SciCombinator

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Concept: Diethylcarbamazine

172

Infection with Wuchereria bancrofti can cause severe disease characterized by subcutaneous fibrosis and extracellular matrix remodeling. Matrix metalloproteinases (MMPs) are a family of enzymes governing extracellular remodeling by regulating cellular homeostasis, inflammation, and tissue reorganization, while tissue-inhibitors of metalloproteinases (TIMPs) are endogenous regulators of MMPs. Homeostatic as well as inflammation-induced balance between MMPs and TIMPs is considered critical in mediating tissue pathology.

Concepts: Inflammation, Extracellular matrix, Infection, Matrix metalloproteinase, Diethylcarbamazine, Filariasis, Wuchereria bancrofti, Tissue inhibitor of metalloproteinases

170

Wolbachia endosymbionts carried by filarial nematodes give rise to the neglected diseases African river blindness and lymphatic filariasis afflicting millions worldwide. Here we identify new Wolbachia-disrupting compounds by conducting high-throughput cell-based chemical screens using a Wolbachia-infected, fluorescently labeled Drosophila cell line. This screen yielded several Wolbachia-disrupting compounds including three that resembled Albendazole, a widely used anthelmintic drug that targets nematode microtubules. Follow-up studies demonstrate that a common Albendazole metabolite, Albendazole sulfone, reduces intracellular Wolbachia titer both in Drosophila melanogaster and Brugia malayi, the nematode responsible for lymphatic filariasis. Significantly, Albendazole sulfone does not disrupt Drosophila microtubule organization, suggesting that this compound reduces titer through direct targeting of Wolbachia. Accordingly, both DNA staining and FtsZ immunofluorescence demonstrates that Albendazole sulfone treatment induces Wolbachia elongation, a phenotype indicative of binary fission defects. This suggests that the efficacy of Albendazole in treating filarial nematode-based diseases is attributable to dual targeting of nematode microtubules and their Wolbachia endosymbionts.

Concepts: Model organism, Diethylcarbamazine, Filariasis, Neglected diseases, Brugia timori, Hookworm, Elephantiasis, Onchocerciasis

169

The main strategy adopted for Lymphatic Filariasis (LF) elimination globally is annual mass drug administration (MDA) for 4 to 6 rounds. At least 65% of the population at risk should be treated in each round for LF elimination to occur. In Kenya, MDA using diethylcarbamazine citrate (DEC) and albendazole data shows declining compliance (proportion of eligible populations who receive and swallow the drugs) levels (85%-62.8%). The present study’s aim was to determine the role of personal opinions and experiences in compliance with MDA.

Concepts: Diethylcarbamazine, Filariasis

168

Lymphatic filariasis (LF) is a disabling and disfiguring disease resulting from a mosquito-borne parasitic infection. It is a major public health problem in many countries with a warm climate. Research and control activities have mainly focused on LF in rural areas where it also has its major impact. However, with rapid and unplanned growth of cities in the developing world, there is a need also to consider LF transmission and control in urban settings. Here, we review currently available knowledge on urban LF and the environmental and socio-economic basis for its occurrence. Among the three parasite species causing LF in humans, only Wuchereria bancrofti has been documented to have a significant potential for urban transmission. This is primarily because one of its vectors, Culex quinquefasciatus, thrives and proliferates excessively in crowded city areas with poor sanitary, sewerage and drainage facilities. For this reason, urban LF also often shows a marked focality in distribution, with most cases clustered in areas inhabited by the less privileged city populations. More knowledge on urban LF is needed, in particular on its socio-economic and human behavioural context, on the potential for transmission in regions where other LF vector species predominate, and on rapid methods for identification and mapping of risk areas, to provide a strong evidence base for its control.

Concepts: Malaria, Population, Anopheles, City, Vector, Diethylcarbamazine, Filariasis, Wuchereria bancrofti

168

The current antibody tests used for monitoring in lymphatic filariasis (LF) elimination programs suffer from poor specificity because of the considerable geographical overlap with other filarial infections such as Loa loa (Ll), Onchocerca volvulus (Ov), and Mansonella perstans (Mp).

Concepts: Nematodes, Parasitic diseases, Diethylcarbamazine, Filariasis, Wuchereria bancrofti, Insect-borne diseases, Loa loa filariasis, Mansonella

65

Parasite host switches may trigger disease emergence, but prehistoric host ranges are often unknowable. Lymphatic filariasis and loiasis are major human diseases caused by the insect-borne filarial nematodes Brugia, Wuchereria and Loa. Here we show that the genomes of these nematodes and seven tropical bird lineages exclusively share a novel retrotransposon, AviRTE, resulting from horizontal transfer (HT). AviRTE subfamilies exhibit 83-99% nucleotide identity between genomes, and their phylogenetic distribution, paleobiogeography and invasion times suggest that HTs involved filarial nematodes. The HTs between bird and nematode genomes took place in two pantropical waves, >25-22 million years ago (Myr ago) involving the Brugia/Wuchereria lineage and >20-17 Myr ago involving the Loa lineage. Contrary to the expectation from the mammal-dominated host range of filarial nematodes, we hypothesize that these major human pathogens may have independently evolved from bird endoparasites that formerly infected the global breadth of avian biodiversity.

Concepts: Disease, Bacteria, Evolution, Malaria, Diethylcarbamazine, Filariasis, Brugia timori, Wuchereria bancrofti

28

Lymphatic filariasis (LF) is a leading cause of morbidity in the tropical world. It is caused by the filarial parasites Wuchereria bancrofti, Brugia malayi and Brugia timori and transmitted by vector mosquitoes. Currently a programme for the elimination of LF, Global Lympahtic Filariasis Elimination Programme (GPELF), is underway with the strategy of mass administration of single dose of diethylcarbamazine or ivermectin, in combination with an antihelminthic drug, albendazole. However, antifilarial drugs used in the progarmme are only microfilaricidal but not or only partially macrofilaricidal. Hence, there is a need to identify new targets for developing antifilarial drugs. Filarial parasites harbour rickettsial endosymbionts, Wolbachia sp., which play an important role in their biology and hence are considered as potential targets for antifilarial chemotherapy development. In this study, one of the cell division proteins of Wolbachia of the major lymphatic filarial parasite, Wuchereria bancrofti, viz., filamentation temperature-sensitive protein Z (FtsZ), was explored as a drug target. The gene coding for FtsZ protein was amplified from the genomic DNA of W. bancrofti, cloned and sequenced. The derived amino acid sequence of the gene revealed that FtsZ protein is 396 amino acids long and contained the tubulin motif (GGGTGTG) involved in GTP binding and the GTP hydrolyzing motif (NLDFAD). The FtsZ gene of endosymbiont showed limited sequence homology, but exhibited functional homology with β-tubulin of its host, W. bancrofti, as it had both the functional motifs and conserved amino acids that are critical for enzymatic activity. β-tubulin is the target for the anti-helminthic activity of albendazole and since FtsZ shares the functional homology with it may also be sensitive to albendazole. Therefore, the effect of albendazole was tested against Wolbachia occurring in mosquitoes instead of filarial parasites as the drug has lethal effect on the latter. Third instar larvae of Culex quinquefasciatus were treated with 0.25mg/ml of albendazole (test) or tetracycline (positive control) in the rearing medium for different intervals and tested for the presence of Wolbachia by FtsZ PCR. All the treated larvae were negative for the presence of the FtsZ band, whereas all the control larvae were positive. The findings of the study thus indicated that FtsZ is sensitive to albendazole. In view of this albendazole appears to have dual targets; FtsZ in Wolbachia and β- tubulin in W. bancrofti. Further, the functional domain of the gene was assessed for polymorphism among recombinant clones representing 120W. bancrofti parasites, prevalent across wide geographic areas of India and found to be highly conserved among them. Since it is highly conserved and plays an important role in Wolbachia cell division it appears to be a potential target for anti-filarial chemotherapy development.

Concepts: DNA, Protein, Amino acid, Diethylcarbamazine, Filariasis, Brugia timori, Brugia malayi, Wuchereria bancrofti

28

The therapeutic effects of a controlled parasitic nematode infection on the course of inflammatory bowel disease (IBD) have been demonstrated in both animal and human models. However the inability of individual well characterized nematode proteins to recreate these beneficial effects has limited the application of component immunotherapy to human disease. The nematodes that cause chronic human lymphatic filariasis, Brugia malayi and Wuchereria bancrofti, are among the parasites that induce immune suppression. Filarial lymphatic pathology has been shown to involve NFk B pathway dependent production of vascular endothelial growth factor (VEGF), and stimulation of VEGF expression has also been reported by interleukin 8 (IL8) via NFkB pathways. Previously we have shown that the filarial asparaginyl-tRNA synthetase (rBmAsnRS) interacts with IL8 receptors using a combination of extracellular loops that differ from those bound by IL8. To test the hypothesis that rBmAsnRS might induce an anti-inflammatory effect in vivo, we studied the effects of rBmAsnRS in an established murine colitis model using T-cell transfer mice. T cell transfer colitis mice treated intraperitoneally with 100 μg of rBmAsnRS four times over two weeks, showed resolution of cellular infiltration in the colonic mucosa, along with induction of a CD8(+) cellular response. In addition, rBmAsnrs induced a rise in IL10 production from CD3+, LPS- and CPG-stimulated splenic cells. In summary, this work demonstrates a novel anti-inflammatory nematode protein, supports the Hygiene Hypothesis and supports continued refinement of alternative immunotherapies for treatment of IBD.

Concepts: Immune system, Inflammation, Ulcerative colitis, Inflammatory bowel disease, Nematodes, Diethylcarbamazine, Filariasis, Brugia timori

28

Lymphatic filariasis is caused by three closely related nematode parasites: Wuchereria bancrofti, Brugia malayi and Brugia timori. These species have many ecological variants that differ in several aspects of their biology such as mosquito vector species, host range, periodicity, and morphology. Although the genome of B. malayi (the first genome sequenced from a parasitic nematode) has been available for more than five years, very little is known about genetic variability among the lymphatic dwelling filariae. The genetic diversity among these worms is not only interesting from a biological perspective, but it may have important practical implications for the Global Program to Eliminate Lymphatic Filariasis, as the parasites may respond differently to diagnostic tests and/or medical interventions. Therefore, better information on their genetic variability is urgently needed. With improved methods for nucleic acid extraction and recent advances in sequencing chemistry and instrumentation, this gap can be filled relatively inexpensively. Improved information on filarial genetic diversity may increase the chances of success for lymphatic filariasis elimination programs.

Concepts: Malaria, Nematodes, Vector, Diethylcarbamazine, Filariasis, Brugia timori, Brugia malayi, Wuchereria bancrofti

28

Anthelmintic mass drug administration (MDA) has limited pathology and transmission of filariases, schistosomiasis and gastrointestinal nematodiases in many areas of the world. This record has led to the adoption of ambitious goals for eliminating these infections on a global scale within the next decade or two by expansion of MDA with available drugs. This review considers the attributes of anthelmintics that favor or limit attainment of the scaled-up plans for elimination, and highlights situations for which new or reformulated drugs may be needed.

Concepts: Drug, Praziquantel, World, Limited, Diethylcarbamazine