SAR studies on azasterols as potential anti-trypanosomal and anti-leishmanial agents

There is an urgent need for the development of new drugs for the treatment of neglected tropical diseases such as human African trypanosomiasis, Chagas disease and leishmaniasis. Azasterols, have been shown to have activity against the parasites which cause these diseases. In this paper we report synthesis of new azasterols and subsequent analysis of the SAR. The chemistry focused on variations in the ester at the 3β-position of the sterol and the position of the nitrogen in the side chain. The data allowed us to derive preliminary pharmacophore models for the activity of the azasterols against the parasites which cause these diseases.     

Transglutaminase-catalyzed reactions in the growth, maturation and development of parasitic nematodes

Parasitic nematodes cause several debilitating diseases in humans and animals. New drugs that are parasite specific and minimally toxic to the host are needed to counter these infections effectively. The identification and inhibition of enzymes that are vital for the growth and survival of parasites offer new approaches for developing effective chemotherapeutic agents. Several enzymes in nematodes fall into this category. Here, Ramaswamy Chandrashekar and Kapil Mehta examine in detail the role of transglutaminase, a protein-crosslinking enzyme, in the normal growth and development of nematodes, with an emphasis on filarial parasites.     

Dominant parasites of fish in Georgia, USSR

Intensive fish breeding in artificial freshwater reservoirs and ponds is often accompanied by epidemics of invasive parasitic diseases. In the USSR, much attention is given to the study of fish parasites and diseases, revealing a range of protozoan and helminth parasites that can cause significant economic losses to the fish industry (Table I ; Refs 1-5).     

Global protein expression analysis in apicomplexan parasites: current status

Members of the phylum Apicomplexa are important protozoan parasites that cause some of the most serious, and in some cases, deadly diseases in humans and animals. They include species from the genus Plasmodium, Toxoplasma, Eimeria, Neospora, Cryptosporidium, Babesia and Theileria. The medical, veterinary and economic impact of these pathogens on a global scale is enormous. Although chemo- and immuno-prophylactic strategies are available to control some of these parasites, they are inadequate. Currently, there is an urgent need to design new vaccines or chemotherapeutics for apicomplexan diseases. High-throughput global protein expression analyses using gel or non-gel based protein separation technologies coupled with mass spectrometry and bioinformatics provide a means to identify new drug and vaccine targets in these pathogens. Protein identification based proteomic projects in apicomplexan parasites is currently underway, with the most significant progress made in the malaria parasite, Plasmodium falciparum. More recently, preliminary two-dimensional gel electrophoresis maps of Toxoplasma gondii and Neospora caninum tachyzoites and Eimeria tenella sporozoites, have been produced, as well as for micronemes in E. tenella. In this review, the status of proteomics in the analysis of global protein expression in apicomplexan parasites will be compared and the challenges associated with these investigations discussed.     

Diversification and host switching in avian malaria parasites

The switching of parasitic organisms to novel hosts, in which they may cause the emergence of new diseases, is of great concern to human health and the management of wild and domesticated populations of animals. We used a phylogenetic approach to develop a better statistical assessment of host switching in a large sample of vector-borne malaria parasites of birds (Plasmodium and Haemoproteus) over their history of parasite-host relations. Even with sparse sampling, the number of parasite lineages was almost equal to the number of avian hosts. We found that strongly supported sister lineages of parasites, averaging 1.2% sequence divergence, exhibited highly significant host and geographical fidelity. Event-based matching of host and parasite phylogenetic trees revealed significant cospeciation. However, the accumulated effects of host switching and long distance dispersal cause these signals to disappear before 4% sequence divergence is achieved. Mitochondrial DNA nucleotide substitution appears to occur about three times faster in hosts than in parasites, contrary to findings on other parasite-host systems. Using this mutual calibration, the phylogenies of the parasites and their hosts appear to be similar in age, suggesting that avian malaria parasites diversified along with their modern avian hosts. Although host switching has been a prominent feature over the evolutionary history of avian malaria parasites, it is infrequent and unpredictable on time scales germane to public health and wildlife management.     

Proteomics of trypanosomatids of human medical importance

Leishmania spp., Trypanosoma cruzi, and Trypanosoma brucei are protozoan parasites that cause a spectrum of fatal human diseases around the world. Recent completion of the genomic sequencing of these parasites has enormous relevance to the study of their biology and the pathogenesis of the diseases they cause because it opens the door to high-throughput proteomic technologies. This review encompasses studies using diverse proteomic approaches with these organisms to describe and catalogue global protein profiles, reveal changes in protein expression during development, elucidate the subcellular localisation of gene products, and evaluate host–parasite interactions.     

The Truman Show for protozoan parasites: A review of in vitro cultivation platforms

Protozoan parasites are responsible for severe disease and suffering in humans worldwide. Apart from disease transmission via insect vectors and contaminated soil, food, or water, transmission may occur congenitally or by way of blood transfusion and organ transplantation. Several recent outbreaks associated with fresh produce and potable water emphasize the need for vigilance and monitoring of protozoan parasites that cause severe disease in humans globally. Apart from the tropical parasite Plasmodium spp., other protozoa causing debilitating and fatal diseases such as Trypanosoma spp. and Naegleria fowleri need to be studied in more detail. Climate change and socioeconomic issues such as migration continue to be major drivers for the spread of these neglected tropical diseases beyond endemic zones. Due to the complex life cycles of protozoa involving multiple hosts, vectors, and stringent growth conditions, studying these parasites has been challenging. While in vivo models may provide insights into host–parasite interaction, the ethical aspects of laboratory animal use and the challenge of ready availability of parasite life stages underline the need for in vitro models as valid alternatives for culturing and maintaining protozoan parasites. To our knowledge, this review is the first of its kind to highlight available in vitro models for protozoa causing highly infectious diseases. In recent years, several research efforts using new technologies such as 3D organoid and spheroid systems for protozoan parasites have been introduced that provide valuable tools to advance complex culturing models and offer new opportunities toward the advancement of parasite in vitro studies. In vitro models aid scientists and healthcare providers in gaining insights into parasite infection biology, ultimately enabling the use of novel strategies for preventing and treating these diseases.     

Navigating the boundaries between metabolism and epigenetics in trypanosomes

Epigenetic marks enable cells to acquire new biological features that favor their adaptation to environmental changes. These marks are chemical modifications on chromatin-associated proteins and nucleic acids that lead to changes in the chromatin landscape and may eventually affect gene expression. The chemical tags of these epigenetic marks are comprised of intermediate cellular metabolites. The number of discovered associations between metabolism and epigenetics has increased, revealing how environment influences gene regulation and phenotype diversity. This connection is relevant to all organisms but underappreciated in digenetic parasites, which must adapt to different environments as they progress through their life cycles. This review speculates and proposes associations between epigenetics and metabolism in trypanosomes, which are protozoan parasites that cause human and livestock diseases.     

中国狗寄生虫名录

1.本文将中国已发现之狗寄生虫,列成名录。 2.迄目前止,中国已知之狗寄生虫自然感染者有原虫12种、线虫18种、吸虫34种、絛虫17种、蛭1种,蜱25种、螨4种、舌形虫2种、昆虫18种,计131种;实验感染者有线虫2种、棘头虫1种、吸虫13种,计16种,共147种。 3.上海发现的马氏斜睾吸虫Plagiorchis(M.)massino Petrov and Tichonov,1927及Alaria sp.均为国内狗寄生虫之新纪录。     

Proteolysis and Toxoplasma invasion

Apicomplexan parasites including Toxoplasma gondii cause widespread human and animal diseases, often with the most severe manifestations involving the central nervous system. The need for new therapeutic agents along with the fascinating biology of these parasites has fueled a keen interest in understanding how key steps in the life cycle are regulated. Proteolysis is intimately associated with cell and tissue invasion by these obligate intracellular parasites and recent studies have begun to identify the proteases involved in these processes. Based on clues from inhibitor experiments and cleavage site mapping studies, several groups are using emerging genome information, chemical proteomics and molecular genetics to identify and validate proteases that regulate secretory organelle biogenesis and invasion protein activity. These studies are revealing roles for an assortment of proteases including cathepsins, subtilases and rhomboids in cell and tissue invasion. The identification of highly selective inhibitors for these proteases has the potential to not only further dissect their roles in infection but also to ameliorate disease.     

The application of gene expression microarray technology to kinetoplastid research

Protozoan parasites in the order Kinetoplastida cause severe disease primarily in tropical and subtropical areas. Vaccines to control these diseases have shown some promise, but none are in active clinical use. Drug treatments are available for all of the acute infections, but the emergence of resistance and an unresponsive chronic phase are current problems. Rapid advances in genomic technology open the possibility of discovering new genes that can contribute to vaccine initiatives or serve as targets for development of new drugs. The DNA microarray is a genomic technology, which is being applied to new gene discovery in kinetoplastid parasites. Both cDNA and genomic microarrays for Leishmania major have identified a number of new genes that are expressed in a stage-specific fashion and preliminary results from a L. donovani genomic microarray also demonstrated new gene discovery. A microarray of Trypanosoma brucei genomic fragments identified new genes whose expression differs between the insect borne stage and the human infectious stage of the parasite. The next few years, building on this foundational work, should witness the most exciting stage as microarrays are applied to questions such as the basis of drug resistance, post kala azar dermal leishmaniasis, the regulation of differentiation to infectious stages, linking coordinately regulated pathways of genes and development of genetically defined parasites that may have potential as live attenuated vaccines.     

Phytomonas: Trypanosomatids Adapted to Plant Environments

Over 100 years after trypanosomatids were first discovered in plant tissues, Phytomonas parasites have now been isolated across the globe from members of 24 different plant families. Most identified species have not been associated with any plant pathology and to date only two species are definitively known to cause plant disease. These diseases (wilt of palm and coffee phloem necrosis) are problematic in areas of South America where they threaten the economies of developing countries. In contrast to their mammalian infective relatives, our knowledge of the biology of Phytomonas parasites and how they interact with their plant hosts is limited. This review draws together a century of research into plant trypanosomatids, from the first isolations and experimental infections to the recent publication of the first Phytomonas genomes. The availability of genomic data for these plant parasites opens a new avenue for comparative investigations into trypanosomatid biology and provides fresh insight into how this important group of parasites have adapted to survive in a spectrum of hosts from crocodiles to coconuts.     

Parasites as threats to biodiversity in shrinking ecosystems

Shrinking ecosystems concentrate both individuals and species into restricted areas, promoting transmission and exchange of parasites. Fragmentation increases edge and brings an influx of new species into the disturbed or agricultural habitats between fragments, introducing new parasites and possibly leading to the development of new and more pathogenic strains of parasite. Environmental contaminants act as stressors, and may compromise immune systems. Global climate changes challenge the adaptability of organisms, and may allow the invasion of new parasites. Because each of these effects increases the potential for parasites to become pathogenic, the importance of disease is expected to increase in shrinking ecosystems, with the emergence of new diseases and increasing numbers of epidemics. Increased pathogenicity of generalist parasites may pose a threat to species with restricted distributions or small populations.     

Distribution of lethal haemosporidoses pathogens in poultry

Peculiarities of geographical distribution and distribution among hosts of the haemosporidian parasites, which cause lethal diseases in poultry, are specified. So far, 11 species of such parasites have been described. This represents about 5% of bird haemosporidian parasites. The haemosporidians cause the lethal epizooties in turkeys, chickens, ducks, geese, pigeons and domesticated ostriches. One species of parasites belongs to the family Haemoproteidae, six--to Plasmodiidae, and four--to Leucocytozoidae. The agents of lethal haemosporidioses have been recorded in domestic birds of the orders Galliformes, Anseriformes, Columbiformes and Struthiorniformes. The majority of these parasites (eight species of 73%) occurs in the galliform birds. Each other order obtaines only one species of parasites. Five species parasitize turkey, which is the main host of the agent of lethal haemosporidioses. The majority of highly virulent haemosporidian species have been recorded throughout a global territory, which includes the Holarctic, Ethiopian and Oriental zoogeorgaphical regions. Three species of these parasites have been found in the Neotropical region, while none species has been recorded in Australia. The majority of highly virulent haemosporidian species have quite clear outlined areas, that is important to know for the prophilactic purposes including the quarantine of bird introducing from endemic territories.     

Agrochemicals against Malaria,Sleeping Sickness,Leishmaniasis and Chagas Disease

In tropical regions, protozoan parasites can cause severe diseases with malaria, leishmaniasis, sleeping sickness, and Chagas disease standing in the forefront. Many of the drugs currently being used to treat these diseases have been developed more than 50 years ago and can cause severe adverse effects. Above all, resistance to existing drugs is widespread and has become a serious problem threatening the success of control measures. In order to identify new antiprotozoal agents, more than 600 commercial agrochemicals have been tested on the pathogens causing the above mentioned diseases. For all of the pathogens, compounds were identified with similar or even higher activities than the currently used drugs in applied in vitro assays. Furthermore, in vivo activity was observed for the fungicide/oomyceticide azoxystrobin, and the insecticide hydramethylnon in the Plasmodium berghei mouse model, and for the oomyceticide zoxamide in the Trypanosoma brucei rhodesiense STIB900 mouse model, respectively.     

Control of lymphoproliferation by Theileria annulata

The economic importance of bovine theilerioses has prompted several new approaches to understanding the diseases in the hope of developing more efficient methods of control. Most Theileria species that infect cattle cause a lymphoproli ferative disease. Sporozoites, injected into the host bloodstream by the tick vectors, rapidly invade host lymphocytes and stimulate rapid division of infected cells. As these rupture, merozoites are released which invade red blood cells ready to infect feeding ticks again. The process by which Theileria parasites can control host lymphocytes, and induce them to divide in synchrony with the parasites themselves, is poorly understood but seems to be the key to pathogenesis. In this article, Michael Dyer and Andrew Tait discuss the possible mechanisms of cellular control in the light of recent work revealing sequences homologous to oncogenes in the DNA of T. annulata.     

Genomes and genome projects of protozoan parasites

Protozoan parasites are causing some of the most devastating diseases world-wide. It has now been recognised that a major effort is needed to be able to control or eliminate these diseases. Genome projects for the most important protozoan parasites have been initiated in the hope that the read-out of these projects will help to understand the biology of the parasites and identify new targets for urgently needed drugs. Here, I will review the current status of protozoan parasite genome projects, present findings obtained as a result of the availability of genomic data and discuss the potential impact of genome information on disease control.     

What happens when Trypanosoma brucei leaves Africa

Julius Lukes and co-workers evaluated the evolutionary origin of Trypanosoma equiperdum and Trypanosoma evansi, parasites that cause horse and camel diseases. Although similar to T. brucei, the sleeping-sickness parasite, these trypanosomes do not cycle through the tsetse fly and have been able to spread beyond Africa. Transmission occurs sexually, or via blood-sucking flies or vampire bats. They concluded that these parasites, which resemble yeast petite mutants, are T. brucei sub-species, which have evolved recently through changes in mitochondrial DNA.     

The future impact of societal and cultural factors on parasitic disease -- some emerging issues

A variety of societal and cultural factors will increase host exposure or susceptibility to infectious agents, particularly parasites. Such factors have already had a major impact on the emergence of infectious diseases and the situation is likely to worsen further as we enter the new millennium. The changes that are enhancing the spread and transmission of parasitic diseases, as well as those which are adversely affecting host responsiveness, are examined with reference to specific parasites.     

Economic losses caused by foodborne parasitic diseases

Fragmentary data indicate that zoonotic parasites cause human illnesses with medical costs and productivity and disability losses totalling billions of dollars annually. Food is an important vehicle for some of these parasitic diseases. The cost to public health is not reflected in the priorities given to these parasitic diseases in either research or public health planning. In this article, Tanya Roberts, Darwin Murrell and Suzanne Marks discuss the cost of toxoplasmosis, taeniasis, cysticercosis, trichinellosis and other foodborne parasitic diseases.