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Helminths use small microRNAs (miRNAs) to manipulate their host's immune responses by 'cross-kingdom' gene regulation, but the exact mechanisms remain unclear. Helminths communicate with their host cells by releasing miRNAs encapsulated in extracellular vesicles (EVs); this EV cargo is selectively packaged for specific microRNAs. Helminth miRNAs share structural similarities with mammalian miRNAs, allowing them to be loaded onto the host's argonaute (AGO) proteins. Helminth miRNAs use a multifaceted strategy, regulating host targets, mimicking host miRNAs to commandeer their biogenesis components, and potentially binding to other host miRNAs. Unravelling the complex mechanism of 'cross-kingdom' gene regulation could transform our approach to combating helminth infections and deepen our insight into host–parasite dynamics. MicroRNAs (miRNAs) are small noncoding RNAs that oversee gene modulation. They are integral to cellular functions and can migrate between species, leading to cross-kingdom gene suppression. Recent breakthroughs in helminth genome studies have sparked curiosity about helminth RNA regulators and their ability to regulate genes across species. Growing data indicate that helminth miRNAs have a significant impact on the host's immune system. Specific miRNAs from helminth parasites can merge with the host's miRNA system, implying that parasites could exploit their host's regulatory machinery and function. This review highlights the role of cross-kingdom helminth-derived miRNAs in the interplay between host and parasite, exploring potential routes for their uptake, processing, and consequences in host interaction. [ABSTRACT FROM AUTHOR]

As an immune-privileged organ, the placenta can tolerate the introduction of antigens without inducing a strong inflammatory response that would lead to abortion. However, for the control of intracellular pathogens, a strong Th1 response characterized by the production of interferon-γ is needed. Thus, invasion of the placenta by intracellular parasites puts the maternal immune system in a quandary: The proinflammatory response needed to eliminate the pathogen can also lead to abortion. Toxoplasma is a highly successful parasite that causes lifelong chronic infections and is a major cause of abortions in humans and livestock. Here, we discuss how Toxoplasma strain type and parasite effectors influence host cell signaling pathways, and we speculate about how this might affect the outcome of gestation.

Recent advances have rapidly facilitated development of new and improved high-resolution, high-throughput volume electron microscopy techniques. Investigating cell structures and interactions at higher resolution and in three dimensions is becoming increasingly important in parasitology. Understanding the different capabilities of light, X-ray, electron, and ion microscopy technologies is essential for choosing the right technique to solve current and challenging parasitology research questions. Volume electron microscopy techniques are underutilised in most fields of parasitology despite recent improvements in accessibility, user-friendliness, and cost. To best understand parasite, host, and vector morphologies, host–parasite interactions, and to develop new drug and vaccine targets, structural data should, ideally, be obtained and visualised in three dimensions (3D). Recently, there has been a significant uptake of available 3D volume microscopy techniques that allow collection of data across centimetre (cm) to Angstrom (Å) scales by utilising light, X-ray, electron, and ion sources. Here, we present and discuss microscopy tools available for the collection of 3D structural data, focussing on electron microscopy-based techniques. We highlight their strengths and limitations, such that parasitologists can identify techniques best suited to answer their research questions. Additionally, we review the importance of volume microscopy to the advancement of the field of parasitology. [ABSTRACT FROM AUTHOR]

Lateral attachment of the flagellum to the cell body is mediated by the flagellum attachment zone (FAZ) and defines kinetoplastid cell morphogenesis and pathogenicity. Two interacting proteins, FLA1 and FLA1BP, dominate the attachment in the FAZ extracellular domain and we propose that FLA1 and FLA1BP structure has evolved as a consequence of surface protein coat architecture. The FLA and FLABP gene family have duplicated and expanded in the African trypanosomes, Trypanosoma brucei and Trypanosoma congolense but not in Trypanosoma vivax. A recent T. vivax vaccine candidate generated antibodies that bound to the cell adjacent to the FAZ and we suggest that accessibility to an invariant antigen results from T. vivax expressing only a single FLA1/FLA1BP pair, which needs to maintain flagellum attachment throughout its life cycle across different surface architectures. A key morphological feature of kinetoplastid parasites is the position and length of flagellum attachment to the cell body. This lateral attachment is mediated by the flagellum attachment zone (FAZ), a large complex cytoskeletal structure, which is essential for parasite morphogenesis and pathogenicity. Despite the complexity of the FAZ only two transmembrane proteins, FLA1 and FLA1BP, are known to interact and connect the flagellum to the cell body. Across the different kinetoplastid species, each only has a single FLA/FLABP pair, except in Trypanosoma brucei and Trypanosoma congolense where there has been an expansion of these genes. Here, we focus on the selection pressure behind the evolution of the FLA/FLABP proteins and the likely impact this will have on host–parasite interactions. [ABSTRACT FROM AUTHOR]

Trypanosomes and leishmanias are widely known parasites of humans. However, they are just two out of several phylogenetic lineages that constitute the family Trypanosomatidae. Although dixeny - the ability to infect two hosts - is a derived trait of vertebrate-infecting parasites, the majority of trypanosomatids are monoxenous. Like their common ancestor, the monoxenous Trypanosomatidae are mostly parasites or commensals of insects. This review covers recent advances in the study of insect trypanosomatids, highlighting their diversity as well as genetic, morphological and biochemical complexity, which, until recently, was underappreciated. The investigation of insect trypanosomatids is providing an important foundation for understanding the origin and evolution of parasitism, including colonization of vertebrates and the appearance of human pathogens.

Malaria-causing Plasmodium parasites undergo multiple phenotypic transitions as they cycle between diverse niches in the mammalian and mosquito hosts. Recent applications of single-cell technologies to Plasmodium have enabled the systematic investigation of the distinct stages across the life cycle. Most single-cell data have focused on the parasite exclusively, but a few studies have started to profile both parasite and host cells to shed light on the heterogeneity of cell states that underpin host–parasite interactions. In this opinion article, we highlight how atlasing initiatives are starting to be used to infer functional interactions between parasite and host and could be a powerful tool in drug discovery and vaccine development. Single-cell transcriptomics has been used to profile the life cycle of multiple Plasmodium species, illuminating developmental trajectories and revealing rare or transient cell states, including the dormant hypnozoite typical of relapsing malaria infections. Host–parasite interactions are essential for progression through the life cycle and could provide new opportunities for antimalarial interventions, but very few single-cell studies have reported on the host side. Parallel single-cell RNA sequencing profiling of host and parasite transcriptional responses has started to shine a light on the interdependency between host and parasite states. Single-cell multi-omics technologies will be essential to map out heterogenous host-parasite interactions across the life cycle and establish how parasite cell fate decisions and overall fitness may be modulated by the host in the context of infection and vaccination. [ABSTRACT FROM AUTHOR]

The human malaria parasite, Plasmodium falciparum, depends on a coordinated regulation of gene expression for development and propagation within the human host. Recent developments suggest that gene regulation in the parasite is largely controlled by epigenetic mechanisms. Here, we discuss recent advancements contributing to our understanding of the mechanisms controlling gene regulation in the parasite, including nucleosome landscape, histone modifications, and nuclear architecture. In addition, various processes involved in regulation of parasite-specific genes and gene families are examined. Finally, we address the use of epigenetic processes as targets for novel antimalarial therapies. Collectively, these topics highlight the unique biology of P. falciparum, and contribute to our understanding of mechanisms regulating gene expression in this deadly parasite.

The blood–brain barrier (BBB) efficiently protects the central nervous system (CNS) from infectious insults. Yet, the apicomplexan parasite Toxoplasma gondii has a remarkable capability to establish latent cerebral infection in humans and other vertebrates. In addition to the proposed mechanisms for access to the brain parenchyma, recent findings highlight a paramount role played by the BBB in restricting parasite passage and minimizing parasite loads in the brain. Consistent with clinically asymptomatic primary infections in humans, mounting evidence indicates that the original colonization of the brain by T. gondii encompasses previously unappreciated, nondisruptive translocation processes that precede the onset of parasite-limiting immune responses. Within the extensive cerebral vascular network, passage of Toxoplasma gondii to the brain parenchyma takes place principally across cortical capillaries. Early passage of T. gondii occurs in the absence of a generalized increase in BBB permeability, perivascular leukocyte cuffs or hemorrhage, albeit with focal BBB permeability elevations. Inflammatory responses and transient dysregulation of the BBB during T. gondii infection facilitate parasite translocation to the brain parenchyma. Mechanisms proposed for T. gondii passage to the brain parenchyma include growth across endothelium (transcellular traversal), direct transmigration (paracellular traversal), and trafficking within parasitized leukocytes (Trojan horse). [ABSTRACT FROM AUTHOR]

Several arthropod taxa live exclusively on vertebrate blood. This food source lacks essential metabolites required for the maintenance of metabolic homeostasis, and as such, these arthropods have formed symbioses with nutrient-supplementing microbes that facilitate their hosts hematophagous feeding ecology. Herein we highlight metabolic contributions of bacterial symbionts that reside within tsetse flies, bed bugs, lice, reduviid bugs, and ticks, with specific emphasis on B vitamin and cofactor biosynthesis. Importantly, these arthropods can transmit pathogens of medical and veterinary relevance and/or cause infestations that induce psychological and dermatological distress. Microbial metabolites, and the biochemical pathways that generate them, can serve as specific targets of novel control mechanisms aimed at disrupting the metabolism of hematophagous arthropods, thus combatting pest invasion and vector-borne pathogen transmission.

Most host-parasite systems exhibit remarkable heterogeneity in the contribution to transmission of certain individuals, locations, host infectious states, or parasite strains. While significant advancements have been made in the understanding of the impact of transmission heterogeneity in epidemic dynamics and parasite persistence and evolution, the knowledge base of the factors contributing to transmission heterogeneity is limited. We argue that research efforts should move beyond considering the impact of single sources of heterogeneity and account for complex couplings between conditions with potential synergistic impacts on parasite transmission. Using theoretical approaches and empirical evidence from various host-parasite systems, we investigate the ecological and epidemiological significance of couplings between heterogeneities and discuss their potential role in transmission dynamics and the impact of control.

The enigmatic haptomonad forms of Leishmania parasites adhere to the sandfly stomodeal valve, damaging this feeding valve and promoting parasite transmission. Yanase et al. recently identified the first parasite proteins involved in adhesion and showed their essentiality in binding to and damaging the valve., Competing Interests: Declaration of interests The author declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The liver is a major entry point and gatekeeper for invasive pathogens. However, high-resolution, spatiotemporal transcriptomic analysis of host–pathogen interactions has remained challenging. Afriat et al. have deconvoluted Plasmodium berghei liver-stage maturation at an unprecedented scale and discovered molecular signatures of heterogeneity during pre-erythrocytic development of malarial parasites. [ABSTRACT FROM AUTHOR]

Parasitic helminths have coexisted with human beings throughout time. Success in eradicating helminths has limited helminth-induced morbidity and mortality but is also correlated with increasing rates of 'western' diseases, including metabolic syndrome and type 2 diabetes. Recent studies in mice describe how type 2 immune cells, traditionally associated with helminth infection, maintain adipose tissue homeostasis and promote adipose tissue beiging, protecting against obesity and metabolic dysfunction. Here, we review these studies and discuss how helminths and helminth-derived molecules may modulate these physiologic pathways to improve metabolic functions in specific tissues, such as adipose and liver, as well as at the whole-organism level.

Entamoeba histolytica was named 'histolytica' (from histo-, 'tissue'; lytic-, 'dissolving') for its ability to destroy host tissues. Direct killing of host cells by the amoebae is likely to be the driving factor that underlies tissue destruction, but the mechanism was unclear. We recently showed that, after attaching to host cells, amoebae bite off and ingest distinct host cell fragments, and that this contributes to cell killing. We review this process, termed 'amoebic trogocytosis' (trogo-, 'nibble'), and how this process interplays with phagocytosis, or whole cell ingestion, in this organism. 'Nibbling' processes have been described in other microbes and in multicellular organisms. The discovery of amoebic trogocytosis in E. histolytica may also shed light on an evolutionarily conserved process for intercellular exchange.

Host organisms show altered phenotypic reactions when parasitised, some of which result from adaptive host manipulation, a phenomenon that has long been debated. Here, we provide an overview and discuss the rationale in distinguishing adaptive versus nonadaptive host behavioural manipulation. We discuss Poulin's criteria of adaptive host behavioural manipulation within the context of Tinbergen's four questions of ethology, while highlighting the importance of both the proximate and evolutionary explanations of such traits. We also provide guidelines for future studies exploring the adaptiveness of host behavioural manipulation. Through this article, we seek to encourage researchers to consider both the proximate and ultimate causes of host behavioural manipulation to infer on the adaptiveness of such traits. Host manipulation has evolved as a primary life history strategy in all major parasitic lineages, and its adaptive significance is well established. Although adaptiveness is an evolutionary concept, the complexity of analysing the evolutionary parameters of a manipulative trait has given rise to an ongoing debate on the criteria of adaptive host manipulation. The importance of both proximate and ultimate mechanisms for inferring the adaptiveness of host manipulation is discussed by reviewing Poulin's criteria considering Tinbergen's four questions of ethology. There are important parallels between Tinbergen's four questions and Poulin's criteria of adaptive host behavioural manipulation, from an ethological perspective. Their one-to-one analysis provides deeper insights into the importance of both proximate and ultimate mechanisms of adaptive host behavioural manipulation. [ABSTRACT FROM AUTHOR]

Ascariasis is a globally spread intestinal nematode infection of humans and a considerable concern in pig husbandry. Ascaris accomplishes a complex body migration from the intestine via the liver and lung before returning to the intestine. Tissue migration and the habitat shared with a complex microbial community pose the question of how the nematode interacts with microbes and host cells from various tissues. This review addresses the current knowledge of the trilateral relationship between Ascaris , its microbial environment, and host cells, and discusses novel approaches targeting these interactions to combat this widespread infection of livestock and man. Recent studies are uncovering a complex interplay between gastrointestinal helminths, gut microbes, and the immune system. Parasitic helminth infections are associated with alterations to the intestinal microbiome and metabolome, and these interactions are thought to influence host susceptibility to infections with nematodes and bacterial pathogens. Technological advances make it possible to probe these interactions in considerable depth, and the large roundworm Ascaris presents a particularly interesting opportunity: Ascaris infections in pigs essentially mirror the human disease, and the pig is being rapidly developed as a human-relevant model for infectious diseases. [ABSTRACT FROM AUTHOR]

Aquatic snails, the intermediate hosts of schistosomes, harbor a diverse unexplored microbiome. We speculate that this may play a critical role in host–parasite interactions. We summarize our current knowledge of snail microbiomes and highlight future research priorities. [ABSTRACT FROM AUTHOR]

Competing Interests: Declaration of interests The author declares no competing interests.

Despite years of research, malaria remains a significant global health burden, with poor diagnostic tests and increasing antimalarial drug resistance challenging diagnosis and treatment. While 'single-omics'-based approaches have been instrumental in gaining insight into the biology and pathogenicity of the Plasmodium parasite and its interaction with the human host, a more comprehensive understanding of malaria pathogenesis can be achieved through 'multi-omics' approaches. Integrative methods, which combine metabolomics, lipidomics, transcriptomics, and genomics datasets, offer a holistic systems biology approach to studying malaria. This review highlights recent advances, future directions, and challenges involved in using integrative metabolomics approaches to interrogate the interactions between Plasmodium and the human host, paving the way towards targeted antimalaria therapeutics and control intervention methods., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Like humans, animals use plants and other materials as medication against parasites. Recent decades have shown that the study of insects can greatly advance our understanding of medication behaviors. The ease of rearing insects under laboratory conditions has enabled controlled experiments to test critical hypotheses, while their spectrum of reproductive strategies and living arrangements - ranging from solitary to eusocial communities - has revealed that medication behaviors can evolve to maximize inclusive fitness through both direct and indirect fitness benefits. Studying insects has also demonstrated in some cases that medication can act through modulation of the host's innate immune system and microbiome. We highlight outstanding questions, focusing on costs and benefits in the context of inclusive host fitness., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The microbiota in the intermediate snail hosts of human schistosomes can significantly affect host biology. For decades, researchers have developed axenic snails to manipulate the symbiotic microbiota. This review summarizes the characteristics of symbiotic microbes in intermediate snail hosts and describes their interactions with snails, affecting snail growth, development, and parasite transmission ability. We focus on advances in axenic and gnotobiotic technologies for studying snail-microbe interactions and exploring the role of microbiota in snail susceptibility to Schistosoma infection. We discuss the challenges related to axenic and gnotobiotic snails, possible solutions to address these challenges, and future research directions to deepen our understanding of snail-microbiota interactions, with the aim to develop microbiota-based strategies for controlling snail populations and reducing their competence in transmitting parasites., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Host specificity encompasses the range and diversity of host species that a parasite is capable of infecting and is considered a crucial measure of a parasite's potential to shift hosts and trigger disease emergence. Yet empirical studies rarely consider that regional observations only reflect a parasite's 'realized' host range under particular conditions: the true 'fundamental' range of host specificity is typically not approached. We provide an overview of challenges and directions in modelling host specificity under variable environmental conditions. Combining tractable modelling frameworks with multiple data sources that account for the strong interplay between a parasite's evolutionary history, transmission mode, and environmental filters that shape host–parasite interactions will improve efforts to quantify emerging disease risk in times of global change. Increasing interest in emerging infectious diseases and parasite spillover coincides with a rise in studies reporting and comparing host specificity for a multihost parasite. Intuitively, higher host specificity means less spillover risk but, to date, a systematic consensus on such a relationship is lacking. Host specificity can vary in space and time due to changing compositions of potential host species and constraints in environmental conditions. Ecoevolutionary dynamics and contemporary conditions synergistically determine 'realized' host specificity across regional scales. Modelling advances to capture spatiotemporal variation in the distributions and biotic interactions of species provide the basis to quantify variation in realized host specificity and progress towards determining how this relates to spillover risk. [ABSTRACT FROM AUTHOR]

Cerebral malaria (CM) is a severe neurological complication caused by Plasmodium falciparum parasites; it is characterized by the sequestration of infected red blood cells within the cerebral microvasculature. New findings, combined with a better understanding of the central nervous system (CNS) barriers, have provided greater insight into the players and events involved in CM, including site-specific T cell responses in the human brain. Here, we review the updated roles of innate and adaptive immune responses in CM, with a focus on the role of the perivascular macrophage-endothelium unit in antigen presentation, in the vascular and perivascular compartments. We suggest that these events may be pivotal in the development of CM., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Protozoan pathogens such as Plasmodium spp., Leishmania spp., Toxoplasma gondii, and Trypanosoma spp. are often associated with high-mortality, acute and chronic diseases of global health concern. For transmission and immune evasion, protozoans have evolved diverse strategies to interact with a range of host tissue environments. These interactions are linked to disease pathology, yet our understanding of the association between parasite colonization and host homeostatic disruption is limited. Recently developed techniques for cellular barcoding have the potential to uncover the biology regulating parasite transmission, dissemination, and the stability of infection. Understanding bottlenecks to infection and the in vivo tissue niches that facilitate chronic infection and spread has the potential to reveal new aspects of parasite biology., Competing Interests: Declaration of interests The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Malaria is an infectious disease, caused by Plasmodium parasites, that remains a major global health problem. Infection begins when salivary gland sporozoites are transmitted through the bite of an infected mosquito. Once within the host, sporozoites navigate through the dermis, into the bloodstream, and eventually invade hepatocytes. While we have an increasingly sophisticated cellular description of this journey, our molecular understanding of the extracellular interactions between the sporozoite and mammalian host that regulate migration and invasion remain comparatively poor. Here, we review the current state of our understanding, highlight the technical limitations that have frustrated progress, and outline how new approaches will help to address this knowledge gap with the ultimate aim of improving malaria treatments. Highlights Cellular descriptions of sporozoite behaviors and host cell interactions are increasingly well defined; however, signals triggering sporozoite behavioral switches remain unknown. The molecular basis of sporozoite–host recognition is poorly characterized due to technical challenges that have limited progress. New genetic and biochemical techniques are addressing some of these challenges and have identified extracellular sporozoite–host interactions involved in host infection. Using these new tools to understand the molecular basis of host–sporozoite interactions will help to improve antimalarial treatments and vaccines. [ABSTRACT FROM AUTHOR]

There is increasing attention on the complex interactions occurring between gastrointestinal parasitic helminths and the microbial flora (microbiota) inhabiting the host gut. However, little is known about the occurrence, structure, and function of microbial populations residing within parasite organs and tissues. In this article, we argue that an in-depth understanding of the interplay between parasites and their microbiomes may significantly enhance current knowledge of parasite biology and physiology, and may lead to the discovery of entirely novel, anthelmintic-independent interventions against parasites and parasitic diseases. Highlights In spite of a plethora of evidence supporting key roles of resident bacteria for parasite fitness and survival (i.e., in filarial nematodes and whipworms), little is known of microbial populations inhabiting organs and tissues of gastrointestinal nematodes of major socioeconomic significance. To date, one of the few well characterised examples is the symbiotic relationship between bacteria of the genus Wolbachia and filarial nematodes. Notably, our understanding of this symbiosis has already been successfully exploited for therapeutic purposes. The relentless advancement in sequencing techniques, together with the rise of novel microbiome editing tools provide unprecedented opportunities to investigate helminth microbiomes and exploit parasite–microbiome relationships for the development of novel strategies of parasite control. [ABSTRACT FROM AUTHOR]

Despite the recent successes of artemisinin-based antimalarial drugs, many still die from severe malaria, and eradication efforts are hindered by the limited drugs currently available to target transmissible gametocyte parasites and liver-resident dormant Plasmodium vivax hypnozoites. Host-targeted therapy is a new direction for infectious disease drug development and aims to interfere with host molecules, pathways, or networks that are required for infection or that contribute to disease. Recent advances in our understanding of host pathways involved in parasite development and pathogenic mechanisms in severe malaria could facilitate the development of host-targeted interventions against Plasmodium infection and malaria disease. This review discusses new opportunities for host-targeted therapeutics for malaria and the potential to harness drug polypharmacology to simultaneously target multiple host pathways using a single drug intervention. Highlights Host-targeted therapy is a strategy for eliminating or reducing symptoms of infectious disease, and it holds promise for application to malaria. New insights into the malaria parasite–host interaction may lead to novel interventions to target liver-dormant forms called hypnozoites or to counteract the complications associated with cerebral malaria. Systematic approaches that exploit the polyphamacology of drugs developed for other indications could facilitate repurposing drugs that impact one or more points in the malaria parasite life cycle and also address severe complications of the disease. [ABSTRACT FROM AUTHOR]

Gastrointestinal helminth parasites share their habitat with a myriad of other organisms, that is, the commensal microbiota. Increasing evidence, particularly in humans and rodent models of helminth infection, points towards a multitude of interactions occurring between parasites and the gut microbiota, with a profound impact on both host immunity and metabolic potential. Despite this information, the exploration of the effects that parasite infections exert on populations of commensal gut microbes of veterinary species is a field of research in its infancy. In this article, we summarise studies that have contributed to current knowledge of helminth–microbiota interactions in species of veterinary interest, and identify possible avenues for future research in this area, which could include the exploitation of such relationships to improve parasite control and delay or prevent the development of anthelmintic resistance. [ABSTRACT FROM AUTHOR]