Vitamin A mediates conversion of monocyte-derived macrophages into tissue-resident macrophages during alternative activation.

It remains unclear whether activated inflammatory macrophages can adopt features of tissue-resident macrophages, or what mechanisms might mediate such a phenotypic conversion. Here we show that vitamin A is required for the phenotypic conversion of interleukin 4 (IL-4)-activated monocyte-derived F4/80intCD206+PD-L2+MHCII+ macrophages into macrophages with a tissue-resident F4/80hiCD206-PD-L2-MHCII-UCP1+ phenotype in the peritoneal cavity of mice and during the formation of liver granulomas in mice infected with Schistosoma mansoni. The phenotypic conversion of F4/80intCD206+ macrophages into F4/80hiCD206- macrophages was associated with almost complete remodeling of the chromatin landscape, as well as alteration of the transcriptional profiles. Vitamin A-deficient mice infected with S. mansoni had disrupted liver granuloma architecture and increased mortality, which indicates that failure to convert macrophages from the F4/80intCD206+ phenotype to F4/80hiCD206- may lead to dysregulated inflammation during helminth infection.

A planetary health innovation for disease, food and water challenges in Africa.

Many communities in low- and middle-income countries globally lack sustainable, cost-effective and mutually beneficial solutions for infectious disease, food, water and poverty challenges, despite their inherent interdependence1-7. Here we provide support for the hypothesis that agricultural development and fertilizer use in West Africa increase the burden of the parasitic disease schistosomiasis by fuelling the growth of submerged aquatic vegetation that chokes out water access points and serves as habitat for freshwater snails that transmit Schistosoma parasites to more than 200 million people globally8-10. In a cluster randomized controlled trial (ClinicalTrials.gov: NCT03187366) in which we removed invasive submerged vegetation from water points at 8 of 16 villages (that is, clusters), control sites had 1.46 times higher intestinal Schistosoma infection rates in schoolchildren and lower open water access than removal sites. Vegetation removal did not have any detectable long-term adverse effects on local water quality or freshwater biodiversity. In feeding trials, the removed vegetation was as effective as traditional livestock feed but 41 to 179 times cheaper and converting the vegetation to compost provided private crop production and total (public health plus crop production benefits) benefit-to-cost ratios as high as 4.0 and 8.8, respectively. Thus, the approach yielded an economic incentive-with important public health co-benefits-to maintain cleared waterways and return nutrients captured in aquatic plants back to agriculture with promise of breaking poverty-disease traps. To facilitate targeting and scaling of the intervention, we lay the foundation for using remote sensing technology to detect snail habitats. By offering a rare, profitable, win-win approach to addressing food and water access, poverty alleviation, infectious disease control and environmental sustainability, we hope to inspire the interdisciplinary search for planetary health solutions11 to the many and formidable, co-dependent global grand challenges of the twenty-first century.

Development of prediction models to identify hotspots of schistosomiasis in endemic regions to guide mass drug administration.

Schistosomiasis is a neglected tropical disease affecting over 150 million people. Hotspots of Schistosoma transmission-communities where infection prevalence does not decline adequately with mass drug administration-present a key challenge in eliminating schistosomiasis. Current approaches to identify hotspots require evaluation 2-5 y after a baseline survey and subsequent mass drug administration. Here, we develop statistical models to predict hotspots at baseline prior to treatment comparing three common hotspot definitions, using epidemiologic, survey-based, and remote sensing data. In a reanalysis of randomized trials in 589 communities in five endemic countries, a regression model predicts whether Schistosoma mansoni infection prevalence will exceed the WHO threshold of 10% in year 5 ("prevalence hotspot") with 86% sensitivity, 74% specificity, and 93% negative predictive value (NPV; assuming 30% hotspot prevalence), and a regression model for Schistosoma haematobium achieves 90% sensitivity, 90% specificity, and 96% NPV. A random forest model predicts whether S. mansoni moderate and heavy infection prevalence will exceed a public health goal of 1% in year 5 ("intensity hotspot") with 92% sensitivity, 79% specificity, and 96% NPV, and a boosted trees model for S. haematobium achieves 77% sensitivity, 95% specificity, and 91% NPV. Baseline prevalence is a top predictor in all models. Prediction is less accurate in countries not represented in training data and for a third hotspot definition based on relative prevalence reduction over time ("persistent hotspot"). These models may be a tool to prioritize high-risk communities for more frequent surveillance or intervention against schistosomiasis, but prediction of hotspots remains a challenge.

Endogenous PGD2 acting on DP2 receptor counter regulates Schistosoma mansoni infection-driven hepatic granulomatous fibrosis.

Identifying new molecular therapies targeted at the severe hepatic fibrosis associated with the granulomatous immune response to Schistosoma mansoni infection is essential to reduce fibrosis-related morbidity/mortality in schistosomiasis. In vitro cell activation studies suggested the lipid molecule prostaglandin D2 (PGD2) as a potential pro-fibrotic candidate in schistosomal context, although corroboratory in vivo evidence is still lacking. Here, to investigate the role of PGD2 and its cognate receptor DP2 in vivo, impairment of PGD2 synthesis by HQL-79 (an inhibitor of the H-PGD synthase) or DP2 receptor inhibition by CAY10471 (a selective DP2 antagonist) were used against the fibrotic response of hepatic eosinophilic granulomas of S. mansoni infection in mice. Although studies have postulated PGD2 as a fibrogenic molecule, HQL-79 and CAY10471 amplified, rather than attenuated, the fibrotic response within schistosome hepatic granulomas. Both pharmacological strategies increased hepatic deposition of collagen fibers - an unexpected outcome accompanied by further elevation of hepatic levels of the pro-fibrotic cytokines TGF-ß and IL-13 in infected animals. In contrast, infection-induced enhanced LTC4 synthesis in the schistosomal liver was reduced after HQL-79 and CAY10471 treatments, and therefore, inversely correlated with collagen production in granulomatous livers. Like PGD2-directed maneuvers, antagonism of cysteinyl leukotriene receptors CysLT1 by MK571 also promoted enhancement of TGF-ß and IL-13, indicating a key down-regulatory role for endogenous LTC4 in schistosomiasis-induced liver fibrosis. An ample body of data supports the role of S. mansoni-driven DP2-mediated activation of eosinophils as the source of LTC4 during infection, including: (i) HQL-79 and CAY10471 impaired systemic eosinophilia, drastically decreasing eosinophils within peritoneum and hepatic granulomas of infected animals in parallel to a reduction in cysteinyl leukotrienes levels; (ii) peritoneal eosinophils were identified as the only cells producing LTC4 in PGD2-mediated S. mansoni-induced infection; (iii) the magnitude of hepatic granulomatous eosinophilia positively correlates with S. mansoni-elicited hepatic content of cysteinyl leukotrienes, and (iv) isolated eosinophils from S. mansoni-induced hepatic granuloma synthesize LTC4 in vitro in a PGD2/DP2 dependent manner. So, our findings uncover that granulomatous stellate cells-derived PGD2 by activating DP2 receptors on eosinophils does stimulate production of anti-fibrogenic cysLTs, which endogenously down-regulates the hepatic fibrogenic process of S. mansoni granulomatous reaction - an in vivo protective function which demands caution in the future therapeutic attempts in targeting PGD2/DP2 in schistosomiasis.

Dynamic profiles of lncRNAs reveal a functional natural antisense RNA that regulates the development of Schistosoma japonicum.

Schistosomes are flatworm parasites that undergo a complex life cycle involving two hosts. The regulation of the parasite's developmental processes relies on both coding RNAs and non-coding RNAs. However, the roles of non-coding RNAs, including long non-coding RNAs (lncRNAs) in schistosomes remain largely unexplored. Here we conduct advanced RNA sequencing on male and female S. japonicum during their pairing and reproductive development, resulting in the identification of nearly 8,000 lncRNAs. This extensive dataset enables us to construct a comprehensive co-expression network of lncRNAs and mRNAs, shedding light on their interactions during the crucial reproductive stages within the mammalian host. Importantly, we have also revealed a specific lncRNA, LNC3385, which appears to play a critical role in the survival and reproduction of the parasite. These findings not only enhance our understanding of the dynamic nature of lncRNAs during the reproductive phase of schistosomes but also highlight LNC3385 as a potential therapeutic target for combating schistosomiasis.

Winners vs. losers: Schistosoma mansoni intestinal and liver eggs exhibit striking differences in gene expression and immunogenicity.

The eggs of the blood fluke Schistosoma mansoni are the main cause of the clinical manifestations of chronic schistosomiasis. After laying, the egg "winners" attach to the endothelium of the mesenteric vein and, after a period of development, induce the growth of a small granuloma, which facilitates their passage to the intestinal lumen. Egg "losers" carried by the bloodstream to non-specific tissues also undergo full development and induce large granuloma formation, but their life ends there. Although these trapped eggs represent a dead end in the parasite life cycle, the vast majority of studies attempting to describe the biology of the S. mansoni eggs have studied these liver-trapped "losers" instead of migrating intestinal "winners". This raises the fundamental question of how these eggs differ. With robust comparative transcriptomic analysis performed on S. mansoni eggs isolated 7 weeks post infection, we show that gene expression is critically dependent on tissue localization, both in the early and late stages of development. While mitochondrial genes and venom allergen-like proteins are significantly upregulated in mature intestinal eggs, well-described egg immunomodulators IPSE/alpha-1 and omega-1, together with micro-exon genes, are predominantly expressed in liver eggs. In addition, several proteases and protease inhibitors previously implicated in egg-host interactions display clear tissue-specific gene expression patterns. These major differences in gene expression could be then reflected in the observed different ability of liver and intestinal soluble egg antigens to elicit host immune responses and in the shorter viability of miracidia hatched from liver eggs. Our comparative analysis provides a new perspective on the biology of parasite's eggs in the context of their development and tissue localization. These findings could contribute to a broader and more accurate understanding of parasite eggs interactions with the host, which have historically been often restricted to liver eggs and sometimes inaccurately generalized.

S. mansoni -derived omega-1 prevents OVA-specific allergic airway inflammation via hampering of cDC2 migration.

Chronic infection with Schistosoma mansoni parasites is associated with reduced allergic sensitization in humans, while schistosome eggs protects against allergic airway inflammation (AAI) in mice. One of the main secretory/excretory molecules from schistosome eggs is the glycosylated T2-RNAse Omega-1 (ω1). We hypothesized that ω1 induces protection against AAI during infection. Peritoneal administration of ω1 prior to sensitization with Ovalbumin (OVA) reduced airway eosinophilia and pathology, and OVA-specific Th2 responses upon challenge, independent from changes in regulatory T cells. ω1 was taken up by monocyte-derived dendritic cells, mannose receptor (CD206)-positive conventional type 2 dendritic cells (CD206+ cDC2), and by recruited peritoneal macrophages. Additionally, ω1 impaired CCR7, F-actin, and costimulatory molecule expression on myeloid cells and cDC2 migration in and ex vivo, as evidenced by reduced OVA+ CD206+ cDC2 in the draining mediastinal lymph nodes (medLn) and retainment in the peritoneal cavity, while antigen processing and presentation in cDC2 were not affected by ω1 treatment. Importantly, RNAse mutant ω1 was unable to reduce AAI or affect DC migration, indicating that ω1 effects are dependent on its RNAse activity. Altogether, ω1 hampers migration of OVA+ cDC2 to the draining medLn in mice, elucidating how ω1 prevents allergic airway inflammation in the OVA/alum mouse model.

Sja-let-7 suppresses the development of liver fibrosis via Schistosoma japonicum extracellular vesicles.

Schistosomiasis is a fatal zoonotic parasitic disease that also threatens human health. The main pathological features of schistosomiasis are granulomatous inflammation and subsequent liver fibrosis, which is a complex, chronic, and progressive disease. Extracellular vesicles (EVs) derived from schistosome eggs are broadly involved in host-parasite communication and act as important contributors to schistosome-induced liver fibrosis. However, it remains unclear whether substances secreted by the EVs of Schistosoma japonicum, a long-term parasitic "partner" in the hepatic portal vein of the host, also participate in liver fibrosis. Here, we report that EVs derived from S. japonicum worms attenuated liver fibrosis by delivering sja-let-7 into hepatic stellate cells (HSCs). Mechanistically, activation of HSCs was reduced by targeting collagen type I alpha 2 chain (Col1α2) and downregulation of the TGF-ß/Smad signaling pathway both in vivo and in vitro. Overall, these results contribute to further understanding of the molecular mechanisms underlying host-parasite interactions and identified the sja-let-7/Col1α2/TGF-ß/Smad axis as a potential target for treatment of schistosomiasis-related liver fibrosis.

Schistosome Infection Impacts Hematopoiesis.

Helminth infections are common in animals. However, the impact of a helminth infection on the function of hematopoietic stem cells (HSCs) and other hematopoietic cells has not been comprehensively defined. In this article, we describe the hematopoietic response to infection of mice with Schistosoma mansoni, a parasitic flatworm that causes schistosomiasis. We analyzed the frequency or number of hematopoietic cell types in the bone marrow, spleen, liver, thymus, and blood and observed multiple hematopoietic changes caused by infection. Schistosome infection impaired bone marrow HSC function after serial transplantation. Functional HSCs were present in the infected liver. Infection blocked bone marrow erythropoiesis and augmented spleen erythropoiesis, observations consistent with the anemia and splenomegaly prevalent in schistosomiasis patients. This work defines the hematopoietic response to schistosomiasis, a debilitating disease afflicting more than 200 million people, and identifies impairments in HSC function and erythropoiesis.

Helminth egg derivatives as proregenerative immunotherapies.

The immune system is increasingly recognized as an important regulator of tissue repair. We developed a regenerative immunotherapy from the helminth Schistosoma mansoni soluble egg antigen (SEA) to stimulate production of interleukin (IL)-4 and other type 2-associated cytokines without negative infection-related sequelae. The regenerative SEA (rSEA) applied to a murine muscle injury induced accumulation of IL-4-expressing T helper cells, eosinophils, and regulatory T cells and decreased expression of IL-17A in gamma delta (γδ) T cells, resulting in improved repair and decreased fibrosis. Encapsulation and controlled release of rSEA in a hydrogel further enhanced type 2 immunity and larger volumes of tissue repair. The broad regenerative capacity of rSEA was validated in articular joint and corneal injury models. These results introduce a regenerative immunotherapy approach using natural helminth derivatives.

Beyond schistosomiasis: unraveling co-infections and altered immunity.

Schistosomiasis is a neglected tropical disease caused by the helminth Schistosoma spp. and has the second highest global impact of all parasites. Schistosoma are transmitted through contact with contaminated fresh water predominantly in Africa, Asia, the Middle East, and South America. Due to the widespread prevalence of Schistosoma, co-infection with other infectious agents is common but often poorly described. Herein, we review recent literature describing the impact of Schistosoma co-infection between species and Schistosoma co-infection with blood-borne protozoa, soil-transmitted helminths, various intestinal protozoa, Mycobacterium, Salmonella, various urinary tract infection-causing agents, and viral pathogens. In each case, disease severity and, of particular interest, the immune landscape, are altered as a consequence of co-infection. Understanding the impact of schistosomiasis co-infections will be important when considering treatment strategies and vaccine development moving forward.

The anthelmintic meclonazepam activates a schistosome transient receptor potential channel.

Parasitic flatworms cause various clinical and veterinary infections that impart a huge burden worldwide. The most clinically impactful infection is schistosomiasis, a neglected tropical disease caused by parasitic blood flukes. Schistosomiasis is treated with praziquantel (PZQ), an old drug introduced over 40 years ago. New drugs are urgently needed, as while PZQ is broadly effective it suffers from several limitations including poor efficacy against juvenile worms, which may prevent it from being completely curative. An old compound that retains efficacy against juvenile worms is the benzodiazepine meclonazepam (MCLZ). However, host side effects caused by benzodiazepines preclude development of MCLZ as a drug and MCLZ lacks an identified parasite target to catalyze rational drug design for engineering out human host activity. Here, we identify a transient receptor potential ion channel of the melastatin subfamily, named TRPMMCLZ, as a parasite target of MCLZ. MCLZ potently activates Schistosoma mansoni TRPMMCLZ through engagement of a binding pocket within the voltage-sensor-like domain of the ion channel to cause worm paralysis, tissue depolarization, and surface damage. TRPMMCLZ reproduces all known features of MCLZ action on schistosomes, including a lower activity versus Schistosoma japonicum, which is explained by a polymorphism within this voltage-sensor-like domain-binding pocket. TRPMMCLZ is distinct from the TRP channel targeted by PZQ (TRPMPZQ), with both anthelmintic chemotypes targeting unique parasite TRPM paralogs. This advances TRPMMCLZ as a novel druggable target that could circumvent any target-based resistance emerging in response to current mass drug administration campaigns centered on PZQ.

Oxamniquine derivatives overcome Praziquantel treatment limitations for Schistosomiasis.

Human schistosomiasis is a neglected tropical disease caused by Schistosoma mansoni, S. haematobium, and S. japonicum. Praziquantel (PZQ) is the method of choice for treatment. Due to constant selection pressure, there is an urgent need for new therapies for schistosomiasis. Previous treatment of S. mansoni included the use of oxamniquine (OXA), a drug that is activated by a schistosome sulfotransferase (SULT). Guided by data from X-ray crystallography and Schistosoma killing assays more than 350 OXA derivatives were designed, synthesized, and tested. We were able to identify CIDD-0150610 and CIDD-0150303 as potent derivatives in vitro that kill (100%) of all three Schistosoma species at a final concentration of 71.5 µM. We evaluated the efficacy of the best OXA derivates in an in vivo model after treatment with a single dose of 100 mg/kg by oral gavage. The highest rate of worm burden reduction was achieved by CIDD -150303 (81.8%) against S. mansoni, CIDD-0149830 (80.2%) against S. haematobium and CIDD-066790 (86.7%) against S. japonicum. We have also evaluated the ability of the derivatives to kill immature stages since PZQ does not kill immature schistosomes. CIDD-0150303 demonstrated (100%) killing for all life stages at a final concentration of 143 µM in vitro and effective reduction in worm burden in vivo against S. mansoni. To understand how OXA derivatives fit in the SULT binding pocket, X-ray crystal structures of CIDD-0150303 and CIDD-0150610 demonstrate that the SULT active site will accommodate further modifications to our most active compounds as we fine tune them to increase favorable pharmacokinetic properties. Treatment with a single dose of 100 mg/kg by oral gavage with co-dose of PZQ + CIDD-0150303 reduced the worm burden of PZQ resistant parasites in an animal model by 90.8%. Therefore, we conclude that CIDD-0150303, CIDD-0149830 and CIDD-066790 are novel drugs that overcome some of PZQ limitations, and CIDD-0150303 can be used with PZQ in combination therapy.

Advances in new target molecules against schistosomiasis: A comprehensive discussion of physiological structure and nutrient intake.

Schistosomiasis, a severe parasitic disease, is primarily caused by Schistosoma mansoni, Schistosoma japonicum, or Schistosoma haematobium. Currently, praziquantel is the only recommended drug for human schistosome infection. However, the lack of efficacy of praziquantel against juvenile worms and concerns about the emergence of drug resistance are driving forces behind the research for an alternative medication. Schistosomes are obligatory parasites that survive on nutrients obtained from their host. The ability of nutrient uptake depends on their physiological structure. In short, the formation and maintenance of the structure and nutrient supply are mutually reinforcing and interdependent. In this review, we focus on the structural features of the tegument, esophagus, and intestine of schistosomes and their roles in nutrient acquisition. Moreover, we introduce the significance and modes of glucose, lipids, proteins, and amino acids intake in schistosomes. We linked the schistosome structure and nutrient supply, introduced the currently emerging targets, and analyzed the current bottlenecks in the research and development of drugs and vaccines, in the hope of providing new strategies for the prevention and control of schistosomiasis.

Inhibition of hepatic natural killer cell function via the TIGIT receptor in schistosomiasis-induced liver fibrosis.

Schistosomiasis is a zoonotic parasitic disease. Schistosoma japonicum eggs deposited in the liver tissue induce egg granuloma formation and liver fibrosis, seriously threatening human health. Natural killer (NK) cells kill activated hepatic stellate cells (HSCs) or induce HSC apoptosis and inhibit the progression of liver fibrosis. However, the function of NK cells in liver fibrosis caused by S. japonicum infection is significantly inhibited. The mechanism of this inhibition remains unclear. Twenty mice were percutaneously infected with S. japonicum cercariae. Before infection and 2, 4, 6, and 8 weeks after infection, five mice were euthanized and dissected at each time point. Hepatic NK cells were isolated and transcriptome sequenced. The sequencing results showed that Tigit expression was high at 4-6 weeks post infection. This phenomenon was verified by reverse transcription quantitative PCR (RT-qPCR) and flow cytometry. NK cells derived from Tigit-/- and wild-type (WT) mice were co-cultured with HSCs. It was found that Tigit-/- NK cells induced apoptosis in a higher proportion of HSCs than WT NK cells. Schistosomiasis infection models of Tigit-/- and WT mice were established. The proportion and killing activity of hepatic NK cells were significantly higher in Tigit-/- mice than in WT mice. The degree of liver fibrosis in Tigit-/- mice was significantly lower than that in WT mice. NK cells were isolated from Tigit-/- and WT mice and injected via the tail vein into WT mice infected with S. japonicum. The degree of liver fibrosis in mice that received NK cell infusion reduced significantly, but there was no significant difference between mice that received NK cells from Tigit-/- and WT mice, respectively. Our findings indicate that Tigit knockout enhanced the function of NK cells and reduced the degree of liver fibrosis in schistosomiasis, thus providing a novel strategy for treating hepatic fibrosis induced by schistosomiasis.

Long non-coding RNAs are essential for Schistosoma mansoni pairing-dependent adult worm homeostasis and fertility.

The trematode parasite Schistosoma mansoni causes schistosomiasis, which affects over 200 million people worldwide. Schistosomes are dioecious, with egg laying depending on the females' obligatory pairing with males. Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides with low or no protein-coding potential that have been involved in other species with reproduction, stem cell maintenance, and drug resistance. In S. mansoni, we recently showed that the knockdown of one lncRNA affects the pairing status of these parasites. Here, we re-analyzed public RNA-Seq data from paired and unpaired adult male and female worms and their gonads, obtained from mixed-sex or single-sex cercariae infections, and found thousands of differentially expressed pairing-dependent lncRNAs among the 23 biological samples that were compared. The expression levels of selected lncRNAs were validated by RT-qPCR using an in vitro unpairing model. In addition, the in vitro silencing of three selected lncRNAs showed that knockdown of these pairing-dependent lncRNAs reduced cell proliferation in adult worms and their gonads, and are essential for female vitellaria maintenance, reproduction, and/or egg development. Remarkably, in vivo silencing of each of the three selected lncRNAs significantly reduced worm burden in infected mice by 26 to 35%. Whole mount in situ hybridization experiments showed that these pairing-dependent lncRNAs are expressed in reproductive tissues. These results show that lncRNAs are key components intervening in S. mansoni adult worm homeostasis, which affects pairing status and survival in the mammalian host, thus presenting great potential as new therapeutic target candidates.

A cercarial invadolysin interferes with the host immune response and facilitates infection establishment of Schistosoma mansoni.

Schistosoma mansoni employs immune evasion and immunosuppression to overcome immune responses mounted by its snail and human hosts. Myriad immunomodulating factors underlie this process, some of which are proteases. Here, we demonstrate that one protease, an invadolysin we have termed SmCI-1, is released from the acetabular glands of S. mansoni cercaria and is involved in creating an immunological milieu favorable for survival of the parasite. The presence of SmCI-1 in the cercarial stage of S. mansoni is released during transformation into the schistosomula. SmCI-1 functions as a metalloprotease with the capacity to cleave collagen type IV, gelatin and fibrinogen. Additionally, complement component C3b is cleaved by this protease, resulting in inhibition of the classical and alternative complement pathways. Using SmCI-1 knockdown cercariae, we demonstrate that SmCI-1 protects schistosomula from complement-mediated lysis in human plasma. We also assess the effect of SmCI-1 on cytokine release from human peripheral blood mononuclear cells, providing compelling evidence that SmCI-1 promotes an anti-inflammatory microenvironment by enhancing production of IL-10 and suppressing the production of inflammatory cytokines like IL-1B and IL-12p70 and those involved in eosinophil recruitment and activation, like Eotaxin-1 and IL-5. Finally, we utilize the SmCI-1 knockdown cercaria in a mouse model of infection, revealing a role for SmCI-1 in S. mansoni survival.

Protective human IgE responses are promoted by comparable life-cycle dependent Tegument Allergen-Like expression in Schistosoma haematobium and Schistosoma mansoni infection.

Schistosoma haematobium is the most prevalent of the human-infecting schistosome species, causing significant morbidity in endemically exposed populations. Despite this, it has been relatively understudied compared to its fellow species, S. mansoni. Here we provide the first comprehensive characterization of the S. haematobium Tegument Allergen-Like protein family, a key protein family directly linked to protective immunity in S. mansoni infection. Comparable with observations for S. mansoni, parasite phylogenetic analysis and relative gene expression combined with host serological analysis support a cross-reactive relationship between S. haematobium TAL proteins, exposed to the host immune system as adult worms die, and closely related proteins, exposed during penetration by the infecting cercarial and early schistosomulae stages. Specifically, our results strengthen the evidence for host immunity driven by cross-reactivity between family members TAL3 and TAL5, establishing it for the first time for S. haematobium infection. Furthermore, we build upon this relationship to include the involvement of an additional member of the TAL protein family, TAL11 for both schistosome species. Finally, we show a close association between experience of infection and intensity of transmission and the development of protective IgE responses to these antigens, thus improving our knowledge of the mechanisms by which protective host immune responses develop. This knowledge will be critical in understanding how control efforts such as mass drug administration campaigns influence the development of host immunity and subsequent patterns of infection and disease within endemic populations.

Type 2 immunity: a two-edged sword in schistosomiasis immunopathology.

Schistosomiasis is the second most debilitating neglected tropical disease globally after malaria, with no available therapy to control disease-driven immunopathology. Although schistosomiasis induces a markedly heterogenous immune response, type 2 immunity is the dominating immune response following oviposition. While type 2 immunity has a crucial role in granuloma formation and host survival during the acute stage of disease, its chronic activation can result in tissue scarring, fibrosis, and organ impairment. Here, we discuss recent advances in schistosomiasis, demonstrating how different immune and non-immune cells and signaling pathways are involved in the induction, maintenance, and regulation of type 2 immunity. A better understanding of these immune responses during schistosomiasis is essential to inform the potential development of candidate therapeutic strategies that fine-tune type 2 immunity to ideally modulate schistosomiasis immunopathology.

Interleukin-13 Activates Distinct Cellular Pathways Leading to Ductular Reaction, Steatosis, and Fibrosis.

Fibroproliferative diseases are driven by dysregulated tissue repair responses and are a major cause of morbidity and mortality because they affect nearly every organ system. Type 2 cytokine responses are critically involved in tissue repair; however, the mechanisms that regulate beneficial regeneration versus pathological fibrosis are not well understood. Here, we have shown that the type 2 effector cytokine interleukin-13 simultaneously, yet independently, directed hepatic fibrosis and the compensatory proliferation of hepatocytes and biliary cells in progressive models of liver disease induced by interleukin-13 overexpression or after infection with Schistosoma mansoni. Using transgenic mice with interleukin-13 signaling genetically disrupted in hepatocytes, cholangiocytes, or resident tissue fibroblasts, we have revealed direct and distinct roles for interleukin-13 in fibrosis, steatosis, cholestasis, and ductular reaction. Together, these studies show that these mechanisms are simultaneously controlled but distinctly regulated by interleukin-13 signaling. Thus, it may be possible to promote interleukin-13-dependent hepatobiliary expansion without generating pathological fibrosis. VIDEO ABSTRACT.