Skin uses interdependent cellular networks for barrier integrity and host immunity, but most underlying mechanisms remain obscure. Herein, we demonstrate that the human parasitic helminth Schistosoma mansoni inhibited pruritus evoked by itch-sensing afferents bearing the Mas-related G-protein-coupled receptor A3 (MrgprA3) in mice. MrgprA3 neurons controlled interleukin (IL)-17+ γδ T cell expansion, epidermal hyperplasia and host resistance against S. mansoni through shaping cytokine expression in cutaneous antigen-presenting cells. MrgprA3 neuron activation downregulated IL-33 but induced IL-1β and tumor necrosis factor in macrophages and type 2 conventional dendritic cells partially through the neuropeptide calcitonin gene-related peptide. Macrophages exposed to MrgprA3-derived secretions or bearing cell-intrinsic IL-33 deletion showed increased chromatin accessibility at multiple inflammatory cytokine loci, promoting IL-17/IL-23-dependent changes to the epidermis and anti-helminth resistance. This study reveals a previously unrecognized intercellular communication mechanism wherein itch-inducing MrgprA3 neurons initiate host immunity against skin-invasive parasites by directing cytokine expression patterns in myeloid antigen-presenting cell subsets.

• MeSH
• Dendritic Cells immunology   MeSH
• Interleukin-33 * metabolism   immunology   MeSH
• Skin immunology   parasitology   MeSH
• Humans MeSH
• Macrophages immunology   metabolism   MeSH
• Myeloid Cells immunology   metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Neurons immunology   metabolism   MeSH
• Pruritus immunology   MeSH
• Receptors, G-Protein-Coupled * metabolism   immunology   genetics   MeSH
• Schistosoma mansoni * immunology   MeSH
• Schistosomiasis mansoni * immunology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Il33 protein, mouse MeSH Browser
• Interleukin-33 * MeSH
• Receptors, G-Protein-Coupled * MeSH

BACKGROUND: In Europe, avian schistosomes of the genus Trichobilharzia are the most common etiological agents involved in human cercarial dermatitis (swimmer's itch). Manifested by a skin rash, the condition is caused by an allergic reaction to cercariae of nonhuman schistosomes. Humans are an accidental host in this parasite's life cycle, while water snails are the intermediate, and waterfowl are the final hosts. The study aimed to conduct a molecular and phylogenetic analysis of Trichobilharzia species occurring in recreational waters in North-Eastern Poland. METHODOLOGY: The study area covered three water bodies (Lake Skanda, Lake Ukiel, and Lake Tyrsko) over the summer of 2021. In total, 747 pulmonate freshwater snails (Radix spp., Lymnaea stagnalis) were collected. Each snail was subjected to 1-2 h of light stimulation to induce cercarial expulsion. The phylogenetic analyses of furcocercariae were based on the partial sequence of the ITS region (ITS1, 5.8S rDNA, ITS2 and 28SrDNA). For Radix spp. phylogenetic analyses were based on the ITS-2 region. RESULTS: The prevalence of the Trichobilharzia species infection in snails was 0.5%. Two out of 478 (0.4%) L. stagnaliswere found to be infected with Trichobilharzia szidati. Moreover, two out of 269 (0.7%) snails of the genus Radix were positive for schistosome cercariae. Both snails were identified as Radix auricularia. One of them was infected with Trichobilharzia franki and the other with Trichobilharzia sp. CONCLUSIONS: Molecular identification of avian schistosome species, both at the intermediate and definitive hosts level, constitutes an important source of information on a potential threat and prognosis of local swimmer's itch occurrence, and helps to determine species diversity in a particular area.

• Keywords
• Avian schistosomes, Cercariae, Cercarial dermatitis, Trichobilharzia,
• MeSH
• DNA, Helminth genetics   MeSH
• Phylogeny * MeSH
• Snails parasitology   MeSH
• Trematode Infections parasitology   veterinary   epidemiology   MeSH
• Lakes parasitology   MeSH
• Humans MeSH
• Schistosomatidae * genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Poland epidemiology   MeSH
• Names of Substances
• DNA, Helminth MeSH

Helminth neuroinfections represent serious medical conditions, but the diversity of the host-parasite interplay within the nervous tissue often remains poorly understood, partially due to the lack of laboratory models. Here, we investigated the neuroinvasion of the mouse spinal cord by Trichobilharzia regenti (Schistosomatidae). Active migration of T. regenti schistosomula through the mouse spinal cord induced motor deficits in hindlimbs but did not affect the general locomotion or working memory. Histological examination of the infected spinal cord revealed eosinophilic meningomyelitis with eosinophil-rich infiltrates entrapping the schistosomula. Flow cytometry and transcriptomic analysis of the spinal cord confirmed massive activation of the host immune response. Of note, we recorded striking upregulation of the major histocompatibility complex II pathway and M2-associated markers, such as arginase or chitinase-like 3. Arginase also dominated the proteins found in the microdissected tissue from the close vicinity of the migrating schistosomula, which unselectively fed on the host nervous tissue. Next, we evaluated the pathological sequelae of T. regenti neuroinvasion. While no demyelination or blood-brain barrier alterations were noticed, our transcriptomic data revealed a remarkable disruption of neurophysiological functions not yet recorded in helminth neuroinfections. We also detected DNA fragmentation at the host-schistosomulum interface, but schistosomula antigens did not affect the viability of neurons and glial cells in vitro. Collectively, altered locomotion, significant disruption of neurophysiological functions, and strong M2 polarization were the most prominent features of T. regenti neuroinvasion, making it a promising candidate for further neuroinfection research. Indeed, understanding the diversity of pathogen-related neuroinflammatory processes is a prerequisite for developing better protective measures, treatment strategies, and diagnostic tools.

• MeSH
• Arginase metabolism   MeSH
• Biomarkers metabolism   MeSH
• Chemokines metabolism   MeSH
• Eosinophils metabolism   MeSH
• Major Histocompatibility Complex MeSH
• Immunity MeSH
• Trematode Infections immunology   metabolism   pathology   MeSH
• Host-Parasite Interactions MeSH
• Spinal Cord parasitology   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Neuroglia parasitology   MeSH
• Neurons parasitology   MeSH
• Schistosomatidae immunology   MeSH
• Gene Expression Profiling MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Arginase MeSH
• Biomarkers MeSH
• Chemokines MeSH

BACKGROUND: Avian schistosomes, the causative agents of human cercarial dermatitis (or swimmer's itch), die in mammals but the mechanisms responsible for parasite elimination are unknown. Here we examined the role of reactive nitrogen species, nitric oxide (NO) and peroxynitrite, in the immune response of mice experimentally infected with Trichobilharzia regenti, a model species of avian schistosomes remarkable for its neuropathogenicity. METHODS: Inducible NO synthase (iNOS) was localized by immunohistochemistry in the skin and the spinal cord of mice infected by T. regenti. The impact of iNOS inhibition by aminoguanidine on parasite burden and growth was then evaluated in vivo. The vulnerability of T. regenti schistosomula to NO and peroxynitrite was assessed in vitro by viability assays and electron microscopy. Additionally, the effect of NO on the activity of T. regenti peptidases was tested using a fluorogenic substrate. RESULTS: iNOS was detected around the parasites in the epidermis 8 h post-infection and also in the spinal cord 3 days post-infection (dpi). Inhibition of iNOS resulted in slower parasite growth 3 dpi, but the opposite effect was observed 7 dpi. At the latter time point, moderately increased parasite burden was also noticed in the spinal cord. In vitro, NO did not impair the parasites, but inhibited the activity of T. regenti cathepsins B1.1 and B2, the peptidases essential for parasite migration and digestion. Peroxynitrite severely damaged the surface tegument of the parasites and decreased their viability in vitro, but rather did not participate in parasite clearance in vivo. CONCLUSIONS: Reactive nitrogen species, specifically NO, do not directly kill T. regenti in mice. NO promotes the parasite growth soon after penetration (3 dpi), but prevents it later (7 dpi) when also suspends the parasite migration in the CNS. NO-related disruption of the parasite proteolytic machinery is partly responsible for this effect.

• Keywords
• 3-Nitrotyrosine, Cathepsin B, Nitric oxide, Nitric oxide synthase, Peroxynitrite, Schistosomatidae, Trichobilharzia,
• MeSH
• Central Nervous System parasitology   MeSH
• Guanidines pharmacology   MeSH
• Trematode Infections drug therapy   MeSH
• Skin parasitology   MeSH
• Peroxynitrous Acid pharmacology   MeSH
• Humans MeSH
• Spinal Cord parasitology   MeSH
• Mice MeSH
• Nitric Oxide pharmacology   MeSH
• Peptide Hydrolases drug effects   metabolism   MeSH
• Helminth Proteins drug effects   metabolism   MeSH
• Birds parasitology   MeSH
• Schistosoma drug effects   growth & development   pathogenicity   MeSH
• Schistosomatidae drug effects   growth & development   pathogenicity   MeSH
• Schistosomiasis drug therapy   MeSH
• Nitric Oxide Synthase drug effects   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Guanidines MeSH
• Peroxynitrous Acid MeSH
• Nitric Oxide MeSH
• pimagedine MeSH Browser
• Peptide Hydrolases MeSH
• Helminth Proteins MeSH
• Nitric Oxide Synthase MeSH

BACKGROUND: Helminth neuroinfections represent a serious health problem, but host immune mechanisms in the nervous tissue often remain undiscovered. This study aims at in vitro characterization of the response of murine astrocytes and microglia exposed to Trichobilharzia regenti which is a neuropathogenic schistosome migrating through the central nervous system of vertebrate hosts. Trichobilharzia regenti infects birds and mammals in which it may cause severe neuromotor impairment. This study was focused on astrocytes and microglia as these are immunocompetent cells of the nervous tissue and their activation was recently observed in T. regenti-infected mice. RESULTS: Primary astrocytes and microglia were exposed to several stimulants of T. regenti origin. Living schistosomulum-like stages caused increased secretion of IL-6 in astrocyte cultures, but no changes in nitric oxide (NO) production were noticed. Nevertheless, elevated parasite mortality was observed in these cultures. Soluble fraction of the homogenate from schistosomulum-like stages stimulated NO production by both astrocytes and microglia, and IL-6 and TNF-α secretion in astrocyte cultures. Similarly, recombinant cathepsins B1.1 and B2 triggered IL-6 and TNF-α release in astrocyte and microglia cultures, and NO production in astrocyte cultures. Stimulants had no effect on production of anti-inflammatory cytokines IL-10 or TGF-β1. CONCLUSIONS: Both astrocytes and microglia are capable of production of NO and proinflammatory cytokines IL-6 and TNF-α following in vitro exposure to various stimulants of T. regenti origin. Astrocytes might be involved in triggering the tissue inflammation in the early phase of T. regenti infection and are proposed to participate in destruction of migrating schistosomula. However, NO is not the major factor responsible for parasite damage. Both astrocytes and microglia can be responsible for the nervous tissue pathology and maintaining the ongoing inflammation since they are a source of NO and proinflammatory cytokines which are released after exposure to parasite antigens.

• Keywords
• Anti-inflammatory cytokines, Astrocytes, Avian schistosome, Cathepsin B, Microglia, Neuroinfection, Nitric oxide, Proinflammatory cytokines, Trichobilharzia regenti,
• MeSH
• Astrocytes immunology   parasitology   MeSH
• Interleukin-6 metabolism   MeSH
• Cells, Cultured MeSH
• Mice MeSH
• Neuroglia immunology   parasitology   MeSH
• Nitric Oxide metabolism   MeSH
• Schistosomatidae immunology   MeSH
• Tumor Necrosis Factor-alpha metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• interleukin-6, mouse MeSH Browser
• Interleukin-6 MeSH
• Nitric Oxide MeSH
• Tumor Necrosis Factor-alpha MeSH

Cercarial dermatitis (swimmer's itch) is a condition caused by infective larvae (cercariae) of a species-rich group of mammalian and avian schistosomes. Over the last decade, it has been reported in areas that previously had few or no cases of dermatitis and is thus considered an emerging disease. It is obvious that avian schistosomes are responsible for the majority of reported dermatitis outbreaks around the world, and thus they are the primary focus of this review. Although they infect humans, they do not mature and usually die in the skin. Experimental infections of avian schistosomes in mice show that in previously exposed hosts, there is a strong skin immune reaction that kills the schistosome. However, penetration of larvae into naive mice can result in temporary migration from the skin. This is of particular interest because the worms are able to migrate to different organs, for example, the lungs in the case of visceral schistosomes and the central nervous system in the case of nasal schistosomes. The risk of such migration and accompanying disorders needs to be clarified for humans and animals of interest (e.g., dogs). Herein we compiled the most comprehensive review of the diversity, immunology, and epidemiology of avian schistosomes causing cercarial dermatitis.

• MeSH
• Biodiversity MeSH
• Disease Outbreaks MeSH
• Host Specificity MeSH
• Humans MeSH
• Bird Diseases parasitology   transmission   MeSH
• Skin Diseases, Parasitic epidemiology   immunology   parasitology   prevention & control   MeSH
• Birds MeSH
• Schistosomiasis epidemiology   immunology   parasitology   prevention & control   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

Cercarial dermatitis (swimmer's itch) is a common non-communicable water-borne disease. It is caused by penetration of the skin by larvae (cercariae) of schistosomatid flukes and develops as a maculopapular skin eruption after repeated contacts with the parasites. The number of outbreaks of the disease is increasing, and cercarial dermatitis can therefore be considered as an emerging problem. Swimmer's itch is mostly associated with larvae of the bird schistosomes of Trichobilharzia spp. Recent results have shown that mammalian infections (including man) manifest themselves as an allergic reaction which is able to trap and eliminate parasites in the skin. Studies on mammals experimentally infected by bird schistosome cercariae revealed, however, that during primary infection, parasites are able to escape from the skin to the lungs or central nervous system. This review covers basic information on detection of the infectious agents in the field and the clinical course of the disease, including other pathologies which may develop after infection by cercariae, and diagnosis of the disease.

• MeSH
• Central Nervous System microbiology   MeSH
• Cercaria immunology   MeSH
• Dermatitis diagnosis   immunology   parasitology   MeSH
• Skin microbiology   pathology   MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Swimming MeSH
• Lung microbiology   MeSH
• Schistosoma MeSH
• Schistosomiasis complications   diagnosis   immunology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Bird schistosomes, besides being responsible for bird schistosomiasis, are known as causative agents of cercarial dermatitis. Cercarial dermatitis develops after repeated contact with cercariae, mainly of the genus Trichobilharzia, and was described as a type I, immediate hypersensitivity response, followed by a late phase reaction. The immune response is Th2 polarized. Primary infection leads to an inflammatory reaction that is insufficient to eliminate the schistosomes and schistosomula may continue its migration through the body of avian as well as mammalian hosts. However, reinfections of experimental mice revealed an immune reaction leading to destruction of the majority of schistosomula in the skin. Infection with the nasal schistosome Trichobilharzia regenti probably represents a higher health risk than infections with visceral schistosomes. After the skin penetration by the cercariae, parasites migrate via the peripheral nerves, spinal cord to the brain, and terminate their life cycle in the nasal mucosa of waterfowl where they lay eggs. T. regenti can also get over skin barrier and migrate to CNS of experimental mice. During heavy infections, neuroinfections of both birds and mammals lead to the development of a cellular immune response and axonal damage in the vicinity of the schistosomulum. Such infections are manifest by neuromotor disorders.

• Publication type
• Journal Article MeSH

Cercariae of bird schistosomes (genus Trichobilharzia) are able to penetrate the skin of mammals (noncompatible hosts), including humans, and cause a Th2-associated inflammatory cutaneous reaction termed cercarial dermatitis. The present study measured the antibody reactivity and antigen specificity of sera obtained after experimental infection of mice and natural infection of humans. Sera from mice re-infected with T. regenti showed a bias towards the development of antigen-specific IgM and IgG1 antibodies and elevated levels of total serum IgE, indicative of a Th2 polarized immune response. We also demonstrate that cercariae are a source of antigens triggering IL-4 release from basophils collected from healthy human volunteers. Analysis of sera from patients with a history of cercarial dermatitis revealed elevated levels of cercarial-specific IgG, particularly for samples collected from adults (> 14 years old) compared with children (8-14 years old), although elevated levels of antigen-specific IgE were not detected. In terms of antigen recognition, IgG and IgE antibodies in the sera of both mice and humans preferentially bound an antigen of 34 kDa. The 34 kDa molecule was present in both homogenate of cercariae, as well as cercarial excretory/secretory products, and we speculate it may represent a major immunogen initiating the Th2-immune response associated with cercarial dermatitis.

• MeSH
• Antigens, Helminth chemistry   immunology   MeSH
• Basophils immunology   MeSH
• Dermatitis immunology   parasitology   MeSH
• Child MeSH
• Adult MeSH
• Immunoglobulin E MeSH
• Immunoglobulin G blood   MeSH
• Immunoglobulin M blood   MeSH
• Interleukin-4 metabolism   MeSH
• Humans MeSH
• Adolescent MeSH
• Molecular Weight MeSH
• Mice MeSH
• Antibodies, Helminth blood   MeSH
• Schistosomatidae immunology   MeSH
• Age Factors MeSH
• Animals MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antigens, Helminth MeSH
• Immunoglobulin E MeSH
• Immunoglobulin G MeSH
• Immunoglobulin M MeSH
• Interleukin-4 MeSH
• Antibodies, Helminth MeSH

The passage of Trichobilharzia szidati schistosomula through the vertebrate lungs was examined in natural and abnormal hosts--birds (ducks Anas platyrhynchos f. domestica) and mammals (mice Mus musculus Bagg albino/c [BALB/c]), respectively. Using the methods of classical histology, the migratory route of worms was characterized, and the impact of migration on host tissues and the host cell reactions were evaluated. Living schistosomula were recorded in the lungs of ducks 2-10 days post infection (p.i.) and in the lungs of mice 2-4 days p.i. In ducks, the schistosomula migrated from the blood vessels through the blood capillaries to the lung tissue; then, they entered free air space of the lungs. The infection resulted in inflammatory reaction with nodules composed of infiltrated lymphocytes, heterophils, eosinophils and macrophages. These structures were formed around the blood vessels and in the gas-exchange tissues of the parabronchial walls and, consequently, in the walls of secondary bronchi. An extensive inflammation of secondary bronchi and parabronchi was observed. In the lungs of mice, the parasites were localized extravascularly in the alveolar walls. No migratory pattern similar to that in the lungs of ducks was recorded. No specific inflammatory reaction occurred. However, alveolar wall congestion, edema and lymphocyte infiltrates appeared and, therefore, pathogenicity of T. szidati was also confirmed in the murine host.

• MeSH
• Ducks parasitology   MeSH
• Mice, Inbred BALB C MeSH
• Mice MeSH
• Bird Diseases parasitology   MeSH
• Lung parasitology   pathology   MeSH
• Schistosomatidae physiology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH