• ESPs
• EVs
• excretory/secretory products
• extracelular vesicles
• gut biome
• helminths
• immunology
• inflammation
• inflammatory disorders
• trained immunity

• Humans
• Helminths/immunology
• Animals
• Inflammation/immunology
• Inflammation/therapy
• Immunity, Innate
• Therapy with Helminths
• Autoimmune Diseases/immunology
• Autoimmune Diseases/therapy
• Trained Immunity

• PICT-2021-I-A-00807 Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación (ANPCyT); Fondo para la Investigación Científica y Tecnológica (FONCYT), Argentina.
• Fiorini 2024 Fundación Florencio Fiorini, Argentina
• PIP 2022-0763 Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina

• Humans
• Mitogenic index
• T cell clones
• Th17
• Trichinella pseudospiralis

• Trichinellosis/immunology
• Humans
• Female
• Interleukin-17/metabolism
• Interleukin-17/immunology
• Middle Aged
• Animals
• Trichinella/immunology
• Antigens, Helminth/immunology
• Interferon-gamma/metabolism
• Interferon-gamma/immunology
• Chronic Disease
• Trichinella spiralis/immunology
• Leukocytes, Mononuclear/immunology
• Leukocytes, Mononuclear/metabolism
• Interleukin-4/immunology
• Interleukin-4/metabolism
• T-Lymphocytes/immunology

• Immunomodulation
• Lymphatic filariasis
• MIF2
• Type 1 diabetes
• Wuchereria bancrofti

• Humans
• Animals
• Mice
• Wuchereria bancrofti
• Diabetes Mellitus, Type 1
• Macrophage Migration-Inhibitory Factors/genetics
• Macrophage Migration-Inhibitory Factors/metabolism
• Parasites/metabolism
• Streptozocin
• Filarioidea
• Immunologic Factors
• Diabetes Mellitus, Experimental/genetics
• Anti-Inflammatory Agents
• Intramolecular Oxidoreductases

• helminth
• irradiated parasites
• purified parasite products
• vaccination
• whole parasite

• Animals
• Sheep
• Immunity, Mucosal
• Nematoda
• Ruminants
• Nematode Infections/prevention & control
• Nematode Infections/veterinary
• Gastrointestinal Diseases/drug therapy
• Goats
• Communicable Diseases/drug therapy
• Anthelmintics/pharmacology
• Sheep Diseases/prevention & control

• TC SRL5046 International Atomic Energy Agency

• Nrf2
• Trichinella spiralis
• oxidative stress
• resveratrol
• zinc

• Mice
• Animals
• Trichinellosis/parasitology
• Trichinella spiralis
• Resveratrol/therapeutic use
• Antioxidants/metabolism
• Zinc/pharmacology
• Zinc/therapeutic use
• Oxidative Stress
• Anti-Inflammatory Agents/pharmacology
• Biomarkers/metabolism

• CLEC10A
• LacdiNAc
• MGL
• Tn antigen
• fertilization
• immune evasion
• immune suppression
• metastatic cancer cells
• pregnancy
• tolerance

• Male
• Humans
• Ligands
• Galactose
• Antigen-Presenting Cells/metabolism
• Macrophages/metabolism
• Lectins, C-Type/metabolism

• SUBK.A411.23.063 Wroclaw Medical University

• EAE
• cytokines
• multiple sclerosis
•  Antigen B

• chronic infection
• dendritic cells
• pathology
• schistosomiasis
• transcriptomic (RNA-seq)

• Animals
• CD11c Antigen
• Immunity
• Inflammation
• Mice
• Schistosoma mansoni
• Schistosomiasis
• Schistosomiasis mansoni

• G0701437 Medical Research Council
• MR/V033417/1 Medical Research Council
• MR/W018748/1 Medical Research Council
• Wellcome Trust
• Medical Research Council

• TSP-1
• Th1
• Th2
• dendritic cells
• helminths
• immunometabolism
• liver fluke
• metaflammation

• Animals
• Dendritic Cells
• Diabetes Mellitus, Type 2/metabolism
• Fasciola hepatica
• Fatty Acid-Binding Proteins/genetics
• Fatty Acid-Binding Proteins/metabolism
• Homeostasis
• Interleukin-10/metabolism
• Mice
• Mice, Obese
• Proteomics
• Thrombospondin 1/metabolism

• autoimmunity
• cancer
• glycosylation
• immune system
• vaccination

• Animals
• Autoimmunity/immunology
• Cell Communication/immunology
• Humans
• Nanoparticles/chemistry
• Polysaccharides/chemistry
• Polysaccharides/immunology
• Protein Processing, Post-Translational
• Receptors, Chimeric Antigen/immunology
• T-Lymphocytes/immunology

• European Cooperation in Science and Technology

• Necator americanus
• Gut microbiota
• controlled human infection
• helminth
• hookworm
• longitudinal

Subcutaneous dirofilariosis in dogs, caused by Dirofilaria repens, is an underdiagnosed disease, now recognized for its zoonotic potential, and growing distribution and prevalence across Europe and Asia. Our understanding of the pathogenicity in human and canine host remains unclear, but case reports suggest that microfilariae (Mf) as well as adult D. repens may directly cause internal organs damage or may be a factor complicating the course of other ailments. The purpose of the study was to report high Mf in dogs and to discuss potential relevance with co-morbidity. Our data from a modified Knott's test performed on 62 infected dogs indicate that the median Mf count in D. repens infections is 675 Mf/ml and we consider microfilaremia above 10,000 Mf/ml as high intensity. This collection of case reports discusses 4 cases of high intensity D. repens microfilaremia in companion dogs; one presenting pathology from a very high intensity of adult D. repens with post-treatment complications, and 3 dogs in which high microfilaremia was detected incidentally during the management of other primary illnesses. To our knowledge this report describes the highest D. repens microfilaremia ever detected in a dog, at 178,000 Mf/ml. The issue of high microfilaremic infections in dogs is poorly studied and there is growing need to identify the presentation and understand the mechanisms of associated pathogenesis in the host-parasite relationship.

• dirofilariosis
• dog
• immunology
• microfilaremia
• natural Dirofilaria repens infection

• Trichinella spiralis
• excretory–secretory (ES)
• immunomodulatory
• inflammatory disorders

• Adaptive immunity
• T-helper 2 cells
• allergy
• antigen presentation
• conventional dendritic cells

Trichinella spiralis maintains chronic infections within its host. Muscle larvae excretory-secretory products (MLES) typically induce parasite-specific immune responses such as the Th2 response and regulatory T cells (Tregs) by modulating dendritic cell (DC) phenotype via the recognition of pattern recognition receptors (PRRs), such as Nod-like receptors (NLRs). We aimed to investigate the role of NLRP3 in T. spiralis-triggered immune response. We found that larvae burden was increased in NLRP3^−/− mice compared to wild type (WT) mice. Administration of MLES induced higher levels of IL-4, IL-10, TGF-β and population of Tregs in WT mice than in NLRP3^−/− mice. In vitro, we showed that increased expression of CD40 on the surface of MLES-treated DCs was inhibited after NLRP3 knockout. Increased production of IL-1β, IL-18, IL-10 and TGF-β, but not IL-12p70, was significantly diminished in the absence of NLRP3. Furthermore, our results demonstrated that MLES-treated DCs induced higher levels of IL-4, IL-10 and TGF-β and populations of Tregs in vitro. These inductions were abolished by NLRP3 deficiency in DCs, suggesting that NLRP3 in MLES-treated DCs plays a role in promoting the Th2 and Treg response. Taken together, we identified for the first time the involvement of NLRP3 in host defences against T. spiralis.

• NLRP3
• Th2
• Treg
• Trichinella spiralis
• dendritic cell
• excretory-secretory products

Fasciola gigantica infection threatens the health of both humans and animals in the world. The excretory/secretory products (ESPs) of this fluke has been reported to impair the activation and maturation of immune cells. We have previously shown the influence of F. gigantica ESPs (FgESPs) on the maturation of buffalo dendritic cells (DCs). However, the underlying mechanisms remain unclear. The objective of this study was to investigate the potency of FgESPs in shifting the differentiation and immune functions of buffalo DCs.

Buffalo DCs were incubated with FgESPs directly or further co-cultured with lymphocytes in vitro. qRT-PCR was employed to determine the gene expression profile of DCs or the mixed cells, and an ELISA was used to measure cytokine levels in the supernatants. Hoechst and Giemsa staining assays, transmission electron microscopy, caspase-3/7 activity test and histone methylation test were performed to determine DC phenotyping, apoptosis and methylation. To investigate the mechanism involved with DNA methylation, a Co-IP assay and immunofluorescent staining assay were performed to observe if there was any direct interaction between FgESPs and DNMT1/TET1 in buffalo DCs, while RNAi technology was employed to knockdown DNMT1 and TET1 in order to evaluate any different influence of FgESPs on DCs when these genes were absent.

qRT-PCR and ELISA data together demonstrated the upregulation of DC2 and Th2/Treg markers in DCs alone and DCs with a mixed lymphocyte reaction (MLR), suggesting a bias of DC2 that potentially directed Th2 differentiation in vitro. DC apoptosis was also found and evidenced morphologically and biochemically, which might be a source of tolerogenic DCs that led to Treg differentiation. In addition, FgESPs induced methylation level changes of histones H3K4 and H3K9, which correlate with DNA methylation. Co-IP and immunofluorescent subcellular localization assays showed no direct interaction between the FgESPs and DNMT1/TET1 in buffalo DCs. The productions of IL-6 and IL-12 were found separately altered by the knockdown of DNMT1 and TET1 in DCs after FgESPs treatment.

FgESPs may induce the DC2 phenotype or the apoptosis of buffalo DCs to induce the downstream Th2/Treg response of T cells, possibly through a DNMT1- or TET1-dependent manner(s).

• Dendritic cells
• Differentiation
• Excretory/secretory products
• Fasciola gigantica
• Immune functions

The large family of C-type lectin (CLEC) receptors comprises carbohydrate-binding proteins that require Ca²⁺ to bind a ligand. The prototypic receptor is the asialoglycoprotein receptor-1 (ASGR1, CLEC4H1) that is expressed primarily by hepatocytes. The early work on ASGR1, which is highly specific for N-acetylgalactosamine (GalNAc), established the foundation for understanding the overall function of CLEC receptors. Cells of the immune system generally express more than one CLEC receptor that serve diverse functions such as pathogen-recognition, initiation of cellular signaling, cellular adhesion, glycoprotein turnover, inflammation and immune responses. The receptor CLEC10A (C-type lectin domain family 10 member A, CD301; also called the macrophage galactose-type lectin, MGL) contains a carbohydrate-recognition domain (CRD) that is homologous to the CRD of ASGR1, and thus, is also specific for GalNAc. CLEC10A is most highly expressed on immature DCs, monocyte-derived DCs, and alternatively activated macrophages (subtype M2a) as well as oocytes and progenitor cells at several stages of embryonic development. This receptor is involved in initiation of T_H1, T_H2, and T_H17 immune responses and induction of tolerance in naïve T cells. Ligand-mediated endocytosis of CLEC receptors initiates a Ca²⁺ signal that interestingly has different outcomes depending on ligand properties, concentration, and frequency of administration. This review summarizes studies that have been carried out on these receptors.

• ASGR1
• CLEC10A
• IL-10
• IL-12
• T cell
• asialoglycoprotein receptor-1
• calcium
• dendritic cell
• lectin
• macrophage
• tolerance

Polyparasitism occurs when animals harbour multiple parasites concomitantly. It is a common occurrence but is generally understudied in wild and domestic animals. Fasciola hepatica and Echinococcus granulosus, which are helminths of ungulates, frequently coinfect cattle. The effects of this particular type of polyparasitism are not well documented. The metacestode of Echinococcus granulosus is surrounded by the adventitial layer, which constitutes the host immune response to the parasite. This layer in cattle is produced by a granulomatous reaction and is involved in echinococcal cyst (EC) fertility. Due to the systemic immune-modulating abilities of Fasciola hepatica, coinfection possibly generates a favourable environment for EC growth. A total of 203 Echinococcus granulosus sensu stricto cysts were found in 82 cattle, of which 42 ECs were found in 31 animals coinfected with Fasciola hepatica. The overall infection intensity was 3 cysts per animal. Coinfection with Fasciola hepatica decreased the mean infection intensity to 1.4 cysts per animal. Regarding EC size, coinfection resulted in smaller ECs (15.91 vs 22.09 mm), especially for infertile lung cysts. The adventitial layer of ECs in coinfected animals lacked lymphoid follicles and palisading macrophages, which are generally hallmarks of the granulomatous immune response. The ECs in coinfected animals had organized laminated layers, whereas those in animals without coinfection did not. Although coinfection was not statistically associated with EC fertility, we did not find fertile cysts in the livers of coinfected animals. We concluded that coinfection with Fasciola hepatica and Echinococcus granulosus has a detrimental effect on ECs, particularly infertile cysts.

• Aging
• Co-infection
• Helminth infections
• Immune risk phenotype
• Immunosenescence
• Inflammaging
• T helper 1
• T helper 2
• T regulatory cells

• Aged
• Aging
• Animals
• Friends
• Helminthiasis
• Helminths
• Humans
• Immunosenescence

• Autoimmune disorders
• Helminth therapy
• Inflammation
• Microbiota
• Neuropsychiatric disorders

• Animals
• Humans
• Immunomodulation/immunology
• Inflammation/immunology
• Inflammation/psychology
• Inflammation/therapy
• Mental Disorders/immunology
• Mental Disorders/psychology
• Mental Disorders/therapy
• Nervous System Diseases/immunology
• Nervous System Diseases/psychology
• Nervous System Diseases/therapy
• T-Lymphocytes, Regulatory/immunology
• Therapy with Helminths/methods
• Therapy with Helminths/trends

• Anisakis
• BALB/c mice
• C57BL/6J mice
• dendritic cells
• interleukin-10
• interleukin-12

• ASD
• Autism
• Gut-brain axis
• Helminths
• Immunomodulation
• Microbiome
• Treatment
• Trichuris suis

Schistosomiasis is endemic to many regions of the world and affects approximately 200 million people. Conventional adaptive T cell responses are considered to be the primary contributors to the pathogenesis of Schistosoma japonicum infection, leading to liver granuloma and fibrosis. However, the functional polarization of macrophages and the associated underlying molecular mechanisms during the pathogenesis of schistosomiasis remains unknown. In the present study, we found that excretory-secretory (ES) antigens derived from S. japonicum eggs can activate macrophages, which exhibit an M2b polarization. Furthermore, ES antigen-induced M2b polarization was found to be dependent on enhanced NF-κB signaling mediated by the MyD88/MAPK pathway in a TLR2-dependent manner. In addition, the cytokine profile of the liver macrophages from wild-type-infected mice are quite distinct from those found in TLR2 knockout-infected mice by quantitative PCR analysis. More importantly, the size of granuloma and the severity of the fibrosis in the livers of TLR2^-/- mice were significantly reduced compared to that in WT mice. Our findings reveal a novel role for M2b polarization in the pathogenesis of schistosome infection.

Schistosomiasis is a global health concern that affects primarily tropical and subtropical areas. During a schistosome infection, the eggs are trapped in the host liver and products derived from eggs induce a polarized Th2 response, resulting in granuloma formation and eventually fibrosis. Thus, it is important to elucidate the mechanism of granuloma formation and fibrosis development. Here, we show that activated macrophages play a novel role in the promotion of hepatic granuloma formation and liver fibrosis in a Schistosoma japonicum-infected mouse model. In addition, M2b polarization induced by egg products was dependent on enhanced NF-κB signaling mediated by the MyD88/MAPK pathway in a TLR2-dependent manner. Our findings reveal a novel role and mechanism of M2b polarization in the liver pathogenesis in S. japonicum-infected mice.

• Animals
• Antigens, Helminth/genetics
• Antigens, Helminth/metabolism
• Cell Polarity
• Female
• Helminth Proteins/genetics
• Helminth Proteins/metabolism
• Humans
• Liver/metabolism
• Liver/parasitology
• Liver/pathology
• Macrophages/cytology
• Macrophages/metabolism
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Ovum/metabolism
• Rabbits
• Schistosoma japonicum/genetics
• Schistosoma japonicum/metabolism
• Schistosomiasis japonica/parasitology
• Schistosomiasis japonica/pathology
• Schistosomiasis japonica/physiopathology
• Signal Transduction
• Toll-Like Receptors/genetics
• Toll-Like Receptors/metabolism

• the National Natural Science Foundation of China
• the Fourth Round of Three-Year Public Health Action Plan of Shanghai, China

• ChIP-seq
• RNA-seq
• Th2 response
• ZEB1
• cDC1 dendritic cells
• helminth infection
• immune modulation
• integrative genomics

• disease tolerance
• helminth
• immunity
• infection
• intestine

Chronic helminth infection with Schistosoma (S.) mansoni protects against allergic airway inflammation (AAI) in mice and is associated with reduced Th2 responses to inhaled allergens in humans, despite the presence of schistosome‐specific Th2 immunity. Schistosome eggs strongly induce type 2 immunity and allow to study the dynamics of Th2 versus regulatory responses in the absence of worms. Treatment with isolated S. mansoni eggs by i.p. injection prior to induction of AAI to ovalbumin (OVA)/alum led to significantly reduced AAI as assessed by less BAL and lung eosinophilia, less cellular influx into lung tissue, less OVA‐specific Th2 cytokines in lungs and lung‐draining mediastinal lymph nodes and less circulating allergen‐specific IgG1 and IgE antibodies. While OVA‐specific Th2 responses were inhibited, treatment induced a strong systemic Th2 response to the eggs. The protective effect of S. mansoni eggs was unaltered in μMT mice lacking mature (B2) B cells and unaffected by Treg cell depletion using anti‐CD25 blocking antibodies during egg treatment and allergic sensitization. Notably, prophylactic egg treatment resulted in a reduced influx of pro‐inflammatory, monocyte‐derived dendritic cells into lung tissue of allergic mice following challenge. Altogether, S. mansoni eggs can protect against the development of AAI, despite strong egg‐specific Th2 responses.

• Schistosoma mansoni
• B lymphocytes
• Th2 cells
• allergy and immunology
• antigen-presenting cells
• asthma
• helminths

• Co-infection
• Helminths
• Host-pathogen interaction
• Malaria
• Mixed infections
• Plasmodium yoelii 17XL
• Taenia crassiceps

Recent studies have shown that similar host glycan antigens are expressed by helminths such as Echinococcus granulosus hydatid cysts to evade from host immune system. In this work to investigate these antigens further, immunological cross-reactivity between human sera and hydatid cyst wall antigens has been investigated.

Hydatid cyst wall antigens were used in enzyme-linked immunosorbent assay and Western immunoblotting and probed with pooled sera of hydatidosis patients and healthy controls. Sodium metaperiodate treatment was used to investigate glycan antigens.

A band with molecular weight about 53 KDa reacted with both hydatid patients' sera and also normal human sera. It has been shown that this band was a glycan antigen.

A 53 KDa glycan antigen of hydatid cyst wall that reacted with all human sera may have an important role for evasion from host immune system.

• Antigen
• glycan
• hydatid cyst
• immune evasion

The survival of helminths in the host over long periods of time is the result of a process of adaptation or dynamic co-evolution between the host and the parasite. However, infection with helminth parasites causes damage to the host tissues producing the release of danger signals that induce the recruitment of various cells, including innate immune cells such as macrophages (Mo), dendritic cells (DCs), eosinophils, basophils, and mast cells. In this scenario, these cells are able to secrete soluble factors, which orchestrate immune effector mechanisms that depend on the different niches these parasites inhabit. Here, we focus on recent advances in the knowledge of excretory-secretory products (ESP), resulting from helminth recognition by DCs and Mo. Phagocytes and other cells types such as innate lymphocyte T cells 2 (ILC2), when activated by ESP, participate in an intricate cytokine network to generate innate and adaptive Th2 responses. In this review, we also discuss the mechanisms of innate immune cell-induced parasite killing and the tissue repair necessary to assure helminth survival over long periods of time.

• M2 macrophages
• dendritic cells
• effector mechanisms
• excretory-secretory products
• helminths
• phagocytes
• tissue repair

Dendritic cells (DCs) are key directors of tolerogenic and immunogenic immune responses. During the steady state, DCs maintain T cell tolerance to self-antigens by multiple mechanisms including inducing anergy, deletion, and Treg activity. All of these mechanisms help to prevent autoimmune diseases or other hyperreactivities. Different DC subsets contribute to pathogen recognition by expression of different subsets of pattern recognition receptors, including Toll-like receptors or C-type lectins. In addition to the triggering of immune responses in infected hosts, most pathogens have evolved mechanisms for evasion of targeted responses. One such strategy is characterized by adopting the host’s T cell tolerance mechanisms. Understanding these tolerogenic mechanisms is of utmost importance for therapeutic approaches to treat immune pathologies, tumors and infections. Transcriptional profiling has developed into a potent tool for DC subset identification. Here, we review and compile pathogen-induced tolerogenic transcriptional signatures from mRNA profiling data of currently available bacterial- or helminth-induced transcriptional signatures. We compare them with signatures of tolerogenic steady-state DC subtypes to identify common and divergent strategies of pathogen induced immune evasion. Candidate molecules are discussed in detail. Our analysis provides further insights into tolerogenic DC signatures and their exploitation by different pathogens.

• bacteria
• helminths
• immune evasion
• mycobacteria
• steady-state dendritic cells
• tolerogenic dendritic cells
• transcriptional profiling

Trichinella spiralis, as well as its muscle larvae excretory–secretory products (ES L1), given either alone or via dendritic cells (DCs), induce a tolerogenic immune microenvironment in inbred rodents and successfully ameliorate experimental autoimmune encephalomyelitis. ES L1 directs the immunological balance away from T helper (Th)1, toward Th2 and regulatory responses by modulating DCs phenotype. The ultimate goal of our work is to find out if it is possible to translate knowledge obtained in animal model to humans and to generate human tolerogenic DCs suitable for therapy of autoimmune diseases through stimulation with ES L1. Here, the impact of ES L1 on the activation of human monocyte-derived DCs is explored for the first time. Under the influence of ES L1, DCs acquired tolerogenic (semi-matured) phenotype, characterized by low expression of HLA-DR, CD83, and CD86 as well as moderate expression of CD40, along with the unchanged production of interleukin (IL)-12 and elevated production of IL-10 and transforming growth factor (TGF)-β, compared to controls. The interaction with DCs involved toll-like receptors (TLR) 2 and 4, and this interaction was mainly responsible for the phenotypic and functional properties of ES L1-treated DCs. Importantly, ES L1 potentiated Th2 polarizing capacity of DCs, and impaired their allo-stimulatory and Th1/Th17 polarizing properties. Moreover, ES L1-treated DCs promoted the expansion of IL-10- and TGF-β- producing CD4⁺CD25^hiFoxp3^hi T cells in indolamine 2, 3 dioxygenase (IDO)-1-dependent manner and increased the suppressive potential of the primed T cell population. ES L1-treated DCs retained the tolerogenic properties, even after the challenge with different pro-inflammatory stimuli, including those acting via TLR3 and, especially TLR4. These results suggest that the induction of tolerogenic properties of DCs through stimulation with ES L1 could represent an innovative approach for the preparation of tolerogenic DC for treatment of inflammatory and autoimmune disorders.

• Trichinella spiralis
• dendritic cells
• excretory–secretory products
• immunomodulation
• tolerance
• toll-like receptors

• Alternative activation
• CD11b+ dendritic cells
• Helminth infection
• Programmed Death-Ligand 2
• Th2

Despite marked improvement in the quality of lives across the globe, more than 2 million individuals in socioeconomically disadvantaged environments remain infected by helminth (worm) parasites. Owing to the longevity of the worms and paucity of immunologic controls, these parasites survive for long periods within the bloodstream, lymphatics, and gastrointestinal tract resulting in pathologic conditions such as anemia, cirrhosis, and lymphatic filariasis. Despite infection, an asymptomatic state may be maintained by the host immunoregulatory environment, which involves multiple levels of regulatory cells and cytokines; a breakdown of this regulation is observed in pathological disease. The role of TLR expression and function in relation to intracellular parasites has been documented but limited studies are available for multicellular helminth parasites. In this review, we discuss the unique and shared host effector mechanisms elicited by systemic helminth parasites and their derived products, including the role of TLRs and sphingolipids. Understanding and exploiting the interactions between these parasites and the host regulatory network are likely to highlight new strategies to control both infectious and immunological diseases.

• Autoimmunity
• Cytokines
• Dendritic cells
• Echinococcus granulosus
• Immunity
• Lymphocytes

• Allergic airway inflammation
• Lung
• Regulatory B cell
• Schistosoma
• Th2 response

• culture
• excretions-secretions
• immunomodulation
• metacestode

• excretory secretory antigen
• helminths
• immune evasion
• immune regulation
• parasites
• taeniids

• helminth therapy
• immune regulation
• inflammatory bowel disease
• lipids
• multiple sclerosis

Accumulating evidences have assigned a central role to parasite-derived proteins in immunomodulation. Here, we report on the proteomic identification and characterization of immunomodulatory excretory-secretory (ES) products from the metacestode larva (tetrathyridium) of the tapeworm Mesocestoides corti (syn. M. vogae). We demonstrate that ES products but not larval homogenates inhibit the stimuli-driven release of the pro-inflammatory, Th1-inducing cytokine IL-12p70 by murine bone marrow-derived dendritic cells (BMDCs). Within the ES fraction, we biochemically narrowed down the immunosuppressive activity to glycoproteins since active components were lipid-free, but sensitive to heat- and carbohydrate-treatment. Finally, using bioassay-guided chromatographic analyses assisted by comparative proteomics of active and inactive fractions of the ES products, we defined a comprehensive list of candidate proteins released by M. corti tetrathyridia as potential suppressors of DC functions. Our study provides a comprehensive library of somatic and ES products and highlight some candidate parasite factors that might drive the subversion of DC functions to facilitate the persistence of M. corti tetrathyridia in their hosts.

The metacestode larval stages of life-threatening tapeworms grow within the organs of its mammalian hosts, thus causing severe and long-lasting morbidity. Immunosuppression, which mainly depends on factors that are released or leaking from the parasite, plays an important role in both survival and proliferation of the larvae. These parasite-derived molecules are potential targets for developing new anti-parasitic drugs and/or improving the effectiveness of current therapies. Moreover, an optimized use of such factors could help to minimize pathologies resulting from uncontrolled immune responses, like allergies and autoimmune diseases. The authors herein demonstrate that larvae from a parasitic cestode release factors that sufficiently support the suppression of dendritic cells, a set of innate immune cells that recognizes and initiates host immune responses against invading pathogens. Employing modern analytic proteomic tools combined with immunological bioassays, several cestode-derived candidate immunomodulators were identified. This is the first bioassay-guided comprehensive library of candidate immunomodulators from a tissue-dwelling cestode larva. This work validates the unmet value of the Mesocestoides corti system in characterizing the mechanisms of host immunomodulation by metacestodes and reveals the largest database of candidate metacestode-derived immunomodulators until date.

• Animals
• Bone Marrow Cells/immunology
• Bone Marrow Cells/parasitology
• Cestode Infections/immunology
• Cestode Infections/parasitology
• Dendritic Cells/immunology
• Dendritic Cells/parasitology
• Helminth Proteins/chemistry
• Helminth Proteins/genetics
• Helminth Proteins/immunology
• Humans
• Larva/chemistry
• Larva/genetics
• Larva/immunology
• Mesocestoides/chemistry
• Mesocestoides/genetics
• Mesocestoides/immunology
• Mice
• Mice, Inbred BALB C
• Proteomics

• Wellcome Trust
• Academy of Science of South Africa
• German Academic Exchange Service
• Boehringer Ingelheim
• Consehlo Nacional de Desenvolvimento Cientitico e Tecnologica
• Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (BR)