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.

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.

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.

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.

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.

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.

Detangling the Crosstalk Between Ascaris, Trichuris and Gut Microbiota: What´s Next?

Helminth infections remain a global public health issue, particularly in low- and middle-income countries, where roundworms from theTrichuris and Ascaris genera are most prevalent. These geohelminths not only impact human health but most importantly also affect animal well-being, in particular the swine industry. Host-helminth parasite interactions are complex and at the same time essential to understand the biology, dynamics and pathophysiology of these infections. Within these interactions, the immunomodulatory capacity of these helminths in the host has been extensively studied. Moreover, in recent years a growing interest on how helminths interact with the intestinal microbiota of the host has sparked, highlighting how this relationship plays an essential role in the establishment of initial infection, survival and persistence of the parasite, as well as in the development of chronic infections. Identifying the changes generated by these helminths on the composition and structure of the host intestinal microbiota constitutes a field of great scientific interest, since this can provide essential and actionable information for designing effective control and therapeutic strategies. Helminths like Trichuris and Ascaris are a focus of special importance due to their high prevalence, higher reinfection rates, resistance to anthelmintic therapy and unavailability of vaccines. Therefore, characterizing interactions between these helminths and the host intestinal microbiota represents an important approach to better understand the nature of this dynamic interface and explore novel therapeutic alternatives based on management of host microbiota. Given the extraordinary impact this may have from a biological, clinical, and epidemiological public health standpoint, this review aims to provide a comprehensive overview of current knowledge and future perspectives examining the parasite-microbiota interplay and its impact on host immunity.

The energetic costs of sub-lethal helminth parasites in mammals: a meta-analysis.

Parasites, by definition, have a negative effect on their host. However, in wild mammal health and conservation research, sub-lethal infections are commonly assumed to have negligible health effects unless parasites are present in overwhelming numbers. Here, we propose a definition for host health in mammals that includes sub-lethal effects of parasites on the host's capacity to adapt to the environment and maintain homeostasis. We synthesized the growing number of studies on helminth parasites in mammals to assess evidence for the relative magnitude of sub-lethal effects of infection across mammal taxa based on this expanded definition. Specifically, we develop and apply a framework for organizing disparate metrics of parasite effects on host health and body condition according to their impact on an animal's energetic condition, defined as the energetic burden of pathogens on host physiological and behavioural functions that relate directly to fitness. Applying this framework within a global meta-analysis of helminth parasites in wild, laboratory and domestic mammal hosts produced 142 peer-reviewed studies documenting 599 infection-condition effects. Analysing these data within a multiple working hypotheses framework allowed us to evaluate the relative weighted contribution of methodological (study design, sampling protocol, parasite quantification methods) and biological (phylogenetic relationships and host/parasite life history) moderators to variation in the magnitude of health effects. We found consistently strong negative effects of infection on host energetic condition across taxonomic groups, with unusually low heterogeneity in effect sizes when compared with other ecological meta-analyses. Observed effect size was significantly lower within cross-sectional studies (i.e. observational studies that investigated a sub-set of a population at a single point in time), the most prevalent methodology. Furthermore, opportunistic sampling led to a weaker negative effect compared to proactive sampling. In the model of host taxonomic group, the effect of infection on energetic condition in carnivores was not significant. However, when sampling method was included, it explained substantial inter-study variance; proactive sampling showing a strongly significant negative effect while opportunistic sampling detected only a weak, non-significant effect. This may partly underlie previous assumptions that sub-lethal parasites do not have significant effects on host health. We recommend future studies adopt energetic condition as the framework for assessing parasite effects on wildlife health and provide guidelines for the selection of research protocols, health proxies, and relating infection to fitness.

Chemokines and chemokine receptors: Insights from human disease and experimental models of helminthiasis.

Infection with helminth parasites affects more than 1.5 billion people and is concentrated in global areas of extreme poverty, having a significant impact on public health, social life and the economy. Upon entry into the host, helminth parasites often migrate through specific tissues triggering host immunity. The immune response triggered by helminth infections is complex and depends on parasite load, site of infection, acuteness/chronicity of the infection and is species-dependent. In general, susceptibility or resistance to the infection involves the participation of the innate immune response and then the balance between several effector CD4+ T cells subsets, such as Th1, Th2, Th9, Th17, Tfh and Treg, coordinated by immune mediators such as cytokines and chemokines. Chemokines guide the recruitment and activation of leukocytes under inflammatory and homeostatic states. The chemokine system has been associated with several diseases and experimental models with a significant inflammatory component, including infection with helminth parasites. Therefore, this critical review will highlight the main findings concerning chemokine responses elicited by the interaction between helminth parasites and the hosts' immune system, hence contributing to the understanding of the relevance of chemokine synthesis and biology in the immunological response to infection by parasitic helminths.

Relevance of Helminth-Microbiota interplay in the host immune response.

Helminths have been present throughout the evolution of humans, promoting the development and maturation of the host immune system. However, this interaction is not exclusive between these two organisms, as the microbiota is also involved in this human evolutionary process and maintains a balanced relationship inside the host. Consequently, helminths have been forced to interact and co-evolve with the microbiota, shaping microbial communities and allowing the development of reciprocal mechanisms that favour their establishment. This helminth-microbiota association, in turn, induced the activation of different host immunoregulatory pathways to preserve health by preventing the development of some diseases associated with inflammatory immune responses. Unfortunately, this collaborative relationship can be quali- and quantitatively altered by the diet and the use of antibacterial and antihelminthic drugs. Understanding the mechanisms involved in this complex three-way communication that has continued for many years is crucial for preserving health and for the generation of new therapeutic alternatives.

Vertebrates as uninfected disseminators of helminth eggs and larvae.

The passive dispersal of non-mobile organisms by vertebrates (zoochory) is a common mechanism used to explain their often widespread distribution. Transport occurs either internally via the vertebrate digestive tract (endozoochory), or externally be adhering to skin, feathers or fur (ectozoochory), and its success is due to both physiological and ecological factors associated with the disseminating 'hosting' animal. Helminth eggs and larvae are generally non-mobile stages that are largely dependent on the movement of another animal, typically a host, for geographical dissemination. Studies on the zoochory of helminths by vertebrates are extensive and particularly long-standing, stretching back to the 19th century, although this literature is often overlooked when considering the biogeography of parasites. This review assesses the potential of helminths to be dispersed passively by zoochory examining evidence from both laboratory and field studies. The physiological dynamics of the vertebrate intestines and skin surface as hostile environments, as well as the characteristics of eggs and larvae which may facilitate successful transport are evaluated. The various mechanisms of helminth endo- and ectozoochory are presented and the likelihood of long-distance dispersal determined. It is concluded that zoochory is a potentially important means of disseminating parasites.