Infectious Disorders - Drug Targets - Volume 10, Issue 4, 2010

Roughly half of the entire human population is currently either at risk or already infected with a parasite [1]. Parasitic diseases do not discriminate among humans for age, sex, lifestyle, ethnic background, or socioeconomic status, which puts all humans at risk of getting infected and threaten people's life standard and social development. Human societies have long been subjected to parasite infections, most likely since the beginning of human evolution. Unfortunately, highly effective chemotherapies that are used to mitigate the effects of parasitic infections are becoming ineffective in some cases. A major contributor to this is the increase in drug resistance among many parasites [2, 3], such as Plasmodium falciparum, which makes the discovery of new drugs as well as new parasite targets highly imperative. The advent of genetic manipulation of parasites' genomes [4-8] provide the tools for the molecular dissection of drug resistance. For instance, the molecular basis of resistance to chloroquine in the malaria parasite P. falciparum has been elegantly demonstrated by Fidock and his colleagues [9]. More recently, the use of genomics, proteomics, and bioinformatic analyses have provided new critical knowledge of the biology of parasites and other organisms. Moreover, it has provided an insight into host-parasite interaction and the role of these interactions in host infections and the pathology associated with the disease. Microarrays [10-12] are commonly used to explore the effect of potential drugs on parasites gene expression. However, the outcomes of anti-parasitic compounds on gene expression profiles appear to depend on the parasite in question. An important consideration for drug development is to avoid the emergence of drug resistance [13, 14]. This could be accomplished by changing the drug's chemical composition and/or by discovering new parasite targets. In the particular case of malaria, research around sexual stage parasites in human/mosquito, hypnozoite stage of P. vivax and/or targeting the factors involved in host to host parasite transmission might prove relevant to the discovery of new and effective targets. Although genomics and bioinformatics are powerful tools, the discovery of new targets for drug development still requires a hands-on biochemical analysis of parasite biology. This will allow for a better understanding of the mechanisms involved in resistance to drugs currently used around the world to treat infectious diseases. This special issue includes two reviews on giardiasis, Giardia has been included in WHO's 'Neglected Disease Initiative' since 2004 [15]. It is estimated that of the 280 million people infected each year in Asia, Africa, and Latin America, 200 million people have symptomatic giardiasis. Two other articles focus on the virulence and RNA processing of Entamoeba histolytica, and describe different potential targets for drug development. E. histolytica infects 500 million people worldwide with 100,000 deaths each year of this disease. In addition, the last three articles deal with various aspects of malaria, toxoplasmsis, schistosomiasis, and trypanosomiasis. In this issue, I tried to incorporate a wide range of parasites and topics. I concentrated on some of the most malignant species of parasites with high morbidity and/or mortality on their susceptible population. Lastly, I would like to thank the authors and reviewers for their contribution in ensuring the quality of the manuscripts compiled in this issue.

Entamoeba histolytica is able to invade human tissues by means of several molecules and biological properties related to the virulence. Pathogenic amebas use three major virulence factors, Gal/GalNAc lectin, amebapore and proteases, for lyse, phagocytose, kill and destroy a variety of cells and tissues in the host. Responses of the parasite to host components such as mucins and bacterial flora influence the behavior of pathogenic amebas altering their expression of virulence factors. The relative virulence of different strains of E. histolytica has been shown to vary as a consequence of changes in conditions of in vitro cultivation which implies substantial changes in basic metabolic aspects and factors directly and indirectly related to amebic virulence. Comparison of E. histolytica strains with different virulence phenotypes and under different conditions of growth will help to identify new virulence factor candidates and define the interplay between virulence factors and invasive phenotype. Virulence attenuate mutants of E. histolytica are useful also to uncover novel virulence determinants. The comparison of biological properties and virulence factors between E. histolytica and E. dispar, a non-pathogenic species, has been a useful approach to investigate the key factors involved in the experimental presentation of amebiasis and its complex regulation. The molecular mechanisms that regulate these variations in virulence are not yet known. Their elucidation will help us to better understand the gene expression plasticity that enables the effective adaptation of the ameba to changes in growth culture conditions and host factors.

Schistosomiasis is a wide-spread parasitic disease of many tropical and sub-tropical countries. The current central control measure is the use of single drug praziquantel, although the mode of action is not fully realised and the possibility resistance is a concern. The preferred alternative control strategy would involve a target vaccine, which unfortunately hasn't yet been realised. A useful research tool for better understanding the immunological elimination of an active infection is vaccination with live, radiation attenuation parasites. Both of these important research approaches, whether defining the current drug regime or the immunological interactions between the host and parasite, can be better understood through the profiling of the transcriptional status of the parasite. This review will present some of the recent microarray based studies examining the Schistosoma parasite under chemotherapy or immunological stress. Finally some suggestions on how microarray analyses may better help to identify new detoxification or immuno-evasion mechanisms of the parasite and what subsequent functional validations will be needed to support transcriptional findings.

The messenger RNA precursors (pre-mRNA) 3'-end processing occurs in a two-step co-transcriptional coupled reaction, denoted as cleavage and polyadenylation. Both processes depend on trans-acting factors interacting in a coordinated manner with cis-sequence motifs located at the 3' untranslated region of transcripts. In this paper, we reviewed mechanisms involved in pre-mRNA processing in eukaryotic organisms, including our own findings about sequences and proteins potentially involved in mRNA 3'-end formation in the protozoan parasite Entamoeba histolytica. Interestingly, protein sequence comparisons among E. histolytica, yeast, and human pre-mRNA processing machineries showed that amoeba pre-mRNA 3'-end processing machinery appears to be in an intermediate evolutionary position between mammals and yeast. In addition, the presence of non canonical poly(A) polymerases family recently identified in E. histolytica, adds more complexity to the mRNA 3'-end formation process in this ancient eukaryote.

African trypanosomes are responsible for sleeping sickness in man and nagana in cattle, which are both tremendous health burdens in Africa. Most African trypanosome species are killed by human serum. This is due to a serum trypanolytic particle specific of some old world monkeys and great apes, an HDL subclass containing two proteins which appeared recently in mammalian evolution, apolipoprotein L1 and haptoglobin related protein. Nevertheless, two African trypanosome species, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense are able to infect humans, because they developed resistance to trypanolysis. Resistance to human serum in Trypanosoma brucei rhodesiense is due to a single gene called SRA. This mechanism of lysis-resistance is therefore an example of a natural drug-antidote system which evolved during a pathogen-host arms race. The lysis and resistance mechanisms, their molecular components as well as their mode of action are reviewed. I also discuss how components of the system would be suitable drug targets and how the system could be engineered to generate an effective synthetic drug.

Giardia duodenalis (syn. G. lamblia, G. intestinalis) is a flagellated protozoan, member of the order Diplomonadidae, that parasitizes the upper part of the small intestine of mammals, including human, pets and livestock. G. duodenalis is the causative agent of giardiasis, the most common non-bacterial and non-viral diarrheal diseases affecting humans worldwide. Recently, giardiasis was included in the 'Neglected Disease Initiative', estimating that 280 million people are infected each year with G. duodenalis. Transmission occurs via the faecal-oral route by ingestion of cysts, the infective stage of the parasite, either by direct person-to-person transmission or indirectly through water and food. There are several effective drugs that have been approved for the treatment of giardiasis. The 5-nitroimidazole and benzimidazole derivatives, quinacrine, furazolidone, paromomycin, nitazoxanide are the most commonly used, however some of these compounds have sometimes relevant side effects. Single- and multi-drug resistance to some of these compounds, including metronidazole (MTZ), has been reported in human patients and can be induced in vitro. The aims of this review are (i) to provide a bird's eye view on the current knowledge of the mechanisms of action, including resistance mechanisms, of the most commonly used anti-giardial compounds, and (ii) to summarize recent findings on novel promising drugs targeting unique proteins and metabolic pathways of G. duodenalis.

Giardiasis is a worldwide parasitic disease caused by the protozoan Giardia lamblia in humans and other animals, especially live stocks. Here, we briefly review the current state of therapeutic availability for giardiasis, including chemical drugs and vaccines, and the dilemma in the prevention and treatment of this disease, including the emergence of drug resistance and the shortage of vaccine (especially for humans). Future efforts and progress in controlling giardiasis are expected in three aspects: clarification of the drug resistance mechanisms, development of efficient vaccines, and identification of more targets for new drugs and vaccines.

Apicomplexans comprise some of the most life threatening parasites infecting human and livestock and includes Plasmodium and Toxoplasma, the causative agents of malaria and toxoplasmosis respectively, in humans as well as Neospora caninum (abortion in livestock, neosporosis in dogs), Cryptosporidium (Diarrheal cryptosporidiosis and opportunistic infections in AIDS patients) and Eimeria (poultry coccidiosis). These parasites are characterized by a complex life cycle usually alternating between sexual and asexual cycles in different hosts. The need to adapt to different host environments, demands a tight regulation of gene expression during parasite development. Therefore, the understanding of parasite biology will facilitate the control of the infection and the disease. In this review we emphasize the progress made so far in gene regulation in two medically important parasites, namely Plasmodium falciparum and Toxoplasma gondii, as well as other less known apicomplexan. The genome of both Plasmodium and Toxoplasma has been sequenced and since then there has been a significant progress in understanding the molecular mechanisms that control stage specific gene expression in the two parasites. In addition, the information gained in each of the parasite can be used in studying mechanisms that are still elusive in the other apicomplexans that are not readily available. Additionally, they can serve as model systems for other disease causing Apicomplexan parasites.