Molecular Context of ADP-ribosylation in Schistosomes for Drug Discovery and Vaccine Development.

Schistosome infection is regarded as one of the most important and neglected tropical diseases associated with poor sanitation. Like other living organisms, schistosomes employ multiple biological processes, of which some are regulated by a post-translational modification called Adenosine Diphosphate-ribosylation (ADP-ribosylation), catalyzed by ADP-ribosyltransferases. ADP-ribosylation is the addition of ADP-ribose moieties from Nicotinamide Adenine Dinucleotide (NAD+) to various targets, which include proteins and nucleotides. It is crucial in biological processes such as DNA repair, apoptosis, carbohydrate metabolism and catabolism. In the absence of a vaccine against schistosomiasis, this becomes a promising pathway in the identification of drug targets against various forms of this infection. The tegument of the worm is an encouraging immunogenic target for anti-schistosomal vaccine development. Vaccinology, molecular modeling and target-based drug discovery strategies have been used for years in drug discovery and for vaccine development. In this paper, we outline ADP-ribosylation and other different approaches to drug discovery and vaccine development against schistosomiasis.

Behind Enemy Lines: Immunomodulatory Armamentarium of the Schistosome Parasite.

The deeply rooted, intricate relationship between the Schistosoma parasite and the human host has enabled the parasite to successfully survive within the host and surreptitiously evade the host's immune attacks. The parasite has developed a variety of strategies in its immunomodulatory armamentarium to promote infection without getting harmed or killed in the battlefield of immune responses. These include the production of immunomodulatory molecules, alteration of membranes, and the promotion of granuloma formation. Schistosomiasis thus serves as a paradigm for understanding the Th2 immune responses seen in various helminthiases. This review therefore aims to summarize the immunomodulatory mechanisms of the schistosome parasites to survive inside the host. Understanding these immunomodulatory strategies not only provides information on parasite-host interactions, but also forms the basis in the development of novel drugs and vaccines against the schistosome infection, as well as various types of autoimmune and inflammatory conditions.

Schistosomiasis Consortium for Operational Research and Evaluation: Mission Accomplished.

The Schistosomiasis Consortium for Operational Research and Evaluation (SCORE), a program focusing on schistosomiasis control in sub-Saharan Africa between 2008 and 2019, investigated ways to improve coverage and efficacy of ongoing chemotherapy programs and concluded that because of continued transmission, mass distribution of praziquantel cannot eliminate the disease without complementary control activities. Schistosomiasis Consortium for Operational Research and Evaluation's activities comprised large-scale, multicountry field studies comparing various mass drug administration strategies and some specific research avenues, such as assessment of high-sensitivity diagnostics, identification of hotspots, quantification of the role of the snail host, predictive modeling, and changes in schistosome population genetics under drug pressure. The discoveries made and the insights gained regarding cost-effective strategies for delivering preventive chemotherapy should assist policy makers to develop guidelines for the control and ultimate elimination of schistosomiasis.

The Potential Role of Schistosome-Associated Factors as Therapeutic Modulators of the Immune System.

The parasites and eggs of helminths, including schistosomes, are associated with factors that can modulate the nature and outcomes of host immune responses, particularly enhancing type 2 immunity and impairing the effects of type 1 and type 17 immunity. The main species of schistosomes that cause infection in humans are capable of generating a microenvironment that allows survival of the parasite by evasion of the immune response. Schistosome infections are associated with beneficial effects on chronic immune disorders, including allergies, autoimmune diseases, and alloimmune responses. Recently, there has been increasing research interest in the role of schistosomes in immunoregulation during human infection, and the mechanisms underlying these roles continue to be investigated. Further studies may identify potential opportunities to develop new treatments for immune disease. In this review, we provide an update on the advances in our understanding of schistosome-associated modulation of the cells of the innate and adaptive immune systems as well as the potential role of schistosome-associated factors as therapeutic modulators of immune disorders, including allergies, autoimmune diseases, and transplant immunopathology. We also discuss potential opportunities for targeting schistosome-induced immunoregulation for future translation to the clinical setting.

Update on the major imported helminth infections in travelers and migrants.

Helminth infections cause considerable morbidity worldwide and may be frequently underdiagnosed especially in areas of lower endemicity. Patients may harbor latent infections that may become symptomatic years or decades after the initial exposure and timely diagnosis may be critical to prevent complications and improve outcomes. In this context, disease in special populations, such as immunosuppressed patients, may be of particular concern. Heightened awareness and recent diagnostic developments may contribute to the correct management of helminth infections in nonendemic regions. A review of the main helminth infections in travelers and migrants (strongyloidiasis, taeniasis-neurocysticercosis and schistosomiasis) is presented, focusing on epidemiology, developments in diagnosis, treatment and prevention.

Mapping evidence of the concomitant management of schistosomiasis by traditional health practitioners and health care professionals in communities with high prevalent infections: a systematic scoping review protocol.

BACKGROUND: Schistosomiasis is one of the most prevalent parasitic diseases in low- and middle-income countries (LMICs), being regarded as a neglected tropical disease in sub-Saharan Africa. Praziquantel is the conventional treatment recommended for schistosomiasis in mainstream healthcare systems. In many poor settings, while many people reportedly use both traditional medicine and public sector mainstream healthcare systems, little is known if those infected with schistosomiasis use both African traditional and prescribed antischistosomal medicines. This review aims to map evidence of the concomitant management of schistosomiasis by traditional health practitioners (THPs) and health care professionals (HCPs) in communities with a high prevalence schistosomiasis infection in LMICs. METHODS/DESIGN: Guided by Arksey and O'Malley scoping review framework and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), we will map the evidence from relevant studies dating from 2007 to 2019 published in LMICs. An electronic keyword search of the following databases will be conducted: PubMed, Cochrane Library, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and MEDLINE via EBSCOhost, Google Scholar, and WILEY online Library. Peer-reviewed articles, gray literature sources, and reference lists will be included to identify eligible studies. Following title screening, two reviewers will independently screen the abstracts and full texts. Any study that focuses on managing schistosomiasis will be included. The data will be analyzed using thematic analysis with the help of NVIVO software version 12, with the Mixed Method Appraisal Tool (MMAT) being used to assess the quality of the included studies. DISCUSSION: This review will map the evidence in the literature of the concomitant management of schistosomiasis by THPs and HCPs in communities with a high prevalent infection in LMICs. The review findings will be important for policy makers across the healthcare continuum and be used to inform stakeholders' consensus process to explore the development of a generic set of patient-centered quality indicators that are applicable to multiple care settings. It will also identify research gaps in schistosomiasis management in LMICs and provide direction for future research. The results will be disseminated through a peer-reviewed publication and presented in relevant conferences. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017078198.

The role of microRNAs in the pathogenesis, grading and treatment of hepatic fibrosis in schistosomiasis.

Schistosomiasis is a prevalent parasitic disease worldwide. The main pathological changes of hepatosplenic schistosomiasis are hepatic granuloma and fibrosis due to worm eggs. Portal hypertension and ascites induced by hepatic fibrosis are usually the main causes of death in patients with chronic hepatosplenic schistosomiasis. Currently, no effective vaccine exists for preventing schistosome infections. For quite a long time, praziquantel (PZQ) was widely used for the treatment of schistosomiasis and has shown benefit in treating liver fibrosis. However, drug resistance and chemical toxicity from PZQ are being increasingly reported in recent years; therefore, new and effective strategies for treating schistosomiasis-induced hepatic fibrosis are urgently needed. MicroRNA (miRNA), a non-coding RNA, has been proved to be associated with the development of many human diseases, including schistosomiasis. In this review, we present a balanced and comprehensive view of the role of miRNAs in the pathogenesis, grading, and treatment of schistosomiasis-associated hepatic fibrosis. The multiple regulatory roles of miRNAs, such as promoting or inhibiting the development of liver pathology in murine schistosomiasis are also discussed in depth. Additionally, miRNAs may serve as candidate biomarkers for diagnosing liver pathology of schistosomiasis and as novel therapeutic targets for treating schistosomiasis-associated hepatic fibrosis.

Unresolved Splenomegaly in Recently Resettled Congolese Refugees - Multiple States, 2015-2018.

In 2014, panel physicians from the International Organization for Migration (IOM), who conduct Department of State-required predeparture examinations for U.S.-bound refugees at resettlement sites in Uganda, noticed an unusually high number of Congolese refugees with enlarged spleens, or splenomegaly. Many conditions can cause splenomegaly, such as various infections, liver disease, and cancer. Splenomegaly can result in hematologic disturbances and abdominal pain and can increase the risk for splenic rupture from blunt trauma, resulting in life-threatening internal bleeding. On CDC's advice, panel physicians implemented an enhanced surveillance and treatment protocol that included screening for malaria (through thick and thin smears and rapid diagnostic testing), schistosomiasis, and several other conditions; treatment of any condition identified as potentially associated with splenomegaly; and empiric treatment for the most likely etiologies, including malaria and schistosomiasis. CDC recommended further treatment for malaria with primaquine after arrival, after glucose-6-phosphate dehydrogenase testing, to target liver-stage parasites. Despite this recommended treatment protocol, 35 of 64 patients with available follow-up records had splenomegaly that persisted beyond 6 months after resettlement. Among 85 patients who were diagnosed with splenomegaly through abdominal palpation or ultrasound at any point after resettlement, 53 had some hematologic abnormality (leukopenia, anemia, or thrombocytopenia), 16 had evidence of current or recent malaria infection, and eight had evidence of schistosomiasis. Even though primaquine was provided to a minority of patients in this cohort, it should be provided to all eligible patients with persistent splenomegaly, and repeated antischistosomal therapy should be provided to patients with evidence of current or recent schistosomiasis. Given substantial evidence of familial clustering of cases, family members of patients with known splenomegaly should be proactively screened for this condition.

MicroRNA-351 promotes schistosomiasis-induced hepatic fibrosis by targeting the vitamin D receptor.

Aberrant expression of microRNAs (miRNAs) underlies a spectrum of human diseases including organ fibrosis, and hepatic stellate cells (HSCs) are the main effectors of hepatic fibrosis. Here, we showed that the expression of host miR-351 in HSCs was markedly reduced during the early stage of Schistosoma infection. However, this expression was significantly increased during the later stage of infection (after 52 d of infection). The elevated levels of miR-351 promoted hepatic fibrosis by targeting the vitamin D receptor (VDR), which is an antagonist of SMAD signaling. Importantly, efficient and sustained inhibition of miR-351 in liver tissues using the highly hepatotropic recombinant adeno-associated virus serotype 8 (rAAV8), alleviated the hepatic fibrosis, partially protecting the host from lethal schistosomiasis. In addition, we found that miR-351 is negatively regulated by IFN-γ in HSCs during infection. At the early stage of infection, the elevated levels of IFN-γ inhibited the expression of miR-351 in HSCs through activation of signal transducer and activator of transcription 1 and induction of IFN regulatory factor 2, which binds the promotor of pre-miR-351 Our study provides insights into the mechanisms by which miR-351 regulates schistosomiasis hepatic fibrosis and highlights the potential of rAAV8-mediated miR-351 inhibition as a therapeutic intervention for fibrotic diseases.

Cardiac manifestations of parasitic diseases.

The heart may be affected directly or indirectly by a variety of protozoa and helminths. This involvement may manifest in different ways, but the syndromes resulting from impairment of the myocardium and pericardium are the most frequent. The myocardium may be invaded by parasites that trigger local inflammatory response with subsequent myocarditis or cardiomyopathy, as occurs in Chagas disease, African trypanosomiasis, toxoplasmosis, trichinellosis and infection with free-living amoebae. In amoebiasis and echinococcosis, the pericardium is the structure most frequently involved with consequent pericardial effusion, acute pericarditis, cardiac tamponade or constrictive pericarditis. Chronic hypereosinophilia due to helminth infections, especially filarial infections, has been associated with the development of tropical endomyocardial fibrosis, a severe form of restrictive cardiomyopathy. Schistosomiasis-associated lung vasculature involvement may cause pulmonary hypertension (PH) and cor pulmonale Tropical pulmonary eosinophilia, which is characterised by progressive interstitial fibrosis and restrictive lung disease, may lead to PH and its consequences may occur in the course of filarial infections. Intracardiac rupture of an Echinococcus cyst can cause membrane or secondary cysts embolisation to the lungs or organs supplied by the systemic circulation. Although unusual causes of cardiac disease outside the endemic areas, heart involvement by parasites should be considered in the differential diagnosis especially of myocardial and/or pericardial diseases of unknown aetiology in both immunocompetent and immunocompromised individuals. In this review, we updated and summarised the current knowledge on the major heart diseases caused by protozoan and metazoan parasites, which either involve the heart directly or otherwise influence the heart adversely.

[One case report of ectopic schistosomiasis in fallopian tube in Jingmen City].

One cases of ectopic schistosomiasis in fallopian tube was found by the histopathological examination in Jingmen City. After surgery and anthelmintic treatment with praziquantel, the curative effect was satisfactory. This case suggests that in schistosomiasis endemic area, the imaging technology and tissue pathological examination should be used sufficiently for the differential diagnosis of ectopic schistosomiasis, so as to reduce misdiagnosis.

Avaliação das ações de controle da esquistossomose na Estratégia de Saúde da Família em municípios do Vale do Jequitinhonha em Minas Gerais / Evaluation of schistosomiasis control activities in the Family Health Strategy in municipalities in the Jequitinhonha Valley, Minas Gerais, Brazil

RESUMO: Estudo observacional que analisa a qualidade das ações de diagnóstico, tratamento e controle da esquistossomose na Estratégia Saúde da Família (ESF) em área endêmica. Foram utilizados questionários estruturados em 97 profissionais de saúde da ESF e em secretários municipais de saúde de 25 municípios pertencentes à Gerência Regional de Saúde de Pedra Azul, Minas Gerais. Foram utilizados os Modelos de Variáveis Latentes para definir um escore a fim de avaliar a qualidade da proposta. Os resultados mostraram que 57,8% das equipes da ESF realizam suas ações de maneira insatisfatória ou crítica. Os profissionais não realizam ações efetivas para controle da infecção e 8,1% não utilizam o método diagnóstico preconizado pelo governo. As estratégias de vigilância e controle ainda são incipientes. Da mesma forma, os profissionais não receberam treinamento adequado para o desenvolvimento das ações de prevenção e controle da esquistossomose. Falta material educativo para o desempenho das atividades de educação em saúde, sendo que as equipes da ESF realizam atividades educativas nas escolas em 48% dos municípios. Menos da metade dos profissionais entrevistados conhecia o Programa de Controle da Esquistossomose (PCE). É necessário integrar as práticas do PCE à ESF, além de buscar um adequado suporte da gestão municipal por meio de pactuações e do controle social.

ABSTRACT: Observational study that examined the quality of the preventive actions for schistosomiasis control in the Brazilian Family Health Strategy (FHS) in an endemic area. Structured questionnaires were used to interview 97 health professionals of the FHS and the Secretary of Health of 25 municipalities belonging to the State Health Department of Pedra Azul, Minas Gerais, Brazil. Models of latent variables were used to define a score to evaluate the quality of the process. The results showed that 57.8% of the FHS teams' actions were unsatisfactory or critical. The professionals did not perform effective activities for the control of the infection and 8.1% did not use the diagnostic methods required by the government. Similarly, the professionals did not receive adequate training for the development of schistosomiasis prevention and control. There was a lack of educational materials to carry out health education activities, and the FHS teams conducted educational activities in only 48% of the schools of municipalities. Less than half of the professionals interviewed knew about the Schistosomiasis Control Program. We concluded that it is necessary to integrate this Program's practices to the FHS, and seek a suitable support of municipal management through pacts and social control.

[Discussion on multidisciplinary treatment mode of advanced schistosomiasis and its standardized implementation].

Advanced schistosomiasis is the most serious clinical type of schistosomiasis. Its diagnosis and treatment are related to many special departments, such as gastroenterology, general surgery, neurology, endocrinology, radiology, traditional Chinese medicine, blood purification, endoscopy, intervention, and ICU. It is necessary to apply a multidisciplinary treatment (MDT) mode. However, the mode has no universal standard and guide in practice. It is very important for the implementation of MDT mode of advanced schistosomiasis to form a treatment expert team, formulate the formal working procedures, and standardize the treatment schedules. The standardized implementation of MDT mode will be important to provide a more effective clinical decision on advanced schistosomiasis.

Influence of Polymorphism (-G308A) TNF-α on the Periportal Fibrosis Regression of Schistosomiasis After Specific Treatment.

AIMS: Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine and important mediator of severity for periportal fibrosis (PPF). We hypothesized that the (-G380A) polymorphism in the TNF-α gene is associated with regression of PPF after treatment for schistosomiasis mansoni. METHODS: This is a retrospective cohort study, involving 124 Brazilian patients infected with Schistosoma mansoni, who were followed for 2 years after treatment to estimate the likelihood of PPF regression. Sociodemographic and clinical factors were also identified, with emphasis on specific treatment. RESULTS: No statistical difference was observed between sociodemographic and clinical factors among the exposed groups. Genotypes (-308) GA/AA were positively associated with the degree of PFF regression (relative risk [RR] = 0.52; ρ = 0.025), as well as in the image pattern of PPF (RR = 0.56; ρ = 0.048), when compared with the genotype (-308) GG. There was no statistical difference in TNF-α serum levels between the exposed groups. CONCLUSIONS: These results suggest that the (-G308A) polymorphism of the TNF-α gene may be one of the factors that prevents the regression of the degree and pattern of PPF in the Brazilian population, and thus it may potentially be a predictive factor of PPF intensity in schistosomiasis.

Obstrução extrínseca do tronco da coronária esquerda causada por dilatação da artéria pulmonar associada à esquistossomíase / Extrinsic obstruction of the left main coronary artery due to pulmonary artery dilation associated with schistosomiasis

Relatamos o caso de um paciente portador de hipertensão pulmonar de origem esquistossomótica, que procurou pronto atendimento por apresentar quadro de dor torácica em repouso. A apresentação clínica e os demais dados referentes ao caso levantaram a suspeita de insuficiência coronariana aguda, e foi diagnosticada uma obstrução grave do tronco da coronária esquerda. O relato do caso teve por objetivo destacar a necessidade do diagnóstico diferencial da queixa de dor torácica nestes pacientes e ressaltar a opção da intervenção coronariana percutânea como tratamento eficaz e seguro neste cenário.

This report describes a patient with pulmonary hypertension secondary to schistosomiasis, who sought emergency care due to chest pain at rest. The clinical presentation and other information related to the case raised the suspicion of acute coronary failure, and a severe obstruction was identified in the left main coronary artery. The case report aimed to highlight the need for a differential diagnosis of chest pain complaints in these patients, and emphasizes the choice of percutaneous coronary intervention as an effective and safe treatment in this scenario.

Avaliação do aumento da solubilidade aquosa do praziquantel incorporado em microesferas de poli(3-hidroxibutirato) e Eudragit® E / Evaluation of enhanced aqueous solubility of praziquantel incorporated in poly (3-hydroxybutyrate) and Eudragit® E microspheres

O praziquantel é o fármaco de escolha no tratamento da esquistossomose, porém, sua baixa solubilidade aquosa pode comprometer sua biodisponibilidade por via oral. Neste trabalho o praziquantel foi incorporado em microesferas de poli(3-hidroxibutirato) (PHB) e Eudragit® E pela técnica de emulsão-evaporação do solvente, com o intuito de melhorar sua solubilidade aquosa. As micropartículas preparadas com PHB apresentaram forma esférica e eficiência de encapsulação do fármaco de 78%. Quando preparadas com Eudragit® E/PHB na proporção de 50/50, apresentaram-se porosas e com eficiência de encapsulação de 42%. As microesferas preparadas com os polímeros na proporção de 75/25 apresentaram-se mais porosas que as anteriores e com 52% de praziquantel encapsulado. Ensaios de dissolução in vitro demonstraram melhora significativa na solubilidade aquosa do praziquantel incorporado às microesferas de Eudragit® E/PHB 75/25. O aumento da solubilidade está associado à elevada porosidade das microesferas e ao emprego do Eudragit® E como carreador hidrofílico.

Praziquantel is the drug of choice for the treatment of schistosomiasis, however, its low water solubility may undermine the oral bioavailability. In this study, praziquantel was incorporated into microspheres prepared with poly(3-hydroxybutyrate) (PHB) and a polymethacrylate (Eudragit® E), using an emulsion-solvent evaporation method, in order to improve its aqueous solubility. Microparticles prepared with PHB had spherical shape and encapsulation efficiency of 78%. When prepared with Eudragit® E/PHB at a ratio of 50/50 the microspheres were porous and encapsulated 42% of the drug, and for a ratio of 75/25 the microspheres were more porous than those of the previous formulations, with an encapsulation efficiency of 52%. Dissolution in vitro led to a significant improvement in the aqueous solubility of praziquantel incorporated into Eudragit® E/PHB 75/25 microspheres. This increased solubility is linked to the high porosity of the microspheres and the use of Eudragit® E as a hydrophilic carrier.

Combined TLR7/8 and TLR9 ligands potentiate the activity of a Schistosoma japonicum DNA vaccine.

BACKGROUND: Toll-like receptor (TLR) ligands have been explored as vaccine adjuvants for tumor and virus immunotherapy, but few TLR ligands affecting schistosoma vaccines have been characterized. Previously, we developed a partially protective DNA vaccine encoding the 26-kDa glutathione S-transferase of Schistosoma japonicum (pVAX1-Sj26GST). METHODOLOGY/PRINCIPAL FINDINGS: In this study, we evaluated a TLR7/8 ligand (R848) and a TLR9 ligand (CpG oligodeoxynucleotides, or CpG) as adjuvants for pVAX1-Sj26GST and assessed their effects on the immune system and protection against S. japonicum. We show that combining CpG and R848 with pVAX1-Sj26GST immunization significantly increases splenocyte proliferation and IgG and IgG2a levels, decreases CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) frequency in vivo, and enhances protection against S. japonicum. CpG and R848 inhibited Treg-mediated immunosuppression, upregulated the production of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-10, IL-2, and IL-6, and decreased Foxp3 expression in vitro, which may contribute to prevent Treg suppression and conversion during vaccination and allow expansion of antigen-specific T cells against pathogens. CONCLUSIONS: Our data shows that selective TLR ligands can increase the protective efficacy of DNA vaccines against schistosomiasis, potentially through combined antagonism of Treg-mediated immunosuppression and conversion.