological investigations of helminths in waterbodies from different regions of Latvia, supplemented by descriptions of waterbody features and surrounding land use data. We performed a series of generalized linear model and zero-inflated negative binomial regressions to determine the best predictors for frog relative population size and helminth infra-communities. The highest-ranked (by Akaike information criterion correction, AICc) model explaining the water frog population size contained only waterbody variables, followed by the model containing only land use within 500 m, while the model containing helminth predictors had the lowest rank. Regarding helminth infection responses, the relative importance of the water frog population size varied from being non-significant (abundances of larval plagiorchiids and nematodes) to having a similar weight to waterbody features (abundances of larval diplostomids). In abundances of adult plagiorchiids and nematodes the best predictor was the host specimen size. Environmental factors had both direct effects from the habitat features (e.g., waterbody characteristics on frogs and diplostomids) and indirect effects through parasite-host interactions (impacts of anthropogenic habitats on frogs and helminths). Our study suggests the presence of synergy between top-down and bottom-up effects in the water frog-helminth system that creates a mutual dependence of frog and helminth population sizes and helps to balance helminth infections at a level that does not cause over-exploitation of the host resource.

Battle of the sexes: analysis of sex bias in host use and reporting practices in parasitological experiments.

Experimental approaches are among the most powerful tools available to biologists, yet in many disciplines their results have been questioned due to an underrepresentation of female animal subjects. In parasitology, experiments are crucial to understand host-parasite interactions, parasite development, host immune responses, as well as the efficacy of different control methods. However, distinguishing between species-wide and sex-specific effects requires the balanced inclusion of both male and female hosts in experiments and the reporting of results for each sex separately. Here, using data from over 3600 parasitological experiments on helminth-mammal interactions published in the past four decades, we investigate patterns of male versus female subject use and result reporting practices in experimental parasitology. We uncover multiple effects of the parasite taxon used, the type of host used (rats and mice for which subject selection is fully under researcher control versus farm animals), the research subject area and the year of publication, on whether host sex is even specified, whether one or both host sexes have been used (and if only one then which one), and whether the results are presented separately for each host sex. We discuss possible reasons for biases and unjustifiable selection of host subjects, and for poor experimental design and reporting of results. Finally, we make some simple recommendations for increased rigour in experimental design and to reset experimental approaches as a cornerstone of parasitological research.

Modeling the contribution of antibody attack rates to single and dual helminth infections in a natural system.

Within-host models of infection can provide important insights into the processes that affect parasite spread and persistence in host populations. However, modeling can be limited by the availability of empirical data, a problem commonly encountered in natural systems. Here, we used six years of immune-infection observations of two gastrointestinal helminths (Trichostrongylus retortaeformis and Graphidium strigosum) from a population of European rabbits (Oryctolagus cuniculus) to develop an age-dependent, mathematical model that explicitly included species-specific and cross-reacting antibody (IgA and IgG) responses to each helminth in hosts with single or dual infections. Different models of single infection were formally compared to test alternative mechanisms of parasite regulation. The two models that best described single infections of each helminth species were then coupled through antibody cross-immunity to examine how the presence of one species could alter the host immune response to, and the within-host dynamics of, the other species. For both single infections, model selection suggested that either IgA or IgG responses could equally explain the observed parasite intensities by host age. However, the antibody attack rate and affinity level changed between the two helminths, it was stronger against T. retortaeformis than against G. strigosum and caused contrasting age-intensity profiles. When the two helminths coinfect the same host, we found variation of the species-specific antibody response to both species together with an asymmetric cross-immune response driven by IgG. Lower attack rate and affinity of antibodies in dual than single infections contributed to the significant increase of both helminth intensities. By combining mathematical modeling with immuno-infection data, our work provides a tractable model framework for disentangling some of the complexities generated by host-parasite and parasite-parasite interactions in natural systems.

New technologies to study helminth development and host-parasite interactions.

How parasites develop and survive, and how they stimulate or modulate host immune responses are important in understanding disease pathology and for the design of new control strategies. Microarray analysis and bulk RNA sequencing have provided a wealth of data on gene expression as parasites develop through different life-cycle stages and on host cell responses to infection. These techniques have enabled gene expression in the whole organism or host tissue to be detailed, but do not take account of the heterogeneity between cells of different types or developmental stages, nor the spatial organisation of these cells. Single-cell RNA-seq (scRNA-seq) adds a new dimension to studying parasite biology and host immunity by enabling gene profiling at the individual cell level. Here we review the application of scRNA-seq to establish gene expression cell atlases for multicellular helminths and to explore the expansion and molecular profile of individual host cell types involved in parasite immunity and tissue repair. Studying host-parasite interactions in vivo is challenging and we conclude this review by briefly discussing the applications of organoids (stem-cell derived mini-tissues) to examine host-parasite interactions at the local level, and as a potential system to study parasite development in vitro. Organoid technology and its applications have developed rapidly, and the elegant studies performed to date support the use of organoids as an alternative in vitro system for research on helminth parasites.

The enemy of my enemy is my friend: Immune-mediated facilitation contributes to fitness of co-infecting helminths.

The conceptual understanding of immune-mediated interactions between parasites is rooted in the theory of community ecology. One of the limitations of this approach is that most of the theory and empirical evidence has focused on resource or immune-mediated competition between parasites and yet there is ample evidence of positive interactions that could be generated by immune-mediated facilitation. We developed an immuno-epidemiological model and applied it to long-term data of two gastrointestinal helminths in two rabbit populations to investigate, through model testing, how immune-mediated mechanisms of parasite regulation could explain the higher intensities of both helminths in rabbits with dual than single infections. The model framework was selected and calibrated on rabbit population A and then validated on the nearby rabbit population B to confirm the consistency of the findings and the generality of the mechanisms. Simulations suggested that the higher intensities in rabbits with dual infections could be explained by a weakened or low species-specific IgA response and an asymmetric IgA cross-reaction. Simulations also indicated that rabbits with dual infections shed more free-living stages that survived for longer in the environment, implying greater transmission than stages from hosts with single infections. Temperature and humidity selectively affected the free-living stages of the two helminths. These patterns were comparable in the two rabbit populations and support the hypothesis that immune-mediated facilitation can contribute to greater parasite fitness and local persistence.

Is the world wormier than it used to be? We'll never know without natural history collections.

Many disease ecologists and conservation biologists believe that the world is wormier than it used to be-that is, that parasites are increasing in abundance through time. This argument is intuitively appealing. Ecologists typically see parasitic infections, through their association with disease, as a negative endpoint, and are accustomed to attributing negative outcomes to human interference in the environment, so it slots neatly into our worldview that habitat destruction, biodiversity loss and climate change should have the collateral consequence of causing outbreaks of parasites. But surprisingly, the hypothesis that parasites are increasing in abundance through time remains entirely untested for the vast majority of wildlife parasite species. Historical data on parasites are nearly impossible to find, which leaves no baseline against which to compare contemporary parasite burdens. If we want to know whether the world is wormier than it used to be, there is only one major research avenue that will lead to an answer: parasitological examination of specimens preserved in natural history collections. Recent advances demonstrate that, for many specimen types, it is possible to extract reliable data on parasite presence and abundance. There are millions of suitable specimens that exist in collections around the world. When paired with contemporaneous environmental data, these parasitological data could even point to potential drivers of change in parasite abundance, including climate, pollution or host density change. We explain how to use preserved specimens to address pressing questions in parasite ecology, give a few key examples of how collections-based parasite ecology can resolve these questions, identify some pitfalls and workarounds, and suggest promising areas for research. Natural history specimens are 'parasite time capsules' that give ecologists the opportunity to test whether infectious disease is on the rise and to identify what forces might be driving these changes over time. This approach will facilitate major advances in a new sub-discipline: the historical ecology of parasitism.

Sex-the most underappreciated variable in research: insights from helminth-infected hosts.

The sex of a host affects the intensity, prevalence, and severity of helminth infection. In many cases, one sex has been found to be more susceptible than the other, with the prevalence and intensity of helminth infections being generally higher among male than female hosts; however, many exceptions exist. This observed sex bias in parasitism results primarily from ecological, behavioural, and physiological differences between males and females. Complex interactions between these influences modulate the risk of infection. Indeed, an interplay among sex hormones, sex chromosomes, the microbiome and the immune system significantly contributes to the generation of sex bias among helminth-infected hosts. However, sex hormones not only can modulate the course of infection but also can be exploited by the parasites, and helminths appear to have developed molecules and pathways for this purpose. Furthermore, host sex may influence the efficacy of anti-helminth vaccines; however, although little data exist regarding this sex-dependent efficacy, host sex is known to influence the response to vaccines. Despite its importance, host sex is frequently overlooked in parasitological studies. This review focuses on the key contributors to sex bias in the case of helminth infection. The precise nature of the mechanisms/factors determining these sex-specific differences generally remains largely unknown, and this represents an obstacle in the development of control methods. There is an urgent need to identify any protective elements that could be targeted in future therapies to provide optimal disease management with regard to host sex. Hence, more research is needed into the impact of host sex on immunity and protection.

Making sense of sensory behaviors in vector-borne helminths.

Migrations performed by helminths are impressive and diverse, and accumulating evidence shows that many are controlled by sophisticated sensory programs. The migrations of vector-borne helminths are particularly complex, requiring precise, stage-specific regulation. We review the contrasting states of knowledge on snail-borne schistosomes and mosquito-borne filarial nematodes. Rich observational data exist for the chemosensory behaviors of schistosomes, while the molecular sensory pathways in nematodes are well described. Recent investigations on the molecular mechanisms of sensation in schistosomes and filarial nematodes have revealed some features conserved within their respective phyla, but adaptations correlated with parasitism are pronounced. Technological developments are likely to extend these advances, and we forecast how these technologies may be applied.