Helminthic dehydrogenase drives PGE2 and IL-10 production in monocytes to potentiate Treg induction.

Immunoregulation of inflammatory, infection-triggered processes in the brain constitutes a central mechanism to control devastating disease manifestations such as epilepsy. Observational studies implicate the viability of Taenia solium cysts as key factor determining severity of neurocysticercosis (NCC), the most common cause of epilepsy, especially in children, in Sub-Saharan Africa. Viable, in contrast to decaying, cysts mostly remain clinically silent by yet unknown mechanisms, potentially involving Tregs in controlling inflammation. Here, we show that glutamate dehydrogenase from viable cysts instructs tolerogenic monocytes to release IL-10 and the lipid mediator PGE2 . These act in concert, converting naive CD4+ T cells into CD127- CD25hi FoxP3+ CTLA-4+ Tregs, through the G protein-coupled receptors EP2 and EP4 and the IL-10 receptor. Moreover, while viable cyst products strongly upregulate IL-10 and PGE2 transcription in microglia, intravesicular fluid, released during cyst decay, induces pro-inflammatory microglia and TGF-ß as potential drivers of epilepsy. Inhibition of PGE2 synthesis and IL-10 signaling prevents Treg induction by viable cyst products. Harnessing the PGE2 -IL-10 axis and targeting TGF-ß signaling may offer an important therapeutic strategy in inflammatory epilepsy and NCC.

Infection Control Measures and Prevalence of SARS-CoV-2 IgG among 4,554 University Hospital Employees, Munich, Germany.

Hospital staff are at high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the coronavirus disease (COVID-19) pandemic. This cross-sectional study aimed to determine the prevalence of SARS-CoV-2 infection in hospital staff at the University Hospital rechts der Isar in Munich, Germany, and identify modulating factors. Overall seroprevalence of SARS-CoV-2-IgG in 4,554 participants was 2.4%. Staff engaged in direct patient care, including those working in COVID-19 units, had a similar probability of being seropositive as non-patient-facing staff. Increased probability of infection was observed in staff reporting interactions with SARS-CoV-2‒infected coworkers or private contacts or exposure to COVID-19 patients without appropriate personal protective equipment. Analysis of spatiotemporal trajectories identified that distinct hotspots for SARS-CoV-2‒positive staff and patients only partially overlap. Patient-facing work in a healthcare facility during the SARS-CoV-2 pandemic might be safe as long as adequate personal protective equipment is used and infection prevention practices are followed inside and outside the hospital.

Fetomaternal immune cross talk modifies T-cell priming through sustained changes to DC function.

BACKGROUND: Prenatal exposure to infections can modify immune development. These environmental disturbances during early life potentially alter the incidence of inflammatory disorders as well as priming of immune responses. Infection with the helminth Schistosoma mansoni is widely studied for its ability to alter immune responsiveness and is associated with variations in coinfection, allergy, and vaccine efficacy in endemic populations. OBJECTIVE: Exposure to maternal schistosomiasis during early life, even without transmission of infection, can result in priming effects on offspring immune responses to bystander antigenic challenges as related to allergic responsiveness and vaccination, with this article seeking to further clarify the effects and underlying immunologic imprinting. METHODS: Here, we have combined a model of chronic maternal schistosomiasis infection with a thorough analysis of subsequent offspring immune responses to allergy and vaccination models, including viral challenge and steady-state changes to immune cell compartments. RESULTS: We have demonstrated that maternal schistosomiasis alters CD4+ responses during allergic sensitization and challenge in a skewed IL-4/B-cell-dominant response to antigenic challenge associated with limited inflammatory response. Beyond that, we have uncovered previously unidentified alterations to CD8+ T-cell responses during immunization that are dependent on vaccine formulation and have functional impact on the efficacy of vaccination against viral infection in a murine hepatitis B virus model. CONCLUSION: In addition to steady-state modifications to CD4+ T-cell polarization and B-cell priming, we have traced these modified CD8+ responses to an altered dendritic cell phenotype sustained into adulthood, providing evidence for complex priming effects imparted by infection via fetomaternal cross talk.

Dectin-1/2-induced autocrine PGE2 signaling licenses dendritic cells to prime Th2 responses.

The molecular mechanisms through which dendritic cells (DCs) prime T helper 2 (Th2) responses, including those elicited by parasitic helminths, remain incompletely understood. Here, we report that soluble egg antigen (SEA) from Schistosoma mansoni, which is well known to drive potent Th2 responses, triggers DCs to produce prostaglandin E2 (PGE2), which subsequently-in an autocrine manner-induces OX40 ligand (OX40L) expression to license these DCs to drive Th2 responses. Mechanistically, SEA was found to promote PGE2 synthesis through Dectin-1 and Dectin-2, and via a downstream signaling cascade involving spleen tyrosine kinase (Syk), extracellular signal-regulated kinase (ERK), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase 1 and 2 (COX-1 and COX-2). In addition, this pathway was activated independently of the actions of omega-1 (ω-1), a previously described Th2-priming glycoprotein present in SEA. These findings were supported by in vivo murine data showing that ω-1-independent Th2 priming by SEA was mediated by Dectin-2 and Syk signaling in DCs. Finally, we found that Dectin-2-/-, and to a lesser extent Dectin-1-/- mice, displayed impaired Th2 responses and reduced egg-driven granuloma formation following S. mansoni infection, highlighting the physiological importance of this pathway in Th2 polarization during a helminth infection. In summary, we identified a novel pathway in DCs involving Dectin-1/2-Syk-PGE2-OX40L through which Th2 immune responses are induced.

Dynamic, Helminth-Induced Immune Modulation Influences the Outcome of Acute and Chronic Hepatitis B Virus Infection.

BACKGROUND: Chronic hepatitis B develops more frequently in countries with high prevalence of helminth infections. The crosstalk between these 2 major liver-residing pathogens, Schistosoma mansoni and hepatitis B virus (HBV), is barely understood. METHODS: We used state-of-the-art models for both acute and chronic HBV infection to study the pathogen-crosstalk during the different immune phases of schistosome infection. RESULTS: Although liver pathology caused by schistosome infection was not affected by either acute or chronic HBV infection, S mansoni infection influenced HBV infection outcomes in a phase-dependent manner. Interferon (IFN)-γ secreting, HBV- and schistosome-specific CD8 T cells acted in synergy to reduce HBV-induced pathology during the TH1 phase and chronic phase of schistosomiasis. Consequently, HBV was completely rescued in IFN-γ-deficient or in TH2 phase coinfected mice demonstrating the key role of this cytokine. It is interesting to note that secondary helminth infection on the basis of persistent (chronic) HBV infection increased HBV-specific T-cell frequency and resulted in suppression of virus replication but failed to fully restore T-cell function and eliminate HBV. CONCLUSIONS: Thus, schistosome-induced IFN-γ had a prominent antiviral effect that outcompeted immunosuppressive effects of TH2 cytokines, whereas HBV coinfection did not alter schistosome pathogenicity.

Maternal helminth infections and the shaping of offspring immunity.

Helminth infections leave a long-lasting immunological footprint on their hosts. Clinical studies have provided first evidence that maternal helminth infections can result in an altered immune profile in their offspring which can potentially shape how they respond to conditions throughout life. This can relate to changes in offspring induction of immune responses against other diseases. However, whether these changes result in actual changes in offspring ability to control disease is unclear. Our understanding of which immune mechanisms are altered and how they are changed is limited. In this review, we highlight what we know from human and mouse studies about this important context of helminth exposure. Moreover, we discuss how mechanisms such as antibody transfer, antigen exposure, maternal cell uptake, chimerism and epigenetics are all likely to be functional contributors to the striking changes that are seen in offspring born or nursed by helminth exposed mothers.

Chronic schistosomiasis during pregnancy epigenetically reprograms T-cell differentiation in offspring of infected mothers.

Schistosomiasis is a nontransplacental helminth infection. Chronic infection during pregnancy suppresses allergic airway responses in offspring. We addressed the question whether in utero exposure to chronic schistosome infection (Reg phase) in mice affects B-cell and T-cell development. Therefore, we focused our analyses on T-cell differentiation capacity induced by epigenetic changes in promoter regions of signature cytokines in offspring. Here, we show that naïve T cells from offspring of schistosome infected female mice had a strong capacity to differentiate into TH 1 cells, whereas TH 2 differentiation was impaired. In accordance, reduced levels of histone acetylation of the IL-4 promoter regions were observed in naïve T cells. To conclude, our mouse model revealed distinct epigenetic changes within the naïve T-cell compartment affecting TH 2 and TH 1 cell differentiation in offspring of mothers with chronic helminth infection. These findings could eventually help understand how helminths alter T-cell driven immune responses induced by allergens, bacterial or viral infections, as well as vaccines.

Microbes and asthma: Opportunities for intervention.

The worldwide incidence and prevalence of asthma continues to increase. Asthma is now understood as an umbrella term for different phenotypes or endotypes, which arise through different pathophysiologic pathways. Understanding the many factors contributing to development of the disease is important for the identification of novel therapeutic targets for the treatment of certain asthma phenotypes. The hygiene hypothesis has been formulated to explain the increasing prevalence of allergic disease, including asthma. This hypothesis postulates that decreased exposure at a young age to certain infectious agents as a result of improved hygiene, increased antibiotic use and vaccination, and changes in lifestyle and dietary habits is associated with changes in the immune system, which predispose subjects to allergy. Many microbes, during their coevolution with human subjects, developed mechanisms to manipulate the human immune system and to increase their chances of survival. Improving models of asthma, as well as choosing adequate end points in clinical trials, will lead to a more complete understanding of the underlying mechanisms, thus providing an opportunity to devise primary and secondary interventions at the same time as identifying new molecular targets for treatment. This article reports the discussion and conclusion of a workshop under the auspices of the Netherlands Lung Foundation to extend our understanding of how modulation of the immune system by bacterial, parasitic, and viral infections might affect the development of asthma and to map out future lines of investigation.

T cell-derived IL-4/IL-13 protects mice against fatal Schistosoma mansoni infection independently of basophils.

Schistosomiasis is a severe and chronic disease caused by the parasitic trematode Schistosoma mansoni after deposition of eggs in the liver and intestines. The immune response to S. mansoni eggs is characterized by increased Th2 cells, eosinophilia, and high serum IgE levels. Granulomas are formed around the eggs to protect the organs against tissue damage caused by toxic products that are secreted from the eggs. Egg-derived components have further been shown to activate the IgE-mediated release of IL-4 and IL-13 from basophils, suggesting that basophils could be involved in protection against a fatal course of infection. Using T cell-specific IL-4/IL-13-deficient mice and basophil-deficient Mcpt8Cre mice, we determined the contribution of Th2 cells and basophils for protective immunity against S. mansoni egg-induced pathology during the patent stage of infection. Our results demonstrate that T cell-derived IL-4/IL-13 was essential for granuloma formation, IgE production, basophilia, differentiation of alternatively activated macrophages, and protection against fatal infection. Although basophils were recruited into liver granulomas, they appeared to be dispensable as a source of IL-4/IL-13 both for differentiation of Th2 cells and for prevention of weight loss and mortality.

Helicobacter pylori-induced IL-1ß secretion in innate immune cells is regulated by the NLRP3 inflammasome and requires the cag pathogenicity island.

Infection with the gram-negative bacterium Helicobacter pylori is the most prevalent chronic bacterial infection, affecting ∼50% of the world's population, and is the main risk factor of gastric cancer. The proinflammatory cytokine IL-1ß plays a crucial role in the development of gastric tumors and polymorphisms in the IL-1 gene cluster leading to increased IL-1ß production have been associated with increased risk for gastric cancer. To be active, pro-IL-1ß must be cleaved by the inflammasome, an intracellular multiprotein complex implicated in physiological and pathological inflammation. Recently, H. pylori was postulated to activate the inflammasome in murine bone marrow-derived dendritic cells; however, the molecular mechanisms as well as the bacterial virulence factor acting as signal 2 activating the inflammasome remain elusive. In this study, we analyzed the inflammasome complex regulating IL-1ß upon H. pylori infection as well as the molecular mechanisms involved. Our results indicate that H. pylori-induced IL-1ß secretion is mediated by activation of the nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 inflammasome. We also show that reactive oxygen species, potassium efflux, and lysosomal destabilization are the main cellular mechanisms responsible of nucleotide-binding oligomerization domain family, pyrin domain-containing 3 inflammasome activation upon H. pylori infection, and identify vacuolating cytotoxin A and cag pathogenicity island as the bacterial virulence determinants involved. Moreover, in vivo experiments indicate an important role for the inflammasome in the onset and establishment of H. pylori infection and in the subsequent inflammatory response of the host.

Maternal immune response to helminth infection during pregnancy determines offspring susceptibility to allergic airway inflammation.

BACKGROUND: Schistosomiasis, a chronic helminth infection, elicits distinct immune responses within the host, ranging from an initial TH1 and subsequent TH2 phase to a regulatory state, and is associated with dampened allergic reactions within the host. OBJECTIVE: We sought to evaluate whether non-transplacental helminth infection during pregnancy alters the offspring's susceptibility to allergy. METHODS: Ovalbumin-induced allergic airway inflammation was analyzed in offspring from Schistosoma mansoni-infected mothers mated during the TH1, TH2, or regulatory phase of infection. Embryos derived from in vitro fertilized oocytes of acutely infected females were transferred into uninfected foster mice to determine the role of placental environment. The fetomaternal unit was further characterized by helminth-specific immune responses and microarray analyses. Eventually, IFN-γ-deficient mice were infected to evaluate the role of this predominant cytokine on the offspring's allergy phenotype. RESULTS: We demonstrate that offspring from schistosome-infected mothers that were mated in the TH1 and regulatory phases, but not the TH2 immune phase, are protected against the onset of allergic airway inflammation. Interestingly, these effects were associated with distinctly altered schistosome-specific cytokine and gene expression profiles within the fetomaternal interface. Furthermore, we identified that it is not the transfer of helminth antigens but rather maternally derived IFN-γ during the acute phase of infection that is essential for the progeny's protective immune phenotype. CONCLUSION: Overall, we present a novel immune phase-dependent coherency between the maternal immune responses during schistosomiasis and the progeny's predisposition to allergy. Therefore, we propose to include helminth-mediated transmaternal immune modulation into the expanded hygiene hypothesis.

Impact of helminth infections during pregnancy on maternal and newborn Vitamin D and on birth outcomes.

Poor birth outcomes in low- and middle income countries are associated with maternal vitamin D deficiency and chronic helminth infections. Here, we investigated whether maternal Schistosoma haematobium affects maternal or cord vitamin D status as well as birth outcomes. In a prospective cross-sectional study of pregnant women conducted in Lambaréné, Gabon, we diagnosed maternal parasitic infections in blood, urine and stool. At delivery we measured vitamin D in maternal and cord blood. S. haematobium, soil-transmitted helminths, and microfilariae were found at prevalences of 30.2%, 13.0%, and 8.8%, respectively. Insufficient vitamin D and calcium levels were found in 28% and 15% of mothers, and in 11.5% and 1.5% of newborns. Mothers with adequate vitamin D had lower risk of low birthweight babies (aOR = 0.11, 95% CI 0.02-0.52, p = 0.01), whilst offspring of primipars had low cord vitamin D levels, and low vitamin D levels increased the risk of maternal inflammation. Maternal filariasis was associated with low calcium levels, but other helminth infections affected neither vitamin D nor calcium levels in either mothers or newborns. Healthy birth outcomes require maintenance of adequate vitamin D and calcium levels. Chronic maternal helminth infections do not disrupt those levels in a semi-rural setting in sub-Saharan Africa.

Schistosoma mansoni triggers Dectin-2, which activates the Nlrp3 inflammasome and alters adaptive immune responses.

The propensity of helminths, such as schistosomes, to immunomodulate the host's immune system is an essential aspect of their survival. Previous research has demonstrated how soluble schistosomal egg antigens (SEA) dampen TLR-signaling during innate immune responses. We show here that the suppressive effect by SEA on TLR signaling is simultaneously coupled to the activation of the Nlrp3 (NLR family, pyrin domain containing 3) inflammasome and thus IL-1ß production. Therefore, the responsible protein component of SEA contains the second signal that is required to trigger proteolytic pro-IL-1ß processing. Moreover, the SEA component binds to the Dectin-2/FcRγ (Fc receptor γ chain) complex and activates the Syk kinase signaling pathway to induce reactive oxygen species and potassium efflux. As IL-1ß has been shown to be an essential orchestrator against several pathogens we studied the in vivo consequences of Schistosoma mansoni infection in mice deficient in the central inflammasome adapter ASC and Nlrp3 molecule. These mice failed to induce local IL-1ß levels in the liver and showed decreased immunopathology. Interestingly, antigen-specific Th1, Th2, and Th17 responses were down-regulated. Overall, these data imply that component(s) within SEA induce IL-1ß production and unravel a crucial role of Nlrp3 during S. mansoni infection.

Spectrum of Helminth Infections in Migrants from Sub-Saharan Africa to Europe: A Literature Review.

Sub-Saharan Africa (SSA) is endemic to numerous neglected tropical diseases, including many helminth diseases. With the migration of people from this part of the world to Europe, as has been happening on a large scale since 2015, these diseases are becoming more relevant to European physicians. This work aims to summarize the recent literature on this topic and to raise awareness of helminth diseases afflicting SSA migrants. The databases PubMed, Embase, and MEDLINE were screened for literature published in English and German between January 1, 2015 and December 31, 2020. In total, 74 articles were included in this review. The spectrum of helminth infections in migrants from SSA found in the literature review is broad; current research, however, is particularly focused on infections with Schistosoma spp. and Strongyloides stercoralis. Both diseases are often characterized by a long course, with few or no symptoms, with the risk of long-term organ damage. Successful and reliable screening for schistosomiasis and strongyloidiasis is strongly recommended. However, the current diagnostic methods lack sensitivity and specificity, rendering the diagnosis challenging and reliable assessment of disease prevalence difficult. Novel diagnostic methods and a greater awareness of these diseases are urgently needed.

Epilepsy and nodding syndrome in association with an Onchocerca volvulus infection drive distinct immune profile patterns.

Previous studies have described the association of onchocerciasis (caused by Onchocerca volvulus) with epilepsy, including nodding syndrome, although a clear etiological link is still missing. Cases are found in different African countries (Tanzania, South Sudan, Uganda, Democratic Republic of the Congo, Central African Republic and Cameroon). In our study we investigated immunological parameters (cytokine, chemokine, immunoglobulin levels) in individuals from the Mahenge area, Tanzania, presenting with either epilepsy or nodding syndrome with or without O. volvulus infection and compared them to O. volvulus negative individuals from the same endemic area lacking neurological disorders. Additionally, cell differentiation was performed using blood smears and systemic levels of neurodegeneration markers, leiomodin-1 and N-acetyltyramine-O, ß-glucuronide (NATOG) were determined. Our findings revealed that cytokines, most chemokines and neurodegeneration markers were comparable between both groups presenting with epilepsy or nodding syndrome. However, we observed elevated eosinophil percentages within the O. volvulus positive epilepsy/nodding syndrome patients accompanied with increased eosinophilic cationic protein (ECP) and antigen-specific IgG levels in comparison to those without an O. volvulus infection. Furthermore, highest levels of NATOG were found in O. volvulus positive nodding syndrome patients. These findings highlight that the detection of distinct biomarkers might be useful for a differential diagnosis of epilepsy and nodding syndrome in O. volvulus endemic areas. Trial-registration: NCT03653975.

Correction: A novel cell-free method to culture Schistosoma mansoni from cercariae to juvenile worm stages for in vitro drug testing.

[This corrects the article DOI: 10.1371/journal.pntd.0006590.].

Hepatitis E, Schistosomiasis and Echinococcosis-Prevalence in a Cohort of Pregnant Migrants in Germany and Their Influence on Fetal Growth Restriction.

BACKGROUND: Infections, as well as adverse birth outcomes, may be more frequent in migrant women. Schistosomiasis, echinococcosis, and hepatitis E virus (HEV) seropositivity are associated with the adverse pregnancy outcomes of fetal growth restriction and premature delivery. METHODS: A cohort study of 82 pregnant women with a history of migration and corresponding delivery of newborns in Germany was conducted. RESULTS: Overall, 9% of sera tested positive for anti-HEV IgG. None of the patients tested positive for anti-HEV IgM, schistosomiasis, or echinococcus serology. Birth weights were below the 10th percentile for gestational age in 8.5% of the neonates. No association between HEV serology and fetal growth restriction (FGR) frequency was found. CONCLUSIONS: In comparison to German baseline data, no increased risk for HEV exposure or serological signs of exposure against schistosomiasis or echinococcosis could be observed in pregnant migrants. An influence of the anti-HEV serology status on fetal growth restriction could not be found.