New approaches in vaccine development for parasitic infections

Vaccines have had a tremendous impact on the control of infectious diseases. Not only are vaccines potentially the least expensive mechanism to combat infectious diseases, under optimal conditions, widespread vaccination can result in disease eradication - as in the case of smallpox. Despite this great potential, vaccines have had little impact on human parasitic infections. The reasons for this are many - these eukaryotic pathogens are genetically and biologically complex organisms, some with elaborate life cycles and well-honed immune evasion mechanisms. Additionally, our understanding of the mechanisms of immune control of many parasitic infections -- of what constitutes an effective immune response and of how to induce high-quality immunological memory -- is not fully developed. This review attempts to highlight recent advances that could impact vaccine discovery and development in parasitic infections and proposes areas where future studies may lead to breakthroughs in vaccines for the agents of parasitic diseases. There are several other recent reviews highlighting the results of vaccine trials, specifically in the malaria field.     

Immunobiology of cystic echinococcosis

The present report focuses on the ability of cystic echinoccocosis metacestode to survive for a long time, despite host immunity, by developing avoidance strategies. The tactics believed to come into play, ranging from intrinsic parasitic factors to host-related mechanisms, are briefly discussed and the importance of studies on experimental models is highlighted particularly in relation to furthering the theoretical understanding of the dynamic equilibrium between host and parasite, and to the feasibility of practical approaches in controlling the disease by artificial manipulation of the immunoregulatory mechanisms.     

The helminth holobiont: a multidimensional host–parasite–microbiota interaction

Gastrointestinal helminths have developed multiple mechanisms by which they manipulate the host microbiome to make a favorable environment for their long-term survival. While the impact of helminth infections on vertebrate host immunity and its gut microbiota is relatively well studied, little is known about the structure and functioning of microbial populations supported by metazoan parasites. Here we argue that an integrated understanding of the helminth-associated microbiome and its role in the host disease pathogenesis may facilitate the discovery of specific microbial and/or genetic patterns critical for parasite biology and subsequently pave the way for the development of alternative control strategies against parasites and parasitic disease.     

Plant resistance to parasitic plants: molecular approaches to an old foe

Parasitic weeds pose severe constraint on major agricultural crops. Varying levels of resistance have been identified and exploited in the breeding programmes of several crops. However, the level of protection achieved to date is either incomplete or ephemeral. Resistance is mainly determined by the coexistence of several mechanisms controlled by multigenic and quantitative systems. Efficient control of the parasite requires a better understanding of the interaction and their associated resistance mechanisms at the histological, genetic and molecular levels. Application of postgenomic technologies and the use of model plants should improve the understanding of the plant-parasitic plant interaction and drive not only breeding programmes through either marker-assisted selection (MAS) or transgenesis but also the development of alternative methods to control the parasite. This review presents the current approaches targeting the characterization of resistance mechanisms and explores their potentiality to control parasitic plants.     

Treatment of onchocerciasis with ivermectin in Sierra Leone

Ivermectin chemotherapy is proving to be a major advance in the management of onchocerciasis. In this article, James Whitworth reviews the work done on onchocerciasis and ivermectin in Sierra Leone and examines the evidence that mass treatment might control the clinical features of the disease and its transmission in West Africa. Ivermectin is safe and effectively reduces microfilarial (mf) loads, with major improvement in some ocular manifestations o f disease. This alone makes mass distribution to communities at risk of blindness worthwhile, even though the impact on other clinical features is less clear cut. Repeated doses have a cumulative effect on adult worms, which may cause more reduction in transmission than hitherto thought likely.     

Natural product based leads to fight against leishmaniasis

The growing incidence of parasitic resistance against generic pentavalent antimonials, specifically for visceral disease in Indian subcontinent, is a serious issue in Leishmania control. Notwithstanding the two treatment alternatives, that is amphotericin B and miltefosine are being effectively used but their high cost and therapeutic complications limit their use in endemic areas. In the absence of a vaccine candidate, identification, and characterization of novel drugs and targets is a major requirement of leishmanial research. This review describes current drug regimens, putative drug targets, numerous natural products that have shown promising antileishmanial activity alongwith some key issues and strategies for future research to control leishmaniasis worldwide.     

Schistosomiasis control in the People's Republic of China

Schistosomes, snail-transmitted trematodes (blood flukes), cause a major parasitic disease that ranks second only to malaria in terms of human suffering in the tropics. Schistosoma japonicum has occupied its ecological niche in China for thousands of years; through natural selection it has evolved survival mechanisms that make it difficult (if not impossible) to eradicate. As discussed here by Allen Ross, Li Yuesheng, Adrian Sleigh and Don McManus, vaccination, in combination with current control strategies, may significantly reduce the morbidity of this disease and ultimately improve the quality of life for those living adjacent to endemic zones. This article provides a special focus in Hunan province and examines the potential impact of the Three Gorges Super Dam Project on schistosomiasis control.     

Lymphatic filariasis: what mice can tell us

Human lymphatic filariasis is a major tropical disease in which clinical manifestations range from asymptomatic microfilaraemia to chronic pathology. Investigative immunological research into this disease is hampered by the fact that mice are refractory to the full developmental cycle of this parasitic nematode. However, studies using either single-stage infections or immunocompromised mice have greatly added to our knowledge of the filarial-induced immune pathways leading to protective immunity, pathology and immunological tolerance. In this review, Rachel Lawrence discusses the recent advances in our understanding of the immunology of lymphatic filariasis using the mouse model.     

The health impact of polyparasitism in humans: are we under-estimating the burden of parasitic diseases?

Parasitic infections are widespread throughout the tropics and sub-tropics, and infection with multiple parasite species is the norm rather than the exception. Despite the ubiquity of polyparasitism, its public health significance has been inadequately studied. Here we review available studies investigating the nutritional and pathological consequences of multiple infections with Plasmodium and helminth infection and, in doing so, encourage a reassessment of the disease burden caused by polyparasitism. The available evidence is conspicuously sparse but is suggestive that multiple human parasite species may have an additive and/or multiplicative impact on nutrition and organ pathology. Existing studies suffer from a number of methodological limitations and adequately designed studies are clearly necessary. Current methods of estimating the potential global morbidity due to parasitic diseases underestimate the health impact of polyparasitism, and possible reasons for this are presented. As international strategies to control multiple parasite species are rolled-out, there is a number of options to investigate the complexity of polyparasitism, and it is hoped that that the parasitological research community will grasp the opportunity to understand better the health of polyparasitism in humans.     

Microbial (co)infections: Powerful immune influencers

It is well established that by modulating various immune functions, host infection may alter the course of concomitant inflammatory diseases, of both infectious and autoimmune etiologies. Beyond the major impact of commensal microbiota on the immune status, host exposure to viral, bacterial, and/or parasitic microorganisms also dramatically influences inflammatory diseases in the host, in a beneficial or harmful manner. Moreover, by modifying pathogen control and host tolerance to tissue damage, a coinfection can profoundly affect the development of a concomitant infectious disease. Here, we review the diverse mechanisms that underlie the impact of (co)infections on inflammatory disorders. We discuss epidemiological studies in the context of the hygiene hypothesis and shed light on the sometimes dual impact of germ exposure on human susceptibility to inflammatory disease. We then summarize the immunomodulatory mechanisms at play, which can involve pleiotropic effects of immune players and discuss the possibility to harness pathogen-derived compounds to the host benefit.     

L'eutypiose de la vigne : isolement d'une molécule synthétisée par Eutypa lata et toxique pour la vigne

Eutypa dieback, caused by the ascomycet fungus Eutypa lata, is currently the most serious disease of the grapevine. This disease now affects a great number of vineyards throughout the world, its economic impact is very important, and there is no remedy available for the destruction of the parasitic fungus. In this article, we describe the dieback symptoms, the management practices, the economic impact and the present knowledge on the interactions between E. lata and grapevine. We also present findings concerning the role of a toxic compound, hydroxy-4(methyl-3 butene-3 ynyl-1)-3 benzaldehyde, name eutypine, synthesized by the parasitic fungus and which was shown to be involved in the expression of the disease symptoms. The recent progress made in understanding eutypine's mechanism of action has opened new prospects regarding development of efficient tools for stopping this disease.     

针对骨髓移植病患中铁过载的去铁治疗研究进展

骨髓移植是临床上治疗恶性造血系统疾病的常见手段。而铁过载是临床上常见的并发症之一,对病患的造血功能和治疗后恢复有极大的抑制作用。了解铁过载产生的分子或遗传机制能帮助优化去铁化方案,提高去铁化治疗的效率。本文总结了骨髓移植前后铁过载现象发生机制的最新研究进展,并阐述了临床上多种去铁治疗的方案,以期为该类病患铁过载的预防和治疗提供参考。     

Transition from physiological to pathophysiological indices as exemplified by amyloidosis in periodic disease,non-insulin-dependent diabetes mellitus,and Alzheimer’s disease

Theoretical studies on amyloidosis have been performed. The results promote understanding of primary causes and molecular mechanisms of the formation of pathological protein and permits tracing the transitions from physiological indices to pathological ones in periodic disease (PD), non-insulin-dependent diabetes mellitus (NIDDM), and Alzheimer’s disease (AD). Blockage of the biochemical target by a biologically active substance (drug) at the initial stage of disease makes it possible to avoid formation of pathology. The concept of a “situational physiological skip” is introduced. A new class of drugs (situational controllers of metabolism) that affect transitions from the normal state to pathology in initial periods of disease can be developed. The rational way of finding the prototype of a new drug with a new mechanism of action is computer-aided the developmenrt of a drug on the basis of the spatial structure the target protein. The development of inner structure of proteins related to pathology should be based on distinct grouping of patients according to their genotypes and phenotypes.     

RNAi pathways in parasitic protists and worms

Tropical diseases caused by parasitic worms and protists are of major public health concern affecting millions of people worldwide. New therapeutic and diagnostic tools would be of great help in dealing with the public health and economic impact of these diseases. RNA interference (RNAi) pathways utilize small non-coding RNAs to regulate gene expression in a sequence-specific manner. In recent years, a wealth of data about the mechanisms and biological functions of RNAi pathways in distinct groups of eukaryotes has been described. Often, RNAi pathways have unique features that are restricted to groups of eukaryotes. The focus of this review will be on RNAi pathways in specific groups of parasitic eukaryotes that include Trypanosoma cruzi, Plasmodium and Schistosoma mansoni. These parasites are the causative agents of Chagas disease, Malaria, and Schistosomiasis, respectively, all of which are tropical diseases that would greatly benefit from the development of new diagnostic and therapeutic tools. In this context, we will describe specific features of RNAi pathways in each of these parasitic eukaryotic groups and discuss how they could be exploited for the treatment of tropical diseases.     

The impact of maternal obesity in pregnancy on placental glucocorticoid and macronutrient transport and metabolism

Maternal obesity is the most common metabolic disturbance in pregnancy affecting >1 in 5 women in some countries. Babies born to obese women are heavier with more adiposity at birth, and are vulnerable to obesity and metabolic disease across the lifespan suggesting offspring health is ‘programmed’ by fetal exposure to an obese intra-uterine environment. The placenta plays a major role in dictating the impact of maternal health on prenatal development. Maternal obesity impacts the function of integral placental receptors and transporters for glucocorticoids and nutrients, key drivers of fetal growth, though mechanisms remain poorly understood. This review aims to summarise current knowledge in this area, and considers the impact of obesity on the epigenetic machinery of the placenta at this vital juncture in offspring development. Further research is required to advance understanding of these areas in the hope that the trans-generational cycle of obesity can be alleviated.     

Development of genetic systems for Toxoplasma gondii

The protozoan parasite Toxoplasma gondii has recently emerged as an important opportunistic pathogen in humans. Toxoplasma also shares a number of biological features with Plasmodium and Eimeria, which are important pathogens of humans and animals. Because o f the ease o f experimental use, David Sibley, Elmer Pfefferkom and John Boothroyd have undertaken the development of genetics in Toxoplasma as a model intracellular parasite. Toxoplasma is presently the only parasitic protozoan where both classical and molecular genetics are feasible. The recent advances in this system are highlighted here, along with potential applications of genetics for understanding intracellular parasitism.     

The role and therapeutic potential of connexins,pannexins and their channels in Parkinson's disease

Lack of effective medication for slowing down progression of Parkinson's disease (PD) as a highly prevalent neurodegenerative disorder requires novel avenues of scientific investigation to elucidate the underlying molecular and cellular mechanisms. Studying connexins, pannexins and their channels has uncovered their potential role in mediating communication and signaling pathways that drive neurodegenerative diseases, including PD. Indeed, given their critical role in tissue homeostasis, it is not surprising that connexins, pannexins and their channels are frequently involved in pathological processes. For this reason, pharmacological tools to further clarify their functions and to validate connexins, pannexins and their channels as drug targets for the development of novel therapies for PD treatment are urgently needed. In this paper, a state-of-the-art overview is provided of current neuropathological and molecular understanding of PD. Focus is put on the roles of connexins, pannexins and their channels, in particular in the development of potential innovative disease-modifying therapies for PD treatment.     

Neuronal calcium signaling in chronic pain

Acute physiological pain, the unpleasant sensory response to a noxious stimulus, is essential for animals and humans to avoid potential injury. Pathological pain that persists after the original insult or injury has subsided, however, not only results in individual suffering but also imposes a significant cost on society. Improving treatments for long-lasting pathological pain requires a comprehensive understanding of the biological mechanisms underlying pain perception and the development of pain chronicity. In this review, we aim to highlight some of the major findings related to the involvement of neuronal calcium signaling in the processes that mediate chronic pain.     

Construction of the first shuttle vectors for gene cloning and homologous recombination in Mycoplasma agalactiae

Mycoplasma agalactiae is a worldwide ruminant pathogen that causes significant economic losses by inflicting contagious agalactia in sheep and goats. The development of efficient control strategies requires a better understanding of the mycoplasma factors that promote successful infection. However, lack of genetic tools has been a major impediment in studying the pathogenic mechanisms of M. agalactiae. This study describes the identification and cloning of the M. agalactiae origin of replication (oriC) in order to construct the first shuttle vectors for targeted gene disruption, gene complementation and expression studies. Additionally, this report provides the first evidence of the occurrence of homologous recombination and the functionality of heterologous tetM determinant in this pathogen.