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Helminth infections are a major public health problem as they can cause long-term chronic infections in their hosts for which there is no effective vaccine. During the long-term interaction between helminths and their hosts, helminth-derived extracellular vesicles (EVs) can participate in host immunomodulatory processes by secreting bioactive molecules (BMAs). Growing data suggests that microRNAs (miRNAs) in helminth EVs have a significant impact on the host's immune system. The let-7 family is highly conserved among helminth EVs and highly homologous in the host, and its function in host-parasite crosstalk may reflect active selection for compatibility with the host miRNA machinery. In-depth studies targeting this aspect may better elucidate the mechanism of parasite-host interactions. Hence, this review summarizes the current studies on the cross-species involvement of helminth EV-derived let-7 in host immune regulation and discusses the barriers to related research and potential applications of helminth EVs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhong, Guan and Jin.)

Autoimmune diseases (AIDs) affect 5 to 10% of the population. There are more than ∼100 different autoimmune diseases. The AIDs are one of the top 10 causes of death in women under 65; 2nd highest cause of chronic illness; top cause of morbidity in women in the US. The NIH estimates annual direct healthcare costs for autoimmune diseases about $100 billion, in comparison, with cancers investment of $57 billion, heart and stroke cost of $200 billion. The current treatments for autoimmune diseases encompasses: steroids, chemotherapy, immunosuppressants, biological drugs, disease specific drugs (like acethylcholine-estherase for myasthenia gravis). The treatments for autooimmune diseases supress the patient immune network, which leads the patients to be more susceptible to infections. Hence, there is a need to develop immunomodulatory small molecules with minimal side effects to treat autoimmune diseases. The helminths developed secreting compounds which modulate the human defense pathways in order to develop tolerance and survive in the host environment. We have imitated the immunomodulatory activity of the helminth by using a derivative of the helminth secretory molecule. A bi-functional small molecule -tuftsin (T)-phosphorylcholine (PC), coined as TPC, was constructed. This chimeric molecule showed its immunomodulatory activity in 4 murine models of autoimmune diseases, attenuating the clinical score and the inflammatory response by immunomodutating the host immune system. Ex-vivo in human peripheral blood mononuclear cells (PBMCs) and biopsies originated from arteries of patients with giant cell arteritis. This paper decipher the mode of action of TPC immunomodulatory activity. Our data propose the potential for this small molecule to be a novel therapy for patients with autoimmune diseases., Competing Interests: Declaration of competing interest No conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

The global prevalence of autoimmune diseases has surged in recent decades. Consequently, environmental triggers have emerged as crucial contributors to autoimmune diseases, equally relevant to classical risk factors, such as genetic polymorphisms, infections, and smoking. Sequencing-based approaches have demonstrated distinct gut microbiota compositions in individuals with autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, type 1 diabetes mellitus (T1D), and systemic lupus erythematosus, compared to healthy controls. Furthermore, fecal microbiota transplantation and microbial inoculation experiments have supported the hypothesis that alterations in the gut microbiota can influence autoimmune responses and disease outcomes. Herein, we propose that intestinal helminths may serve as a critical factor in inducing alterations in the gut microbiota. The concept of helminth-mediated suppression of autoimmune diseases in humans is supported by substantial evidence, aligning with the long-standing "hygiene hypothesis." This review focused on T1D to explore the interactions between parasites, gut microbiota, and the immune system-a topic that remains a black box within this intricate triangular relationship., (Copyright © 2024 The Author. Published by Elsevier B.V. All rights reserved.)

Understanding determinants of immune response variation is central to developing treatment options. Even et al. show that naive CD4 + T cell transcriptional heterogeneity is altered by helminth infection leading to impaired immune responses independent of commensals., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The global prevalence of type 2 diabetes mellitus (T2D) is increasing rapidly, with an anticipated 600 million cases by 2035. While infectious diseases such as helminth infections have decreased due to improved sanitation and health care, recent research suggests a link between helminth infections and T2D, with helminths such as Schistosoma , Nippostrongylus , Strongyloides , and Heligmosomoides potentially mitigating or slowing down T2D progression in human and animal models. Helminth infections enhance host immunity by promoting interactions between innate and adaptive immune systems. In T2D, type 1 immune responses are suppressed and type 2 responses are augmented, expanding regulatory T cells and innate immune cells, particularly type 2 immune cells and macrophages. This article reviews recent research shedding light on the favorable effects of helminth infections on T2D. The potential defense mechanisms identified include heightened insulin sensitivity and reduced inflammation. The synthesis of findings from studies investigating parasitic helminths and their derivatives underscores promising avenues for defense against T2D.

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., Competing Interests: Declaration of interests The authors declare no competing interests., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The exposure to parasites may influence the immune response to vaccines in endemic African countries. In this study, we aimed to assess the association between helminth exposure to the most prevalent parasitic infections, schistosomiasis, soil transmitted helminths infection and filariasis, and the Ebola virus glycoprotein (EBOV GP) antibody concentration in response to vaccination with the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen in African and European participants using samples obtained from three international clinical trials., Methods/principal Findings: We conducted a study in a subset of participants in the EBL2001, EBL2002 and EBL3001 clinical trials that evaluated the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen against EVD in children, adolescents and adults from the United Kingdom, France, Burkina Faso, Cote d'Ivoire, Kenya, Uganda and Sierra Leone. Immune markers of helminth exposure at baseline were evaluated by ELISA with three commercial kits which detect IgG antibodies against schistosome, filarial and Strongyloides antigens. Luminex technology was used to measure inflammatory and activation markers, and Th1/Th2/Th17 cytokines at baseline. The association between binding IgG antibodies specific to EBOV GP (measured on day 21 post-dose 2 and on Day 365 after the first dose respectively), and helminth exposure at baseline was evaluated using a multivariable linear regression model adjusted for age and study group. Seventy-eight (21.3%) of the 367 participants included in the study had at least one helminth positive ELISA test at baseline, with differences of prevalence between studies and an increased prevalence with age. The most frequently detected antibodies were those to Schistosoma mansoni (10.9%), followed by Acanthocheilonema viteae (9%) and then Strongyloides ratti (7.9%). Among the 41 immunological analytes tested, five were significantly (p < .003) lower in participants with at least one positive helminth ELISA test result: CCL2/MCP1, FGFbasic, IL-7, IL-13 and CCL11/Eotaxin compared to participants with negative helminth ELISA tests. No significant association was found with EBOV-GP specific antibody concentration at 21 days post-dose 2, or at 365 days post-dose 1, adjusted for age group, study, and the presence of any helminth antibodies at baseline., Conclusions/significance: No clear association was found between immune markers of helminth exposure as measured by ELISA and post-vaccination response to the Ebola Ad26.ZEBOV/ MVA-BN-Filo vaccine regimen., Trial Registration: NCT02416453, NCT02564523, NCT02509494. ClinicalTrials.gov., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: VB and CR were full-time employees of Janssen Vaccines and Prevention at the time of the study and may hold shares of Johnson & Johnson., (Copyright: © 2024 Barry et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Monocytes/macrophages are pivotal in host defense, inflammation, and tissue repair. They are actively engaged during helminth infections, playing critical roles in trapping pathogens, eliminating them, repairing tissue damage, and mitigating type 2 inflammation. These cells are indispensable in preserving physiological equilibrium and overseeing pathogen resistance as well as metabolic processes. Furthermore, these immune cells are influenced by cellular metabolism, which adjusts in response to host-derived factors and environmental cues. They secrete effector molecules crucial for anti-helminthic immunity and healing tissues damaged by parasites. Helminth parasites manipulate the immune regulatory capabilities of monocytes/macrophages by secreting anti-inflammatory mediators to dodge host defenses. Infections, especially with helminths, induce metabolic adaptations involving monocytes/macrophages that can lead to enhanced insulin sensitivity. This review provides a synthesis of the activation and diversity of monocytes/macrophages, their involvement in inflammation, and the latest insights into the strategies of monocyte/macrophage-mediated host defense against helminth infections. It also sheds light on recent discoveries concerning the immune regulatory interactions between monocytes/macrophages and helminth parasites., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

The gut microbiota has coevolved with the host for hundreds of millions of years, playing a beneficial role in host health. Human parasitic helminths are widespread and pose a pervasive global public health issue. Although Type 2 immunity provides partial resistance to helminth infections, the composition of the gut microbiota can change correspondingly. Therefore, it raises the question of what role the gut microbiota plays during helminth infection. Akkermansia muciniphila has emerged as a notable representative of beneficial microorganisms in the gut microbiota. Recent studies indicate that A. muciniphila is not merely associated with helminth infection but is also causally linked to infection. Here, we provide an overview of the crosstalk between A. muciniphila and enteric helminth infection. Our goal is to enhance our understanding of the interplay among A. muciniphila , helminths, and their hosts while also exploring the potential underlying mechanisms.

Innate lymphoid cells (ILC) not only are responsible for shaping the innate immune response but also actively modulate T cell responses. However, the molecular processes regulating ILC-T cell interaction are not yet completely understood. The protein butyrophilin 2a2 (Btn2a2), a co-stimulatory molecule first identified on antigen-presenting cells, has a pivotal role in the maintenance of T cell homeostasis, but the main effector cell and the respective ligands remain elusive. We analyzed the role of Btn2a2 in the ILC-T cell cross talk. We found that the expression of Btn2a2 is upregulated in ILC2 following stimulation with IL-33/IL-25/TSLP. In vitro and in vivo experiments indicated that lack of Btn2a2 expression on ILC2 resulted in elevated T cell responses. We observed an enhanced proliferation of T cells as well as increased secretion of the type 2 cytokines IL-4/IL-5/IL-13 following cocultures with Btn2a2-deficient ILC2. In vivo transfer experiments confirmed the regulatory role of Btn2a2 on ILC2 as Btn2a2-deficient ILC2 induced stronger T cell responses and prevented chronic helminth infections. Taken together, we identified Btn2a2 as a significant player in the regulation of ILC2-T cell interactions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Frech, Omata, Schmalzl, Wirtz, Taher, Schett, Zaiss and Sarter.)

Inflammatory bowel disease (IBD) is associated with a dysregulated mucosal immune response in the gastrointestinal tract. The number of patients with IBD has increased worldwide, especially in highly industrialized western societies. The population of patients with IBD in North America is forecasted to reach about four million by 2030; meanwhile, there is no definitive therapy for IBD. Current anti-inflammatory, immunosuppressive, or biological treatment may induce and maintain remission, but not all patients respond to these treatments. Recent studies explored parasitic helminths as a novel modality of therapy due to their potent immunoregulatory properties in humans. Research using IBD animal models infected with a helminth or administered helminth-derived products such as excretory-secretory products has been promising, and helminth-microbiota interactions exert their anti-inflammatory effects by modulating the host immunity. Recent studies also indicate that evidence that helminth-derived metabolites may play a role in anticolitic effects. Thus, the helminth shows a potential benefit for treatment against IBD. Here we review the current feasibility of "helminth therapy" from the laboratory for application in IBD management., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Parasite infections caused by helminths affect hundreds of millions worldwide. Despite their socioeconomic importance and impact on health, there is still an urgent need to develop appropriate control approaches. The recent discovery that helminths, as most eukaryotic organisms, secrete extracellular vesicles (EVs) of different type has opened new avenues for the characterization of novel diagnostic and vaccine candidates that could serve for this purpose. Herein, we describe a method for the isolation of highly pure microvesicles and exosomes, two of the most relevant populations of EVs secreted by helminths, and describe a validated approach to characterize the proteins from different compartments of EVs. These proteins could be further developed into suitable diagnostic and vaccine candidates against these devastating infections., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Coinfection with Plasmodium falciparum and helminths may impact the immune response to these parasites because they induce different immune profiles. We studied the effects of coinfections on the antibody profile in a cohort of 715 Mozambican children and adults using the Luminex technology with a panel of 16 antigens from P. falciparum and 11 antigens from helminths ( Ascaris lumbricoides , hookworm, Trichuris trichiura, Strongyloides stercoralis, and Schistosoma spp.) and measured antigen-specific IgG and total IgE responses. We compared the antibody profile between groups defined by P. falciparum and helminth previous exposure (based on serology) and/or current infection (determined by microscopy and/or qPCR). In multivariable regression models adjusted by demographic, socioeconomic, water, and sanitation variables, individuals exposed/infected with P. falciparum and helminths had significantly higher total IgE and antigen-specific IgG levels, magnitude (sum of all levels) and breadth of response to both types of parasites compared to individuals exposed/infected with only one type of parasite ( P ≤ 0.05). There was a positive association between exposure/infection with P. falciparum and exposure/infection with helminths or the number of helminth species, and vice versa ( P ≤ 0.001). In addition, children coexposed/coinfected tended ( P = 0.062) to have higher P. falciparum parasitemia than those single exposed/infected. Our results suggest that an increase in the antibody responses in coexposed/coinfected individuals may reflect higher exposure and be due to a more permissive immune environment to infection in the host. IMPORTANCE Coinfection with Plasmodium falciparum and helminths may impact the immune response to these parasites because they induce different immune profiles. We compared the antibody profile between groups of Mozambican individuals defined by P. falciparum and helminth previous exposure and/or current infection. Our results show a significant increase in antibody responses in individuals coexposed/coinfected with P. falciparum and helminths in comparison with individuals exposed/infected with only one of these parasites, and suggest that this increase is due to a more permissive immune environment to infection in the host. Importantly, this study takes previous exposure into account, which is particularly relevant in endemic areas where continuous infections imprint and shape the immune system. Deciphering the implications of coinfections deserves attention because accounting for the real interactions that occur in nature could improve the design of integrated disease control strategies.

Multiple sclerosis (MS) is currently thought to arise by interactions between genetic susceptibility and environmental factors. Infections in general trigger autoimmune responses causing clinical manifestations of disease. However, as a result of regulatory T (Treg)- and regulatory B (Breg)-cell induction, helminth infections tend to dampen disease activity. IL-35, the newest member of the IL-12 family, is an inhibitory cytokine composed of an EBI3β chain subunit, and an IL-12p35 subunit. The aim of this study was to investigate the role of IL-35 during parasite infections occurring in individuals with MS. Numbers of IL-35-producing Breg cells are higher in CSF from helminth-infected than from uninfected MS subjects, a finding associated with decreased MRI disease activity. Interestingly, stimulation of CD19 + B cells with IL-35 promotes conversion of these cells to Breg cells producing both IL-35 and IL-10. Coculture of B cells from helminth-infected MS patients inhibits proliferation of Th1 and Th17 myelin peptide-specific T cells, as well as production of IFN-γ and IL-17. Following activation, CD4 + CD25 + Treg cells significantly upregulate expression of EBI3 and IL-12p35 mRNA. Furthermore, CD4 + CD25 - T cells activated in the presence of IL-35 induce a population of cells with regulatory function, known as iTR35. Finally, B cells from normal individuals cultured in vitro in the presence of the helminth antigen SEA increase expression of the transcription BATF, IRF4 and IRF8, acquiring a pattern similar to that of IL-35 Breg cells. These data highlight the important immunoregulatory effects of IL-35 on both Breg and Treg cells, observed in helminth-infected MS subjects., (© 2021 John Wiley & Sons Ltd.)

As long-lived parasites, helminths depend upon immunomodulation of their hosts for survival. The release of excretory-secretory (ES) products, including proteins, lipids and RNAs is how successful host manipulation is achieved. It has recently been discovered that the ES products of helminths contain extracellular vesicles (EVs), with every species investigated found to secrete these lipid-bound structures. EVs are perfect for packaging and delivering immune modulators to target cell types. This review outlines the research carried out on helminth EVs and their constituents thus far, as well as their interaction with components of the mammalian immune system. We discuss how targeting EVs will aid treatment of helminth infection and consider how EVs and their immunomodulatory cargo could be used as therapeutics as we progress through this exciting era., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Helminths are the old dirty friends of humans from decades and may live undetected by the immune system for years in the tissues. They have evolved as good experts at subverting the immune system. Despite of their pathogenicity, they provide protection to their host against certain inflammatory diseases such as diabetes by modulating the immune mechanisms. These parasites are extra-cellular and induce Th2 response which triggers the adaptive immune cells as well as innate immune cells to work synergistically allowing Tregs to work in a toll-like receptor-dependent manure. T-helper cells type-2 also secrete certain anti-inflammatory cytokines including IL-4, IL-10, IL-13 and TGF-β which also provide protection against type-1 diabetes. Several helminths such as T. crassiceps, S. venezuelensis, filarial worms, Schistosoma spp. and T. spiralis have been reported to prevent diabetes in mouse models as well as in some clinical trials. Immunomodulatory talent of helminths is receiving greater attention to prevent diabetes. Herein, an attempt has been made to review and highlight the possible immuno-modulatory mechanisms by which helminths provide protection against diabetes. Moreover, this review also emphasizes on the use of helminth-derived molecules or synthetic derivatives of helminth-antigens in clinical trials to overcome rapidly growing autoimmune disorders including diabetes., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Helminths contribute a larger global burden of disease than both malaria and tuberculosis. These eukaryotes have caused human infections since before our earliest recorded history (i.e.: earlier than 1200 B.C. for Schistosoma spp.). Despite the prevalence and importance of these infections, helminths are considered a neglected tropical disease for which there are no vaccines approved for human use. Similar to other parasites, helminths are complex organisms which employ a plethora of features such as: complex life cycles, chronic infections, and antigenic mimicry to name a few, making them difficult to target by conventional vaccine strategies. With novel vaccine strategies such as viral vectors and genetic elements, numerous constructs are being defined for a wide range of helminth parasites; however, it has yet to be discussed which of these approaches may be the most effective. With human trials being conducted, and a pipeline of potential anti-helminthic antigens, greater understanding of helminth vaccine-induced immunity is necessary for the development of potent vaccine platforms and their optimal design. This review outlines the conventional and the most promising approaches in clinical and preclinical helminth vaccinology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Perera and Ndao.)

Emerging evidence suggests that immune cells not only communicate with each other through cytokines, chemokines, and cell surface receptors, but also by releasing small membranous structures known as extracellular vesicles (EVs). EVs carry a variety of different molecules that can be taken up by recipient cells. Parasitic worms are well known for their immunomodulatory properties, but whether they can affect immune responses by altering EV-driven communication between host immune cells remains unclear. Here we provide evidence that stimulation of bone marrow-derived macrophages (BMDMs) with soluble products of Trichuris suis (TSPs), leads to the release of EVs with anti-inflammatory properties. Specifically, we found that EVs from TSP-pulsed BMDMs, but not those from unstimulated BMDMs can suppress TNFα and IL-6 release in LPS-stimulated BMDMs and BMDCs. However, no polarization toward M1 or M2 was observed in macrophages exposed to EVs. Moreover, EVs enhanced reactive oxygen species (ROS) production in the exposed BMDMs, which was associated with a deregulated redox homeostasis as revealed by pathway analysis of transcriptomic data. Proteomic analysis identified cytochrome p450 (CYP450) as a potential source of ROS in EVs from TSP-pulsed BMDMs. Finally, pharmacological inhibition of CYP450 activity could suppress ROS production in those BMDMs. In summary, we find that TSPs can modulate immune responses not only via direct interactions but also indirectly by eliciting the release of EVs from BMDMs that exert anti-inflammatory effects on recipient cells., Competing Interests: None., (© 2021 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

Background: Type 2 immunity can be modulated by regulatory T (Treg) cell activity. It has been suggested that the deubiquitinase cylindromatosis (CYLD) plays a role in the development or function of Treg cells, implying that it could be important for normal protective immunity, where type 2 responses are prevalent., Objective: We sought to investigate the role of CYLD in Treg cell function and T H 2 cell immune responses under steady-state conditions and during helminth infection., Methods: Foxp3-restricted CYLD conditional knockout (KO) mice were examined in mouse models of allergen-induced airway inflammation and Nippostrongylus brasiliensis infection. We performed multiplex magnetic bead assays, flow cytometry, and quantitative PCR to understand how a lack of CYLD affected cytokine production, homing, and suppression in Treg cells. Target genes regulated by CYLD were identified and validated by microarray analysis, coimmunoprecipitation, short hairpin RNA knockdown, and transfection assays., Results: Treg cell-specific CYLD KO mice showed severe spontaneous pulmonary inflammation with increased migration of Treg cells into the lung. CYLD-deficient Treg cells furthermore produced high levels of IL-4 and failed to suppress allergen-induced lung inflammation. Supporting this, the conditional KO mice displayed enhanced protection against N brasiliensis infection by contributing to type 2 immunity. Treg cell conversion into IL-4-producing cells was due to augmented mitogen-activated protein kinase and nuclear factor κB signaling. Moreover, Scinderin, a member of the actin-binding gelsolin family, was highly upregulated in CYLD-deficient Treg cells, and controlled IL-4 production through forming complexes with mitogen-activated protein kinase kinase/extracellular receptor kinase. Correspondingly, both excessive IL-4 production in vivo and the protective role of CYLD-deficient Treg cells against N brasiliensis were reversed by Scinderin ablation., Conclusions: Our findings indicate that CYLD controls type 2 immune responses by regulating Treg cell conversion into T H 2 cell-like effector cells, which potentiates parasite resistance., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Helminth Extracellular Vesicles (EVs) have emerged as important mediators in host-parasite communications, participating in the parasite survival and its pathogenic effects. In the last decade, a growing amount of information reporting the isolation and characterization of EVs from different helminth species has appeared, but unfortunately, few reports have focused on functional studies of helminth EVs in different cell lines, organoids or animal models. We here review these in vitro and in vivo studies, which clearly demonstrate that helminths secrete EVs, which affect their environment. Helminth EVs are actively internalized by different cell lines, modulating cellular functions important for host-parasite communication. We discuss how these lines of investigation should provide potential new biomarkers of infection, and since helminth EVs can modulate the host immune response, we also discuss how they can provide a new landscape for the development of new vaccine tools against helminthiases as well as immunotherapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The current approaches to reduce the burden of chronic helminth infections in endemic areas are adequate sanitation and periodic administration of deworming drugs. Yet, resistance against some deworming drugs and reinfection can still rapidly occur even after treatment. A vaccine against helminths would be an effective solution at preventing reinfection. However, vaccines against helminth parasites have yet to be successfully developed. While T helper cells and innate lymphoid cells have been established as important components of the protective type 2 response, the roles of B cells and antibodies remain the most controversial. Here, we review the roles of B cells during intestinal helminth infection. We discuss the potential factors that contribute to the context-specific roles for B cells in protection against diverse intestinal helminth parasite species, using evidence from well-defined murine model systems. Understanding the precise roles of B cells during resistance and susceptibility to helminth infection may offer a new perspective of type 2 protective immunity., Competing Interests: The authors have declared that no competing interests exist.

The scientific community identified non stool-based biomarkers as the way forward to support soil-transmitted helminth (STH; Ascaris lumbricoides, Trichuris trichiura and the hookworms Ancylostoma duodenale and Necator americanus) and schistosome (S. mansoni and S. haematobium) deworming programs. This support is needed in making the decision of whether or not to stop preventive chemotherapy intervention efforts and to ultimately transition towards a post-intervention surveillance phase. We applied a two-step micro-array approach to identify antigenic linear epitopes in the STH and S. mansoni proteomes. In a first experiment, we identified antigenic peptides by applying sera from 24 STH and/or S. mansoni infected Ethiopian children on a high-density peptide microarray containing 3.3 million peptides derived from the complete STH and S. mansoni proteomes. A second array experiment with 170,185 peptides that were recognized in the first array was designed to identify non-specific antibody reactivity by applying sera from 24 healthy individuals from Belgium (a non-endemic country). From this array testing cascade, several peptides were identified for STH but none of them appeared to be unique for one species. We therefore concluded that for STH, none of the peptides revealed to be sufficiently sensitive or species specific. For S. mansoni, some promising peptides were identified prompting future investigation. Based on these results, it is unlikely that linear epitopes would be highly useful in detecting species-specific antibody responses to STH in endemic communities. For S. mansoni, one particular peptide of the micro-exon gene 12 (MEG-12) protein deserves further research. In addition, this study emphasizes the need of well-characterized biobanks for biomarker discovery, particularly when the integration of multiple disease programs is envisioned., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: OL and LJS are current employees of Janssen Pharmaceutica NV, a Johnson and Johnson Company and they may own stock or stock options in that company. The remaining co-authors have no conflicts of interest with the content of this article.

Helminths are an emerging source of therapeutics for dysregulated inflammatory diseases. Excretory/secretory (ES) molecules, released during infection, are responsible for many of these immunomodulatory effects and are likely to have evolved as a means for parasite survival in the host. While the mechanisms of action of these molecules have not been fully defined, evidence demonstrates that they target various pathways in the immune response, ranging from initiation to effector cell modulation. These molecules are applied in controlling specific effector mechanisms of type 1 and type 2 immune responses. Recently, studies have further focused on their therapeutic potential in specific disease models. Here we review recent findings on ES molecule modulation of immune functions, specifically highlighting their clinical implications for future use in inflammatory disease therapeutics., Competing Interests: Declaration of Interests W.C.G. has a patent related to the use of helminth ES products in wound healing., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Competing Interests: PG is a co-founder of Paragen Bio, a biotech company that aims to translate and commercialise hookworm-derived proteins for inflammatory diseases. This has previously involved investment from pharma (Abbvie Inc) and venture capitalist firms (OneVentures, Brandon Capital). MS is founder and president of the biotech company NemaGen Discoveries. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Group 2 innate lymphoid cells (ILC2s) reside in multiple tissues, including lymphoid organs and barrier surfaces, and secrete type 2 cytokines including interleukin-5 (IL-5), IL-9, and IL-13. These cells participate in multiple physiological processes including allergic inflammation, tissue repair, metabolic homeostasis, and host defense against helminth infections. Recent studies indicate that neurotransmitters and neuropeptides can play an important role in regulating ILC2 responses; however, the mechanisms that underlie these processes in vivo remain incompletely defined. Here, we identify that activated ILC2s up-regulate choline acetyltransferase (ChAT)-the enzyme responsible for the biosynthesis of acetylcholine (ACh)-after infection with the helminth parasite Nippostrongylus brasiliensis or treatment with alarmins or cytokines including IL-25, IL-33, and thymic stromal lymphopoietin (TSLP). ILC2s also express acetylcholine receptors (AChRs), and ACh administration promotes ILC2 cytokine production and elicits expulsion of helminth infection. In accordance with this, ChAT deficiency in ILC2s leads to defective ILC2 responses and impaired immunity against helminth infection. Together, these results reveal a previously unrecognized role of the ChAT-ACh pathway in promoting type 2 innate immunity to helminth infection., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Innate lymphoid cells (ILCs) are critical mediators of immunological and physiological responses at mucosal barrier sites. Whereas neurotransmitters can stimulate ILCs, the synthesis of small-molecule neurotransmitters by these cells has only recently been appreciated. Group 2 ILCs (ILC2s) are shown here to synthesize and release acetylcholine (ACh) during parasitic nematode infection. The cholinergic phenotype of pulmonary ILC2s was associated with their activation state, could be induced by in vivo exposure to extracts of Alternaria alternata or the alarmin cytokines interleukin-33 (IL-33) and IL-25, and was augmented by IL-2 in vitro. Genetic disruption of ACh synthesis by murine ILC2s resulted in increased parasite burdens, lower numbers of ILC2s, and reduced lung and gut barrier responses to Nippostrongylus brasiliensis infection. These data demonstrate a functional role for ILC2-derived ACh in the expansion of ILC2s for maximal induction of type 2 immunity., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Exposure to different organisms (bacteria, mold, virus, protozoan, helminths, among others) can induce epigenetic changes affecting the modulation of immune responses and consequently increasing the susceptibility to inflammatory diseases. Epigenomic regulatory features are highly affected during embryonic development and are responsible for the expression or repression of different genes associated with cell development and targeting/conducting immune responses. The well-known, "window of opportunity" that includes maternal and post-natal environmental exposures, which include maternal infections, microbiota, diet, drugs, and pollutant exposures are of fundamental importance to immune modulation and these events are almost always accompanied by epigenetic changes. Recently, it has been shown that these alterations could be involved in both risk and protection of allergic diseases through mechanisms, such as DNA methylation and histone modifications, which can enhance Th2 responses and maintain memory Th2 cells or decrease Treg cells differentiation. In addition, epigenetic changes may differ according to the microbial agent involved and may even influence different asthma or allergy phenotypes. In this review, we discuss how exposure to different organisms, including bacteria, viruses, and helminths can lead to epigenetic modulations and how this correlates with allergic diseases considering different genetic backgrounds of several ancestral populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fiuza, Fonseca, Meirelles, Marques, da Silva and Figueiredo.)

Macrophages are fundamental to sustain physiological equilibrium and to regulate the pathogenesis of parasitic and metabolic processes. The functional heterogeneity and immune responses of macrophages are shaped by cellular metabolism in response to the host's intrinsic factors, environmental cues and other stimuli during disease. Parasite infections induce a complex cascade of cytokines and metabolites that profoundly remodel the metabolic status of macrophages. In particular, helminths polarize macrophages to an M2 state and induce a metabolic shift towards reliance on oxidative phosphorylation, lipid oxidation and amino acid metabolism. Accumulating data indicate that helminth-induced activation and metabolic reprogramming of macrophages underlie improvement in overall whole-body metabolism, denoted by improved insulin sensitivity, body mass in response to high-fat diet and atherogenic index in mammals. This review aims to highlight the metabolic changes that occur in human and murine-derived macrophages in response to helminth infections and helminth products, with particular interest in schistosomiasis and soil-transmitted helminths., (© 2020 John Wiley & Sons Ltd.)

The type 2 immune response is associated with helminth infections and allergic inflammation where antibody production of the IgG1 and IgE isotypes can elicit protective or proinflammatory functions. Studies over the past few years revealed important new insights regarding the regulatory mechanisms orchestrating the humoral type 2 immune response. This includes investigations on B-cell extrinsic signals, such IL-4 and IL-21, derived from different T-helper cell subsets or discovery of new follicular helper T cells with regulatory or IgE-promoting activities. In addition, studies on B-cell intrinsic factors required for germinal center formation and class switch recombination, including the transcription factors STAT3, STAT6, and BCL-6, led to a better understanding of these processes in type 2 immune responses. Here, we review the current understanding of mechanisms controlling humoral type 2 immunity in vivo including the generation of IgE-producing plasma cells and the memory IgE response., (© 2020 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

The P2X7 receptor (P2RX7) is an important molecule that functions as a danger sensor, detecting extracellular nucleotides from injured cells and thus signaling an inflammatory program to nearby cells. It is expressed in immune cells and plays important roles in pathogen surveillance and cell-mediated responses to infectious organisms. There is an abundance of literature on the role of P2RX7 in inflammatory diseases and the role of these receptors in host-pathogen interactions. Here, we describe the current knowledge of the role of P2RX7 in the host response to a variety of pathogens, including viruses, bacteria, fungi, protozoa, and helminths. We describe in vitro and in vivo evidence for the critical role these receptors play in mediating and modulating immune responses. Our observations indicate a role for P2X7 signaling in sensing damage-associated molecular patterns released by nearby infected cells to facilitate immunopathology or protection. In this review, we describe how P2RX7 signaling can play critical roles in numerous cells types in response to a diverse array of pathogens in mediating pathogenesis and immunity to infectious agents., (Copyright © 2021 American Society for Microbiology.)

Viral infections are often studied in model mammalian organisms under specific pathogen-free conditions. However, in nature, coinfections are common, and infection with one organism can alter host susceptibility to infection with another. Helminth parasites share a long coevolutionary history with mammalian hosts and have shaped host physiology, metabolism, immunity, and the composition of the microbiome. Published studies suggest that helminth infection can either be beneficial or detrimental during viral infection. Here, we discuss coinfection studies in mouse models and use them to define key determinants that impact outcomes, including the type of antiviral immunity, the tissue tropism of both the helminth and the virus, and the timing of viral infection in relation to the helminth lifecycle. We also explore the current mechanistic understanding of how helminth-virus coinfection impacts host immunity and viral pathogenesis. While much attention has been placed on the impact of the gut bacterial microbiome on immunity to infection, we suggest that enteric helminths, as a part of the eukaryotic macrobiome, also represent an important modulator of disease pathogenesis and severity following virus infection.

Helminths remain one of the most prolific pathogens in the world. Following infection helminths interact with various epithelial cell surfaces, including skin, lung, and gut. Recent works have shown that epithelial cells produce a series of cytokines such as TSLP, IL-33, and IL-25 that lead to the induction of innate and acquired type 2 immune responses, which we named Type 2 epithelial cytokines. Although basophils and eosinophils are relatively rare granulocytes under normal conditions (0.5% and 5% in peripheral blood, respectively), both are found with increased frequency in type 2 immunity, including allergy and helminth infections. Recent reports showed that basophils and eosinophils not only express effector functions in type 2 immune reactions, but also manipulate the response toward helminths. Furthermore, basophils and eosinophils play non-redundant roles in distinct responses against various nematodes, providing the potential to intervene at different stages of nematode infection. These findings would be helpful to establish vaccination or therapeutic drugs against nematode infections., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Obata-Ninomiya, Domeier and Ziegler.)

The role of the gut microbiota during coinfection with soil-transmitted helminths (STH) and Plasmodium spp. is poorly understood. We examined peripheral blood and fecal samples from 130 individuals who were either infected with Plasmodium vivax only, coinfected with P. vivax and STH, infected with STH alone, or not infected with either P. vivax or STH. In addition to a complete blood count (CBC) with differential, transcriptional profiling of peripheral blood samples was performed by transcriptome sequencing (RNA-Seq), fecal microbial communities were determined by 16S rRNA gene sequencing, and circulating cytokine levels were measured by bead-based immunoassays. Differences in blood cell counts, including an increased percentage of neutrophils, associated with a transcriptional signature of neutrophil activation, were driven primarily by P. vivax infection. P. vivax infection was also associated with increased levels of interleukin 6 (IL-6), IL-8, and IL-10; these cytokine levels were not affected by STH coinfection. Surprisingly, P. vivax infection was more strongly associated with differences in the microbiota than STH infection. Children infected with only P. vivax exhibited elevated Bacteroides and reduced Prevotella and Clostridiaceae levels, but these differences were not observed in individuals coinfected with STH. We also observed that P. vivax parasitemia was higher in the STH-infected population. When we used machine learning to identify the most important predictors of the P. vivax parasite burden (among P. vivax -infected individuals), bacterial taxa were the strongest predictors of parasitemia. In contrast, circulating transforming growth factor β (TGF-β) was the strongest predictor of the Trichuris trichiura egg burden. This study provides unexpected evidence that the gut microbiota may have a stronger link with P. vivax than with STH infection. IMPORTANCE Plasmodium (malaria) and helminth parasite coinfections are frequent, and both infections can be affected by the host gut microbiota. However, the relationship between coinfection and the gut microbiota is unclear. By performing comprehensive analyses on blood/stool samples from 130 individuals in Colombia, we found that the gut microbiota may have a stronger relationship with the number of P. vivax (malaria) parasites than with the number of helminth parasites infecting a host. Microbiota analysis identified more predictors of the P. vivax parasite burden, whereas analysis of blood samples identified predictors of the helminth parasite burden. These results were unexpected, because we expected each parasite to be associated with greater differences in its biological niche (blood for P. vivax and the intestine for helminths). Instead, we find that bacterial taxa were the strongest predictors of P. vivax parasitemia levels, while circulating TGF-β levels were the strongest predictor of helminth parasite burdens.

Helminths, including nematodes, cestodes and trematodes, are complex parasitic organisms that infect at least one billion people globally living in extreme poverty. Helminthic infections are associated with severe morbidity particularly in young children who often harbor the highest burden of disease. While each helminth species completes a distinct life cycle within the host, several helminths incite significant lung disease. This impact on the lungs occurs either directly from larval migration and host immune activation or indirectly from a systemic inflammatory immune response. The impact of helminths on the pulmonary immune response involves a sophisticated orchestration and activation of the host innate and adaptive immune cells. The consequences of activating pulmonary host immune responses are variable with several helminthic infections leading to severe, pulmonary compromise while others providing immune tolerance and protection against the development of pulmonary diseases. Further delineation of the convoluted interface between helminth infection and the pulmonary host immune responses is critical to the development of novel therapeutics that are critically needed to prevent the significant global morbidity caused by these parasites., (Copyright © 2020 Weatherhead, Gazzinelli-Guimaraes, Knight, Fujiwara, Hotez, Bottazzi and Corry.)

Gastrointestinal helminth infection still constitutes a major public health issue, particularly in the developing world. As these parasites can undergo a large part of their lifecycle within the intestinal tract the host has developed various structural and cellular specializations at the epithelial barrier to contend with infection. Detailed characterization of these cells will provide important insights about their contributions to the protective responses mediated against helminths. Here, we discuss how key components of the intestinal epithelium may function to limit the initial establishment of helminths, and how these cells are altered during an active response to infection., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Parasitic helminth infection elicits a type 2 cytokine-mediated inflammatory response. During type 2 inflammation, damaged or stimulated epithelial cells exposed to helminths and their products produce alarmins and cytokines including IL-25, IL-33, and thymic stromal lymphopoietin. These factors promote innate immune cell activation that supports the polarization of CD4 + T helper type 2 (Th2) cells. Activated innate and Th2 cells produce the cytokines IL-4, -5, -9, and -13 that perpetuate immune activation and act back on the epithelium to cause goblet cell hyperplasia and increased epithelial cell turnover. Together, these events facilitate worm expulsion and wound healing processes. While the role of Th2 cells in this context has been heavily studied, recent work has revealed that epithelial cell-derived cytokines are drivers of key innate immune responses that are critical for type 2 anti-helminth responses. Cutting-edge studies have begun to fully assess how other factors and pathways, including lipid mediators, chemokines, Fc receptor signaling, danger-associated molecular pattern molecules, and direct cell-cell interactions, also participate in shaping innate cell-mediated type 2 inflammation. In this review, we discuss how these pathways intersect and synergize with pathways controlled by epithelial cell-derived cytokines to coordinate innate immune responses that drive helminth-induced type 2 inflammation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Maternal exposure to antibodies, cytokines or parasitic antigens during gestation may alter the degree of immune competence of offspring. Here we describe the production of cytokines and chemokines, and the ability to activation of the immune response in infants from mothers sensitized to helminths., Methods: It were selected five infants born to helminth-seropositive mothers but who were negative for current helminth infection. Whole blood was cultured without stimulus, with phytohemagglutinin mitogen (5 μg/ml, 24 h) or with purified protein derivative (PPD) (1 μg/ml, 24 h), and the supernatant was assessed for presence of Th1/Th2 cytokines (IFN-γ, TNF-α, IL-10, IL-5, IL-4 and IL-2) and chemokines (CXCL10, CCL2, CXCL9, CCL5 and CXCL8) by cytometric bead array., Results: All infants produced CCL5. Two infants demonstrated a mixed profile of Th1 (CXCL9) and Th2 (CCL2) chemokines in the presence of CXCL10, while one infant showed skewing towards Th2 without CXCL10 and two of them had been impaired immune response (children from sensitized to Schistosoma mansoni mothers)., Conclusion: Infants with Th1 and Th2 profile chemokines demonstrated a good response to vaccination, indicated by CXCL10 levels, but not infants predominantly Th2-skewed profile. These results highlight that children from mothers sensitized to S. mansoni may lead to ineffective immune response to PPD, while mothers sensitized to Ascaris lumbricoides showed no such impairment., (Copyright © 2018. Published by Elsevier B.V.)

Proinflammatory alterations of white adipose tissue (WAT) with increasing age play an important role in mammalian aging. WAT produced eotaxin-1 (CCL11-C-C motif chemokine ligand 11) and monocyte chemoattractant protein 1 (MCP-1) (CCL2) are elevated in old mammals. Obese and old adipose tissues produce excessive proinflammatory cytokines such as interleukin (IL)-6, CCL2, and IL-1-beta that contribute to inflammaging. WAT-based inflammaging involves an altered homeostatic equilibrium between proinflammatory cells such as activated type 1 macrophages, B cells (high IgJ) and T cells, and anti-inflammatory eosinophils and Tregs. Specifically, young and lean individuals exhibit a high eosinophil-to-macrophage ratio with an enrichment of alternative activated tissue macrophages that is reduced in the WAT of aging mice. Eosinophils from young animals adoptively transferred to old mice, home to WAT and reverse many of the immunoinflammatory signatures associated with aging. Whether eosinophil-based therapies for inflammaging could be created remains an open question.

The hunt for effective vaccines against the major helminth diseases of humans has yet to bear fruit despite much effort over several decades. No individual parasite antigen has proved to elicit full protective immunity, suggesting that combinatorial strategies may be required. Recently it has been discovered that extracellular vesicles released by parasitic helminths contain multiple potential immune modulators, which could together be targeted by a future vaccine. Increasing knowledge of helminth extracellular vesicle components, both enclosed by and exposed on the membrane, will open up a new field of targets for an effective vaccine. This review discusses the interactions between helminth extracellular vesicles and the immune system discovered thus far, and the advantages of targeting these lipid-bound packages with a vaccine. In addition, we also comment upon specific antigens that may be the best targets for an anti-helminth vaccine. In the future, extensive knowledge of the parasites' full arsenal in controlling their host may finally provide us with the ideal target for a fully effective vaccine., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Human intestinal helminth infection affects more than 1 billion people often in the world's most deprived communities. These parasites are one of the most prevalent neglected tropical diseases worldwide bringing huge morbidities to the host population. Effective treatments and vaccines for helminths are currently limited, and therefore, it is essential to understand the molecular sensors that the intestinal epithelium utilizes in detecting helminths and how the responding factors produced act as modulators of immunity. Defining the cellular and molecular mechanisms that enable helminth detection and expulsion will be critical in identifying potential therapeutic targets to alleviate disease. However, despite decades of research, we have only recently been able to identify the tuft cell as a key helminth sensor at the epithelial barrier. In this review, we will highlight the key intestinal epithelial chemosensory roles associated with the detection of intestinal helminths, summarizing the recent advances in tuft cell initiation of protective type 2 immunity. We will discuss other potential sensory roles of epithelial subsets and introduce enteroendocrine cells as potential key sensors of the microbial alterations that a helminth infection produces, which, given their direct communication to the nervous system via the recently described neuropod, have the potential to transfer the epithelial immune interface systemically., (Copyright © 2020 Faniyi, Wijanarko, Tollitt and Worthington.)

Soil-transmitted helminths represent a major global health burden with infections and infection-related comorbidities causing significant reductions in the quality of life for individuals living in endemic areas. Repeated infections and chronic colonization by these large extracellular worms in mammals led to the evolution of type-2 immunity characterized by the production of the type-2 cytokines interleukin (IL)-4, IL-5, and IL-13. Although a number of adaptive and innate immune cells produce type-2 cytokines, a key cellular source in the context of helminth infection is group 2 innate lymphoid cells (ILC2s). ILC2s promote mucosal barrier homeostasis, integrity, and repair by rapidly responding to epithelial cues in mucosal tissues. Though tissue-resident ILC2s (nILC2s) have been studied in detail over the last decade, considerably less is known with regard to a subset of inflammatory ILC2s (iILC2s) that migrate to the lungs of mice early after Nippostrongylus brasiliensis infection and are potent early producers of type-2 cytokines. This review will discuss the relationship and differences between nILC2s and iILC2s that establish their unique roles in anti-helminth immunity. We have placed particular emphasis on studies investigating iILC2 origin, function, and their potential long-term contribution to tissue-resident ILC2 reservoirs in settings of helminth infection., (Copyright © 2020 Miller and Reinhardt.)

Infection with soil-transmitted helminths (STH) remains a major burden on global health and agriculture. Our understanding of the immunological mechanisms that govern whether an individual is resistant or susceptible to infection is derived primarily from model infections in rodents. Typically, experimental infections employ an artificially high, single bolus of parasites that leads to rapid expulsion of the primary infection and robust immunity to subsequent challenges. However, immunity in natura is generated slowly, and is only partially effective, with individuals in endemic areas retaining low-level infections throughout their lives. Therefore, there is a gap between traditional model STH systems and observations in the field. Here, we review the immune response to traditional model STH infections in the laboratory. We compare these data to studies of natural infection in humans and rodents in endemic areas, highlighting crucial differences between experimental and natural infection. We then detail the literature to date on the use of "trickle" infections to experimentally model the kinetics of natural infection., (Copyright © 2020 Colombo and Grencis.)