Pathology Of Schistosomiasis Research Articles

Up-regulation of Interleukin-21 Contributes to Liver Pathology of Schistosomiasis by Driving GC Immune Responses and Activating HSCs in Mice

The pathology of schistosome egg-induced liver granuloma, fibrosis and eventually liver scarring is complicated. CD4+ helper T (Th) cells play critical roles in both host humoral immunity and cellular immunity against parasitic infection and immunopathology in schistosomiasis. Follicular helper T (Tfh) cells are another specialized subset of Th cells and involved in infectious diseases. However, the immune regulatory mechanism of Tfh cells in severe liver pathology of schistosomiasis is still poorly understood. In this study, using a S. japonicum-infected mouse model, we studied the dynamics and effects of Tfh cells in vivo and demonstrated that Tfh phenotype molecules ICOS, PD-1 and functional factor IL-21 were positively correlated with disease development by flow cytometry. Meanwhile, our results also showed that Tfh cells enriched in splenic germinal center (GC) and promoted B cells producing IgM with the progress of hepatic immunopathology by B-T co-culture experiments. More importantly, our data indicated that IL-21 contributed to the formation and development of hepatic egg granuloma and subsequent fibrosis by driving GC responses and activating HSCs by immunohistochemical detection and blocking assay in vitro. Our findings contribute to the better understanding of the immunopathogenesis of schistosomiasis and have implications for therapeutic intervention of hepatic fibrotic diseases.

A gene expression atlas of adult Schistosoma mansoni and their gonads

RNA-Seq has proven excellence in providing information about the regulation and transcript levels of genes. We used this method for profiling genes in the flatworm Schistosoma mansoni. This parasite causes schistosomiasis, an infectious disease of global importance for human and animals. The pathology of schistosomiasis is associated with the eggs, which are synthesized as a final consequence of male and female adults pairing. The male induces processes in the female that lead to the full development of its gonads as a prerequisite for egg production. Unpaired females remain sexually immature. Based on an organ-isolation method we obtained gonad tissue for RNA extraction from paired and unpaired schistosomes, with whole adults included as controls. From a total of 23 samples, we used high-throughput cDNA sequencing (RNA-Seq) on the Illumina platform to profile gene expression between genders and tissues, with and without pairing influence. The data obtained provide a wealth of information on the reproduction biology of schistosomes and a rich resource for exploitation through basic and applied research activities.

Elevated serum antibody against Schistosoma japonicum HSP60 as a promising biomarker for liver pathology in schistosomiasis

The pathology associated with Schistosoma japonicum (S. japonicum) infection in humans is attributed to parasite egg-induced granulomatous inflammation and fibrosis in the host liver. Currently, a marker that is reliable, cheap, less device-dependent, and can be easily and repeatedly used on a large scale to monitor the progression of liver pathology in schistosomiasis japonica endemic areas is lacking. The levels of serum S. japonicum heat shock protein 60 (SjHSP60)-specific IgG and its subtype antibodies in animals (mice and rabbits) or patients with schistosomiasis were measured by ELISA. Liver pathologies in mice and rabbits were evaluated by gross pathology and histopathology, and hepatic fibrosis in patients was examined with ultrasound imaging. The results revealed that the titers of the total IgG and subtype IgG1 anti-SjHSP60 antibodies were positively correlated with the severity of liver pathology after S. japonicum infection. Our findings indicate that the SjHSP60 IgG and IgG1 antibody levels can be used as potential candidate biomarkers for evaluation of liver pathology in schistosomiasis; however, validation remains to be explored in further work.

Artichoke leaf extract protects liver of Schistosoma mansoni infected mice through modulation of hepatic stellate cells recruitment

Schistosomiasis is the second most common human parasitic disease worldwide. It is responsible for 300000 deaths per year. Liver fibrosis is the main pathology of schistosomiasis and its complications are the major cause of death in infected cases. Unfortunately, the therapeutic dose of praziquantel (PZQ) – the main drug treatment – doesn't markedly affect fibrosis. In the present study, antiparasitic and hepatoprotective properties of artichoke leaf extract (ALE) were tested on mice experimentally infected with Schistosoma mansoni (S. mansoni) and were compared to PZQ. Four mice groups were infected with S. mansoni. The first three groups received ALE, ALE + PZQ and PZQ respectively. The 4th was the positive control and the 5th was the negative control group. Worm load, egg count, granuloma numbers and diameters were measured to assess ALE anti-schistoaomal properties. Masson's trichrome staining of fibrosis, immune staining of hepatic stellate cells (HSCs) and estimation of liver enzymes were done to assess its hepato-protective action. Although it had no significant effects on worm or tissue egg load and granuloma number, ALE caused significant reduction of granuloma diameter, improvement of liver functions and liver fibrosis. ALE caused statistically significant changes in HSCs distribution. It reduced granuloma size by increasing HSCs recruitment inside granuloma and limited liver fibrosis by their inhibition in the peri- and inter-granuloma liver tissue. It was concluded that despite failure of ALE to treat S. mansoni infection, it can limit liver damage caused by this parasite by modulating HSCs recruitment.

Evidence for Integrin - Venus Kinase Receptor 1 Alliance in the Ovary of Schistosoma mansoni Females Controlling Cell Survival.

In metazoan integrin signaling is an important process of mediating extracellular and intracellular communication processes. This can be achieved by cooperation of integrins with growth factor receptors (GFRs). Schistosoma mansoni is a helminth parasite inducing schistosomiasis, an infectious disease of worldwide significance for humans and animals. First studies on schistosome integrins revealed their role in reproductive processes, being involved in spermatogenesis and oogenesis. With respect to the roles of eggs for maintaining the parasite´s life cycle and for inducing the pathology of schistosomiasis, elucidating reproductive processes is of high importance. Here we studied the interaction of the integrin receptor Smβ-Int1 with the venus kinase receptor SmVKR1 in S. mansoni. To this end we cloned and characterized SmILK, SmPINCH, and SmNck2, three putative bridging molecules for their role in mediating Smβ-Int1/SmVKR1 cooperation. Phylogenetic analyses showed that these molecules form clusters that are specific for parasitic platyhelminths as it was shown for integrins before. Transcripts of all genes colocalized in the ovary. In Xenopus oocytes germinal vesicle breakdown (GVBD) was only induced if all members were simultaneously expressed. Coimmunoprecipitation results suggest that a Smβ-Int1-SmILK-SmPINCH-SmNck2-SmVKR1 complex can be formed leading to the phosphorylation and activation of SmVKR1. These results indicate that SmVKR1 can be activated in a ligand-independent manner by receptor-complex interaction. RNAi and inhibitor studies to knock-down SmILK as a representative complex member concurrently revealed effects on the extracellular matrix surrounding the ovary and oocyte localization within the ovary, oocyte survival, and egg production. By TUNEL assays, confocal laser scanning microscopy (CLSM), Caspase-3 assay, and transcript profiling of the pro-apoptotic BCL-2 family members BAK/BAX we obtained first evidence for roles of this signaling complex in mediating cell death in immature and primary oocytes. These results suggest that the Smβ-Int1/SmVKR1 signaling complex is important for differentiation and survival in oocytes of paired schistosomes.

The Effect of Stem Cells as an Adjuvant on the Immunogenicity of a Potential Anti-Schistosomal Vaccine in Mice

Vaccination against schistosomes can be targeted towards the prevention of infection and/or to the reduction of parasite fecundity and pathology. However, as eggs are responsible mainly for schistosomiasis pathology, so crude soluble egg antigen (SEA) seems suitable to be used as a potential vaccine. Many studies have provided new insights establishing a role for mesenchymal stem cells (MSCs) in liver regeneration and improvement of schistosomiasis hepatic fibrosis, in addition to the need for standardized and effective adjuvant-vaccine formulations. So, the aim of this work is to evaluate the effect of stem cells when used as an adjuvant of a potential anti-schistosomal vaccine (crude SEA) in murine models. The current work was carried out on 100 mice (30 males for harvesting MSCs + 70 females for seven study groups, each of 10). A schedule of vaccination and challenge infection was followed so, GI (control healthy), G2 (control infected only) infected subcutaneously with S. mansoni cercaria (80-90 Schistosoma mansoni cercariae suspended in 0.2 ml distilled Water), G 3 (FCA then infected) received Freund's complete adjuvant (FCA) then infected, G4 (MSCs then infected) received MSCs then infected, G5 (SEA then infected) received SEA vaccine then infected, G6 (SEA+FCA then infected) received SEA vaccine and FCA then infected, G7 (SEA+MSCs then infected) received SEA vaccine and MSCs then infected. The current work was assessed by histopathological study and morphometric analysis (using H&E and Masson's Trichrome stains) to highlight number, size and type of liver granulomas and percentage of liver fibrosis, immunological and molecular studies (RNA extraction, Re- verse Transcriptase and PCR technique) for detection of interleukin-10 mRNA gene expression in liver tissue by reverse transcriptase & polymerase chain reaction (RT & PCR). The results showed that a- SEA alone as a potential anti-schistosomal vaccine was more or less moderately protective, b- MSCs alone before the infection had mild prophylactic effects, c- MSCs as an adjuvant of the crude SEA increased its capabilities with highly significant results regarding the decrease in granuloma number, size, percentage and density of hepatic fi- brosis, and d-There was significant increase in IL-10 mRNA gene expression on using (SEA+MSCs) (G7) if compared to other tested groups.

Release of extracellular vesicles containing small RNAs from the eggs of Schistosoma japonicum.

Background Schistosoma japonicum is a parasitic flatworm that causes human schistosomiasis. Secreted extracellular vesicles (EVs) play a key role in pathogen-host interfaces. Previous studies have shown that S. japonicum adult worms can release microRNA (miRNA)-containing EVs, which can transfer their cargo to mammalian cells and regulate gene expression in recipient cells. Tissue-trapped eggs are generally considered the major contributor to the severe pathology of schistosomiasis; however, the interactions between the host and parasite in this critical stage remain largely unknown.MethodsThe culture medium for S. japonicum eggs in vitro was used to isolate EVs. Transmission electron microscopy (TEM) analysis was used to confirm that vesicles produced by the eggs were EVs based on size and morphology. Total RNA extracted from EVs was analyzed by Solexa technology to determine the miRNA profile. The in vitro internalization of the EVs by mammalian cells was analyzed by confocal microscopy. The presence of EVs associated miRNAs in the primary hepatocytes of infected mice was determined by quantitative real-time PCR (qRT-PCR).ResultsEVs were isolated from the culture medium of in vitro cultivated S. japonicum eggs. TEM analysis confirmed that nanosized vesicles were present in the culture medium. RNA-seq analysis showed that the egg-derived EVs contained small non-coding RNA (sncRNA) populations including miRNAs, suggesting a potential role in host manipulation. This study further showed that Hepa1-6, a murine liver cell line, internalized the purified EVs and their cargo miRNAs that were detectable in the primary hepatocytes of mice infected with S. japonicum.Conclusions Schistosoma japonicum eggs can release miRNA-containing EVs, and the EVs can transfer their cargo to recipient cells in vitro. These results demonstrate the regulatory potential of S. japonicum egg EVs at the parasite-host interface.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1845-2) contains supplementary material, which is available to authorized users.

Receptor Antagonist of IL-13 Exerts a Potential Negative Regulation During Early Infection of Human Schistosomiasis.

The pathology of schistosomiasis is associated with the formation of granulomas, and this process is associated with liver fibrosis. Studies indicate that Th1 cytokines reduce fibrosis in schistosomiasis, while Th2 cytokines play a part in the progression of fibrosis, and IL-13 has a critical role in this process. The IL-13Rα2 receptor, known as a 'receptor antagonist' binds with high affinity to IL-13, and studies have identified that this plays a part in reducing fibrosis and the size of granulomas. The objective of this study was to evaluate the function of IL-13Rα2 and cellular immune response in hepatic fibrosis. A negative correlation between IL-13Rα2 and IL-13 was found, suggesting an increase in cytokine in early fibrosis. Initially, a negative correlation between IFN-γ and IL-13 was found in patients without fibrosis, and subsequently, this correlation was found to be positive in patients with severe fibrosis, thereby highlighting a new mechanism for regulating the progress of periportal fibrosis. There was a positive correlation between the profiles of Th1 and Th2 cytokines, suggesting the presence of both responses, thus regulating the disease. The results contribute to a better understanding of the immune mechanisms that control the process of hepatic fibrogenesis in schistosomiasis in humans.

The formation of egg granulomas in the spleens of mice with late Schistosoma japonicum infection alters splenic morphology.

BackgroundSplenomegaly is a characteristic symptom of schistosome infection. Unlike the well known hepatic pathology of schistosomiasis, splenomegaly has received little scientific research and is generally considered to be a non-specific congestion caused by increased blood pressure within the venous sinuses. Moreover, to date, few studies have reported the deposition of schistosome eggs in the spleen. In a previous study, however, we observed that prolonged S. japonicum infections destroyed the structure of the lymphoid follicles in the spleen of mice at 8 weeks post-infection and found that eggs were frequently deposited in the spleen. These prior observations suggested a relationship between granulomas and splenic morphology which we investigate further in this study.MethodsC57BL/6 mice were infected percutaneously with twenty cercariae of S. japonicum and sacrificed at different times post-infection. The number of eggs present in the homogenates of spleens and livers was quantified by light microscopy. Splenic pathology was observed by immunohistochemistry staining of paraffin-embedded sections. At 18 weeks post-infection the infected mice were divided into two groups (granulomatous spleens and non-granulomatous spleens). Serum antibodies and cytokines in the antigen- or mitogen-stimulated lymphocyte cultures were then determined by ELISA.ResultsWe found that eggs deposition in the spleens of infected mice occurred frequently but only occasionally led to granulomas formation. The lymphoid follicles within the granulomatous spleens maintained their structural integrity until 20 weeks post-infection, unlike the lymphoid follicles in spleens without egg granulomas. Mice with granulomatous spleens accompanied by lymphoid follicles exhibited a germinal center (GC)-like structure and had enhanced humoral immune responses. Splenocytes from granulomatous spleens also showed significantly elevated levels of Th2 cytokines during late infection stages.ConclusionsOur results highlight that lymphoid follicles, which are not completely destroyed or are re-established in the spleen, can change the local immune environment and lead to changes in the splenic morphology of mice with chronic schistosomiasis.

Evaluation of the cytokine mannose-binding lectin as a mediator of periportal fibrosis progression in patients with schistosomiasis.

We hypothesized higher mannose-binding lectin level and classic factors (i.e., age, sex, alcohol consumption, exposure, and specific treatment) are associated with the severity of periportal fibrosis in schistosomiasis. This cross-sectional study involved 79 patients infected with Schistosoma mansoni with severe or mild/moderate periportal fibrosis. Serum concentrations of mannose-binding lectin were obtained by enzyme-linked immunosorbent assay (ELISA). Higher serum level of mannose-binding lectin was significantly associated with advanced periportal fibrosis. Mannose-binding lectin may contribute to liver pathology in schistosomiasis and may represent a risk factor for advanced periportal fibrosis in the Brazilian population studied.

Re-positioning protein-kinase inhibitors against schistosomiasis.

For decades, Praziquantel (PZQ) is the drug of choice against one of the most afflicting helminthic diseases worldwide, schistosomiasis. With respect to the fear of upcoming PZQ resistance, efforts are needed to find new chemotherapeutic options. Protein kinases (PKs) are essential molecules in signaling processes and indispensable to life. Aberrant PK functions take distinctive roles in human diseases and represent targets in chemotherapies. In schistosomes, conserved PKs were found to possess similar pivotal roles contributing not only to reproduction processes, but also to the pathology of schistosomiasis, which is closely associated to egg production. Exploiting the similarity of PKs of humans and schistosomes, PK inhibitors designed to treat human diseases may serve as lead compounds for new drugs against schistosomiasis.

Schistosome infections induce significant changes in the host biliary proteome.

To identify the changes induced by the schistosome infection in bile protein composition, and therefore in bile function, we compared the proteome of the gallbladders collected from non-infected healthy mice and from mice infected with S. bovis during 4months. For this, gallbladders from both groups of mice were homogenized and these homogenates were fractionated by serial centrifugation and acrylamide gel electrophoresis. The proteins were in gel digested and analysed by LC-MS/MS for identification. The present work reports the first data on the proteome of the mouse gallbladder and provides a comprehensive catalogue of biliary proteins that may be of great use in other studies addressing biliary physiology and pathology. We observed that there were significant differences in the biliary proteome of mice infected and non-infected with S. bovis and that chronic schistosome infections may produce important physiological alterations in the bile function.

Receptor tyrosine kinases and schistosome reproduction: new targets for chemotherapy.

Schistosome parasites still represent a serious public health concern and a major economic problem in developing countries. Pathology of schistosomiasis is mainly due to massive egg production by these parasites and to inflammatory responses raised against the eggs which are trapped in host tissues. Tyrosine kinases (TKs) are key molecules that control cell differentiation and proliferation and they already represent important targets in cancer therapy. During recent years, it has been shown that receptor tyrosine kinases (RTK) signaling was active in reproductive organs and that it could regulate sexual maturation of schistosomes and egg production. This opens interesting perspectives for the control of transmission and pathogenesis of schistosomiasis based on new therapies targeting schistosome RTKs. This review relates the numerous data showing the major roles of kinase signaling in schistosome reproduction. It describes the conserved and particular features of schistosome RTKs, their implication in gametogenesis and reproduction processes and summarizes recent works indicating that RTKs and their signaling partners are interesting chemotherapeutical targets in new programs of control.

Basophil depletion downregulates Schistosoma mansoni egg-induced granuloma formation

Granuloma formation around parasite eggs during schistosomal infection is considered to be controlled by Th2 cytokines. However, it is still controversial which cell populations are responsible for the host Th2 cytokine-dependent granuloma formation. Basophils have recently attracted attention because of their ability to produce large amounts of IL-4. Therefore, we investigated whether basophils play an essential role in the induction of granuloma formation induced by Schistosoma mansoni eggs. Together with our previous observation that basophil numbers increased markedly in the spleen at 7weeks postinfection, immunohistochemical staining using anti-mMCP8 monoclonal antibody (mAb) showed basophil infiltration in the granulomatous lesions formed around parasite eggs. To examine the roles of basophils more directly, we treated mice with anti-CD200R3 mAb to deplete basophils. Depletion of basophils resulted in a reduction of basophil number with concomitant downregulation of egg granuloma formation at 7weeks postinfection. Moreover, we observed a significant reduction in the size of egg granulomas formed in basophil-depleted mice in the pulmonary granuloma model. Taken together, these findings indicated that basophils are essential for S. mansoni egg-induced granuloma formation, and this may serve as a novel therapeutic target in ameliorating the pathology of schistosomiasis.

Current drug targets for helminthic diseases

More than 2 billion people are infected with helminth parasites across the globe. The burgeoning drug resistance against current anthelmintics in parasitic worms of humans and livestock requires urgent attention to tackle these recalcitrant worms. This review focuses on the advancements made in the area of helminth drug target discovery especially from the last few couple of decades. It highlights various approaches made in this field and enlists the potential drug targets currently being pursued to target economically important helminth species both from human as well as livestock to combat disease pathology of schistosomiasis, onchocerciasis, lymphatic filariasis, and other important macroparasitic diseases. Research in the helminths study is trending to identify potential and druggable targets through genomic, proteomic, biochemical, biophysical, in vitro experiments, and in vivo experiments in animal models. The availability of major helminths genome sequences and the subsequent availability of genome-scale functional datasets through in silico search and prioritization are expected to guide the experimental work necessary for target-based drug discovery. Organized and documented list of drug targets from various helminths of economic importance have been systematically covered in this review for further exploring their use and applications, which can give physicians and veterinarians effective drugs in hand to enable them control worm infections.

Development of Adult Worms and Granulomatous Pathology Are Collectively Regulated by T- and B-Cells in Mice Infected with Schistosoma japonicum

Schistosoma blood flukes, which cause schistosomiasis affecting 200 million people in the world, are dependent on signals from host CD4+ T cells to facilitate parasite growth and development in the mammalian host and to induce Th2-biased inflammatory granulomas. B cells, however, are reported to down-regulate granulomatous pathology in schistosomiasis, but not to affect the development of blood flukes together with CD4+ T lymphocytes. Thus it is not clear whether B cells mediate parasite development, reproduction and egg granuloma formation of schistosomes without the help of CD4+ T lymphocytes. Using mice that have severe combined immunodeficiency (scid) and mice lacking T cells (nude), we found that the absence of B cells can more seriously hamper the development and paring of adult worms, but granuloma formation of Schistosoma japonicum in scid mice was not down-regulated comparing with that in nude mice. The level of IL-10 in the sera of nude mice was significantly higher than of scid mice at 43 days post infection (p.i.). Thus multiple mechanisms of immune modulation seem to be involved in parasite development and reproduction by helminth-induced regulatory B cells. Our findings have significance for understanding the molecular connections between schistosomes and T- and B-cells, indicating that more research is needed to develop efficient vaccine-based therapies for schistosomiasis.

A DOUBLE AND PARADOXICAL ROLE FOR ANGIOGENESIS

Fibrogenesis and fibrolysis are constant and important features occurring during the pathology of schistosomiasis. New findings have recently indicated that granulation tissue (angiogenesis) is a dominating feature on both occasions. This review article discusses this apparently paradoxical feature displayed by angiogenesis (granulation tissue) during the pathology of schistosomiasis.

Proteomic changes at 8 weeks after infection are associated with chronic liver pathology in experimental schistosomiasis.

Chronic Schistosoma mansoni infection can present as a moderate or severe disease, termed intestinal or hepatosplenic schistosomiasis, respectively. Similarly, either moderate splenomegaly or hypersplenomegaly syndrome develops in CBA/J mice by 20weeks of infection and is similar to intestinal or hepatosplenic schistosomiasis respectively. Using this mouse model and two-dimensional differential in gel electrophoresis, the liver proteomic signatures of uninfected mice and mice infected for 6, 8, 12, or 20weeks were compared, and significant protein spots identified using mass spectrometry. We found the greatest number of changes at 12weeks suggesting that this period represents the peak time of change. Pathway analysis identified specific proteins and pathways that correlated to the pathological changes indicative of severe disease, and these pathways were involved as early as 8weeks after infection. These findings provide insight into the development of severe liver pathology in schistosomiasis and may aid in developing biomarkers for hepatosplenic schistosomiasis.

Cytokine and Chemokine Profile in Individuals with Different Degrees of Periportal Fibrosis due toSchistosoma mansoniInfection

Periportal fibrosis in schistosomiasis has been associated to the host immune response to parasite antigens. We evaluated the immune response in S. mansoni infected individuals with different degrees of periportal fibrosis. Cytokine and chemokines were measured in serum and in supernatants of PBMC cultures stimulated with the soluble adult worm (SWAP) or egg (SEA) antigens, using a sandwich ELISA. The levels of IL-5 in response to SEA were higher in individuals with moderate to severe fibrosis (310.9 pg/mL) compared to individuals without fibrosis (36.8 pg/mL; P = 0.0418). There was also a higher production of TNF-α in cultures stimulated with SWAP in patients with insipient fibrosis (1446 pg/mL) compared to those without fibrosis (756.1 pg/mL; P = 0.0319). The serum levels of IL-13 and MIP-1α were higher in subjects without fibrosis than in those with moderate to severe fibrosis. However a positive association between serum levels of IL-13, TNF-α, MIP-1α, and RANTES and S. mansoni parasite burden was found. From these data we conclude that IL-5 and TNF-α may participate in liver pathology in schistosomiasis. The positive association between IL-13, TNF-α, MIP-1α, and RANTES with parasite burden, however, might predict the development of liver pathology.

CK2 Phosphorylation of Schistosoma mansoni HMGB1 Protein Regulates Its Cellular Traffic and Secretion but Not Its DNA Transactions

BackgroundThe helminth Schistosoma mansoni parasite resides in mesenteric veins where fecundated female worms lay hundred of eggs daily. Some of the egg antigens are trapped in the liver and induce a vigorous granulomatous response. High Mobility Group Box 1 (HMGB1), a nuclear factor, can also be secreted and act as a cytokine. Schistosome HMGB1 (SmHMGB1) is secreted by the eggs and stimulate the production of key cytokines involved in the pathology of schistosomiasis. Thus, understanding the mechanism of SmHMGB1 release becomes mandatory. Here, we addressed the question of how the nuclear SmHMGB1 can reach the extracellular space.Principal FindingsWe showed in vitro and in vivo that CK2 phosphorylation was involved in the nucleocytoplasmic shuttling of SmHMGB1. By site-directed mutagenesis we mapped the two serine residues of SmHMGB1 that were phosphorylated by CK2. By DNA bending and supercoiling assays we showed that CK2 phosphorylation of SmHMGB1 had no effect in the DNA binding activities of the protein. We showed by electron microscopy, as well as by cell transfection and fluorescence microscopy that SmHMGB1 was present in the nucleus and cytoplasm of adult schistosomes and mammalian cells. In addition, we showed that treatments of the cells with either a phosphatase or a CK2 inhibitor were able to enhance or block, respectively, the cellular traffic of SmHMGB1. Importantly, we showed by confocal microscopy and biochemically that SmHMGB1 is significantly secreted by S. mansoni eggs of infected animals and that SmHMGB1 that were localized in the periovular schistosomotic granuloma were phosphorylated.ConclusionsWe showed that secretion of SmHMGB1 is regulated by phosphorylation. Moreover, our results suggest that egg-secreted SmHMGB1 may represent a new egg antigen. Therefore, the identification of drugs that specifically target phosphorylation of SmHMGB1 might block its secretion and interfere with the pathogenesis of schistosomiasis.