The immunobiology of schistosomiasis

Schistosomes are parasitic worms that are a prime example of a complex multicellular pathogen that flourishes in the human host despite the development of a pronounced immune response. Understanding how the immune system deals with such pathogens is a daunting challenge. The past decade has seen the use of a wide range of new approaches to determine the nature and function of the immune response to schistosomes. Here, we attempt to summarize advances in our understanding of the immunology of schistosomiasis, with the bulk of the review reflecting the experimental focus on Schistosoma mansoni infection in mice.     

Pumping iron: a potential target for novel therapeutics against schistosomes

Parasites, as with the vast majority of organisms, are dependent on iron. Pathogens must compete directly with the host for this essential trace metal, which is sequestered within host proteins and inorganic chelates. Not surprisingly, pathogenic prokaryotes and eukaryotic parasites have diverse adaptations to exploit host iron resources. How pathogenic bacteria scavenge host iron is well characterized and is reasonably well known for a few parasitic protozoa, but is poorly understood for metazoan parasites. Strategies of iron acquisition by schistosomes are examined here, with emphasis on possible mechanisms of iron absorption from host serum iron transporters or from digested haem. Elucidation of these metabolic mechanisms could lead to the development of new interventions for the control of schistosomiasis and other helminth diseases.     

Biologie comparée des interactions entre les macrophages et Trypanosoma cruzi,Leishmania spp. et Toxoplasma gondii

Macrophages have a central role in the immune system by eliminating a lot of pathogens. Nevertheless, they are often infected by pathogenic microorganisms in particular parasitic protozoa. They thus play the role of host cell by harbouring the intracellular survival and multiplication of these pathogens. Various mechanisms (receptors/ligands interactions, enzymes…) are involved in recognition and adhesion steps. When suitably activated, they become effector cells and they can control infection at least partially through the production of reactive oxygen derivatives. But parasitic protozoa can escape these defence mechanisms. In addition, macrophages are also antigen presenting cells and they are inductor cells of the immune response. Once again, parasitic protozoa interfere with these functions and induce chronic infections. Biology of Trypanosoma cruzi, Leishmania spp. and Toxoplasma gondii will be briefly reviewed to illustrate these various aspects of cellular parasitism.     

Schistosome glycoconjugates in host-parasite interplay

Schistosomes are digenetic trematodes which cause schistosomiasis, also known as bilharzia, one of the main parasitic infections in man. In tropical and subtropical areas an estimated 200 million people are infected and suffer from the debilitating effects of this chronic disease. Schistosomes live in the blood vessels and strongly modulate the immune response of their host to be able to survive the hostile environment that they are exposed to. It has become increasingly clear that glycoconjugates of schistosome larvae, adult worms and eggs play an important role in the evasion mechanisms that schistosomes utilise to withstand the immunological measures of the host. Upon infection, the host mounts innate as well as adaptive immune responses to antigenic glycan elements, setting the immunological scene characteristic for schistosomiasis. In this review we summarise the structural data now available on schistosome glycans and provide data and ideas regarding the role that these glycans play in the various aspects of the glycobiology and immunology of schistosomiasis.     

血吸虫基因操作研究进展

近年来,血吸虫基因组、转录组、蛋白质组和分泌组研究广泛开展,迫切需要针对单个分子功能深入研究。开展血吸虫基因操作研究不仅可在虫体内深入研究基因功能,对进一步理解血吸虫生长发育机理和寄生生活特征具有重要意义,还可建立抗血吸虫候选疫苗和药物靶标筛选的重要平台。为此,本文总结基因操作技术在血吸虫学中的应用并分析其现状。     

Pharmacology and potential physiological significance of schistosome multidrug resistance transporters

Schistosomes are the causative agents of schistosomiasis, a neglected tropical disease affecting hundreds of millions worldwide and a major global health burden. Current control of schistosomiasis depends largely on a single drug, praziquantel (PZQ). One potential physiological target for new antischistosomal drugs is the parasite's excretory system, which removes wastes and xenobiotics. Multidrug resistance (MDR) transporters that are members of the ATP-binding cassette (ABC) superfamily of proteins are ATP-dependent efflux pumps involved in removal of toxins and xenobiotics from cells. They mediate the phenomenon of multidrug resistance, in which cells resistant to one drug show cross-resistance to a broad range of other agents, and are also associated with reduced drug susceptibility in parasitic helminths. In this review, we survey the different types of ABC transporter genes present within the schistosome genome, and examine recent evidence indicating that at least some of these transporters may play a role in fine-tuning susceptibility of schistosomes to PZQ. Disruption of their function may therefore provide a strategy for enhancing drug action or overcoming or attenuating drug resistance. Furthermore, dissection of the roles these transporters may play in normal schistosome physiology could potentially lead to identification of highly "druggable" targets for new antischistosomals.     

RNA interference in infectious tropical diseases

Introduction of double-stranded RNA (dsRNA) into some cells or organisms results in degradation of its homologous mRNA, a process called RNA interference (RNAi). The dsRNAs are processed into short interfering RNAs (siRNAs) that subsequently bind to the RNA-induced silencing complex (RISC), causing degradation of target mRNAs. Because of this sequence-specific ability to silence target genes, RNAi has been extensively used to study gene functions and has the potential to control disease pathogens or vectors. With this promise of RNAi to control pathogens and vectors, this paper reviews the current status of RNAi in protozoans, animal parasitic helminths and disease-transmitting vectors, such as insects. Many pathogens and vectors cause severe parasitic diseases in tropical regions and it is difficult to control once the host has been invaded. Intracellularly, RNAi can be highly effective in impeding parasitic development and proliferation within the host. To fully realize its potential as a means to control tropical diseases, appropriate delivery methods for RNAi should be developed, and possible off-target effects should be minimized for specific gene suppression. RNAi can also be utilized to reduce vector competence to interfere with disease transmission, as genes critical for pathogenesis of tropical diseases are knockdowned via RNAi.     

Signalling pathways and the host-parasite relationship: putative targets for control interventions against schistosomiasis: signalling pathways and future anti-schistosome therapies

A better understanding of how schistosomes exploit host nutrients, neuro-endocrine hormones and signalling pathways for growth, development and maturation may provide new insights for improved interventions in the control of schistosomiasis. This paper describes recent advances in the identification and characterisation of schistosome tyrosine kinase and signalling pathways. It discusses the potential intervention value of insulin signalling, which may play an important role in glucose uptake and carbohydrate metabolism in schistosomes, providing the nutrients essential for parasite growth, development and, notably, female fecundity. Significant progress has also been made in the characterisation of other schistosome growth factor receptors, such as transforming growth factor beta receptor and epidermal growth factor receptor, and in our understanding of their roles in the host-parasite molecular dialogue and parasite development. The use of parasite signal transduction components as novel vaccine or drug targets may prove invaluable in prevention, treatment and control strategies to combat schistosomiasis.     

Haemostatic abnormalities in hepatosplenic schistosomiasis mansoni

Hepatosplenic schistosomiasis is a complex immuno-regulatory disease and is major health problem in endemic countries. Acute bleeding is one of its most serious complications and often life-threatening. Clinical studies have demonstrated that the patients with hepatosplenic schistosomiasis are prone to develop complex haemostatic abnormalities that may be linked to the potential risk of bleeding from ruptured esophageal varices in these patients. The deficit in haemostatic parameters is more pronounced with the advancement of the disease and is maximal in the patients with experience of haematomesis. Evidences of enhanced generation of thrombin and plasmin indicate the presence of low-grade DIC in advanced hepatosplenic schistosomiasis, which is considered as a principal cause of haemostatic abnormalities in this endemic disease. Demonstration of procoagulant expression in peripheral blood monocytes of the patients and in the livers, spleens and intestines of S. mansoni-infected mice suggest their possible implication in the causation of DIC in S. mansoni infections. Moreover, because in vitro analysis indicates a participation of immune mechanisms in the localized procoagulant expression, it seems likely that the immune responses to schstosomes play a major role in the pathogenic mechanisms of haemostatic abnormalities in hepatosplenic schistosomiasis.     

Pathogen-endoplasmic-reticulum interactions: in through the out door

A key determinant for the survival of intracellular pathogens is their ability to subvert the cellular processes of the host to establish a compartment that allows replication. Although most microorganisms internalized by host cells are efficiently cleared following fusion with lysosomes, many pathogens have evolved mechanisms to escape this degradation. In this Review, we provide insight into the molecular processes that are targeted by pathogens that interact with the endoplasmic reticulum and thereby subvert the immune response, ensure their survival intracellularly and cause disease. We also discuss how the endoplasmic reticulum 'strikes back' and controls microbial growth.     

Biogenic amines and the control of neuromuscular signaling in schistosomes

Biogenic amines are small cationic monoamines that function broadly as neurotransmitters and/or neuromodulators in every animal phylum. They include such ubiquitous substances as serotonin, dopamine and invertebrate-specific phenolamines (tyramine, octopamine), among others. Biogenic amines are important neuroactive agents in all the flatworms, including blood flukes of the genus Schistosoma, the etiological agents of human schistosomiasis. A large body of evidence spanning nearly five decades identifies biogenic amines as major modulators of neuromuscular function in schistosomes, controlling movement, attachment to the host and other fundamental behaviors. Recent advances in schistosome genomics have made it possible to dissect the molecular mechanisms responsible for these effects and to identify the proteins involved. These efforts have already provided important new information about the mode of action of amine transmitters in the parasite. Moreover, these advances are continuing, as the field moves into a post-genomics era, and new molecular tools for gene and protein analysis are becoming available. Here, we review the current status of this research and discuss future prospects. In particular, we focus our attention on the receptors that mediate biogenic amine activity, their structural characteristics, functional properties and "druggability" potential. One of the themes that will emerge from this discussion is that schistosomes have a rich diversity of aminergic receptors, many of which share little sequence homology with those of the human host, making them ideally suited for selective drug targeting. Strategies for the characterization of these important parasite proteins will be discussed.     

Evaluation of Schistosome Promoter Expression for Transgenesis and Genetic Analysis

Schistosome worms of the genus Schistosoma are the causative agents of schistosomiasis, a devastating parasitic disease affecting more than 240 million people worldwide. Schistosomes have complex life cycles, and have been challenging to manipulate genetically due to the dearth of molecular tools. Although the use of gene overexpression, gene knockouts or knockdowns are straight-forward genetic tools applied in many model systems, gene misexpression and genetic manipulation of schistosome genes in vivo has been exceptionally challenging, and plasmid based transfection inducing gene expression is limited. We recently reported the use of polyethyleneimine (PEI) as a simple and effective method for schistosome transfection and gene expression. Here, we use PEI-mediated schistosome plasmid transgenesis to define and compare gene expression profiles from endogenous and nonendogenous promoters in the schistosomula stage of schistosomes that are potentially useful to misexpress (underexpress or overexpress) gene product levels. In addition, we overexpress schistosome genes in vivo using a strong promoter and show plasmid-based misregulation of genes in schistosomes, producing a clear and distinct phenotype- death. These data focus on the schistosomula stage, but they foreshadow strong potential for genetic characterization of schistosome molecular pathways, and potential for use in overexpression screens and drug resistance studies in schistosomes using plasmid-based gene expression.     

Inhibition or Knockdown of ABC Transporters Enhances Susceptibility of Adult and Juvenile Schistosomes to Praziquantel

Parasitic flatworms of the genus Schistosoma cause schistosomiasis, a neglected tropical disease that affects hundreds of millions. Treatment of schistosomiasis depends almost entirely on the drug praziquantel (PZQ). Though essential to treating and controlling schistosomiasis, a major limitation of PZQ is that it is not active against immature mammalian-stage schistosomes. Furthermore, there are reports of field isolates with heritable reductions in PZQ susceptibility, and researchers have selected for PZQ-resistant schistosomes in the laboratory. P-glycoprotein (Pgp; ABCB1) and other ATP binding cassette (ABC) transporters remove a wide variety of toxins and xenobiotics from cells, and have been implicated in multidrug resistance (MDR). Changes in ABC transporter structure or expression levels are also associated with reduced drug susceptibility in parasitic helminths, including schistosomes. Here, we show that the activity of PZQ against schistosome adults and juveniles ex vivo is potentiated by co-administration of either the highly potent Pgp inhibitor tariquidar or combinations of inhibitors targeting multiple ABC multidrug transporters. Adult worms exposed to sublethal PZQ concentrations remain active, but co-administration of ABC transporter inhibitors results in complete loss of motility and disruption of the tegument. Notably, juvenile schistosomes (3–4 weeks post infection), normally refractory to 2 µM PZQ, become paralyzed when transporter inhibitors are added in combination with the PZQ. Experiments using the fluorescent PZQ derivative (R)-PZQ-BODIPY are consistent with the transporter inhibitors increasing effective intraworm concentrations of PZQ. Adult worms in which expression of ABC transporters has been suppressed by RNA interference show increased responsiveness to PZQ and increased retention of (R)-PZQ-BODIPY consistent with an important role for these proteins in setting levels of PZQ susceptibility. These results indicate that parasite ABC multidrug transporters might serve as important targets for enhancing the action of PZQ. They also suggest a potentially novel and readily-available strategy for overcoming reduced PZQ susceptibility of schistosomes.     

Current status of immune mechanisms of killing of intracellular microorganisms

The interaction between intracellular pathogens and the mammalian host follows different pathways that reflect evolved survival mechanisms of both the pathogen and the host to assure each one's own survival. From the host's perspective, different immune mechanisms predominate at different stages of infection. Both phagocytic and non-phagocytic target cells participate in microbial uptake and, in some cases, intracellular destruction. In addition, the development of specific immunity ensures sustained activation of intracellular microbicidal mechanisms in the target cells, and induction of apoptotic or lytic target cell death by cytotoxic T lymphocytes. From the pathogen's perspective, different evasion strategies are employed to counteract host defenses. Understanding microbial survival strategies and the immune mechanisms that result in killing of intracellular pathogens will deepen our insight into the pathogenesis of infection that could be applied towards the development of effective vaccination and immunotherapy.     

Effectors of biotrophic fungi and oomycetes: pathogenicity factors and triggers of host resistance

Many biotrophic fungal and oomycete pathogens share a common infection process involving the formation of haustoria, which penetrate host cell walls and form a close association with plant membranes. Recent studies have identified a class of pathogenicity effector proteins from these pathogens that is transferred into host cells from haustoria during infection. This insight stemmed from the identification of avirulence (Avr) proteins from these pathogens that are recognized by intracellular host resistance (R) proteins. Oomycete effectors contain a conserved translocation motif that directs their uptake into host cells independently of the pathogen, and is shared with the human malaria pathogen. Genome sequence information indicates that oomycetes may express several hundred such host-translocated effectors. Elucidating the transport mechanism of fungal and oomycete effectors and their roles in disease offers new opportunities to understand how these pathogens are able to manipulate host cells to establish a parasitic relationship and to develop new disease-control measures.