SciCombinator

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Concept: Trypanosoma

170

Novel drugs to treat human African trypanosomiasis (HAT) are still urgently needed despite the recent addition of nifurtimox-eflornithine combination therapy (NECT) to WHO Model Lists of Essential Medicines against second stage HAT, where parasites have invaded the central nervous system (CNS). The pharmacology of a potential orally available lead compound, N-methoxy-6-{5-[4-(N-methoxyamidino) phenyl]-furan-2-yl}-nicotinamidine (DB844), was evaluated in a vervet monkey model of second stage HAT, following promising results in mice. DB844 was administered orally to vervet monkeys, beginning 28 days post infection (DPI) with Trypanosoma brucei rhodesiense KETRI 2537. DB844 was absorbed and converted to the active metabolite 6-[5-(4-phenylamidinophenyl)-furanyl-2-yl]-nicotinamide (DB820), exhibiting plasma C(max) values of 430 and 190 nM for DB844 and DB820, respectively, after the 14th dose at 6 mg/kg qd. A 100-fold reduction in blood trypanosome counts was observed within 24 h of the third dose and, at the end of treatment evaluation performed four days post the last drug dose, trypanosomes were not detected in the blood or cerebrospinal fluid of any monkey. However, some animals relapsed during the 300 days of post treatment monitoring, resulting in a cure rate of 3/8 (37.5%) and 3/7 (42.9%) for the 5 mg/kg×10 days and the 6 mg/kg×14 days dose regimens respectively. These DB844 efficacy data were an improvement compared with pentamidine and pafuramidine both of which were previously shown to be non-curative in this model of CNS stage HAT. These data show that synthesis of novel diamidines with improved activity against CNS-stage HAT was possible.

Concepts: Central nervous system, Nervous system, Pharmacology, Trypanosoma brucei, African trypanosomiasis, Trypanosoma, Euglenozoa, Trypanosome

169

BACKGROUND: Specific land cover types and activities have been correlated with Trypanosoma brucei rhodesiense distributions, indicating the importance of landscape for epidemiological risk. However, methods proposed to identify specific areas with elevated epidemiological risk (i.e. where transmission is more likely to occur) tend to be costly and time consuming. This paper proposes an exploratory spatial analysis using geo-referenced human African trypanosomiasis (HAT) cases and matched controls from Serere hospital, Uganda (December 1998 to November 2002) to identify areas with an elevated epidemiological risk of HAT. METHODS: Buffers 3 km from each case and control were used to represent areas in which village inhabitants would carry out their daily activities. It was hypothesised that the selection of areas where several case village buffers overlapped would enable the identification of locations with increased risk of HAT transmission, as these areas were more likely to be frequented by HAT cases in several surrounding villages. The landscape within these overlap areas should more closely relate to the environment in which transmission occurs as opposed to using the full buffer areas. The analysis was carried out for each of four annual periods, for both cases and controls, using a series of threshold values (number of overlapping buffers), including a threshold of one, which represented the benchmark (e.g. use of the full buffer area as opposed to the overlap areas). RESULTS: A greater proportion of the overlap areas for cases consisted of seasonally flooding grassland and lake fringe swamp, than the control overlap areas, correlating well with the preferred habitat of the predominant tsetse species within the study area (Glossina fuscipes fuscipes). The use of overlap areas also resulted in a greater difference between case and control landscapes, when compared with the benchmark (using the full buffer area). CONCLUSIONS: These results indicate that the overlap analysis has enabled the selection of areas more likely to represent epidemiological risk zones than similar analyses using full buffer areas. The identification of potential epidemiological risk zones using this method requires fewer data than other proposed methods and further development may provide vital information for the targeting of control measures.

Concepts: Trypanosoma brucei, African trypanosomiasis, Trypanosoma, Euglenozoa, Buffer, Tsetse fly, Sleeping sickness, Sterile insect technique

169

Anthropogenic land use may influence transmission of multi-host vector-borne pathogens by changing diversity, relative abundance, and community composition of reservoir hosts. These reservoir hosts may have varying competence for vector-borne pathogens depending on species-specific characteristics, such as life history strategy. The objective of this study is to evaluate how anthropogenic land use change influences blood meal species composition and the effects of changing blood meal species composition on the parasite infection rate of the Chagas disease vector Rhodnius pallescens in Panama.

Concepts: Immune system, Infectious disease, Malaria, Chagas disease, Trypanosoma, Trypanosoma cruzi, Triatominae, Natural reservoir

167

We studied a small rural community of 411 inhabitants localized in the state of Campeche in the Yucatan Peninsula, Mexico. In 44 collected triatomines captured inside the houses, human feeding source was revealed in 23 of 44 (52%) samples, and chicken feeding source was revealed in 16 of 44 (36%) samples. In a set of 29 triatomines, mouse was the feeding source in 13 (44%) samples, and dog was the feeding source in 7 (24%) samples. Infection index with Trypanosoma cruzi in collected triatomines was 38%, and all parasites belonged to discrete type unit I. Inhabitants referred high contact with triatomine’s bite in 60 of 128 (47%) samples, but seroprevalence was 2.3% (3/128). Evidence of electrocardiographic alteration compatible with Chagas disease was observed only in one asymptomatic seropositive subject. In conclusion, Triatoma dimidiata in this region are preferentially infected with T. cruzi I and feed on human beings with relative high frequency, but seroprevalence and Chagas disease in humans is relatively low.

Concepts: Infectious disease, Chagas disease, Trypanosoma, Trypanosoma cruzi, Carlos Chagas, Reduviidae, Triatominae, Triatoma

146

Trypanosoma cruzi is dispersed in nature through many transmission mechanisms among a high diversity of vectors and mammalian species, representing particular behaviors and habitats. Thus, each locality has a unique set of conditions underlying the maintenance of this parasite in the wild. The aim of the present study was to evaluate the life-cycle of T. cruzi in free-ranging coatis from the central region of the Brazilian Pantanal using a multi-factorial approach.

Concepts: Chagas disease, Trypanosoma, Trypanosoma cruzi, Coati, Procyonidae, Procyonids, South American Coati, Nasua

43

The role of mammalian skin in harbouring and transmitting arthropod-borne protozoan parasites has been overlooked for decades as these pathogens have been regarded primarily as blood-dwelling organisms. Intriguingly, infections with low or undetected blood parasites are common, particularly in the case of Human African Trypanosomiasis caused by Trypanosoma brucei gambiense. We hypothesise, therefore, the skin represents an anatomic reservoir of infection. Here we definitively show that substantial quantities of trypanosomes exist within the skin following experimental infection, which can be transmitted to the tsetse vector, even in the absence of detectable parasitaemia. Importantly, we demonstrate the presence of extravascular parasites in human skin biopsies from undiagnosed individuals. The identification of this novel reservoir requires a re-evaluation of current diagnostic methods and control policies. More broadly, our results indicate that transmission is a key evolutionary force driving parasite extravasation that could further result in tissue invasion-dependent pathology.

Concepts: Immune system, Bacteria, Skin, Trypanosoma brucei, African trypanosomiasis, Trypanosoma, Euglenozoa, Tsetse fly

34

Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually1. The diseases are caused by infection with the kinetoplastid parasites Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp., respectively. These parasites have similar biology and genomic sequence, suggesting that all three diseases could be cured with drug(s) modulating the activity of a conserved parasite target2. However, no such molecular targets or broad spectrum drugs have been identified to date. Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection. GNF6702 inhibits the kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice. Our data provide genetic and chemical validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases.

Concepts: Immune system, Disease, Infectious disease, Bacteria, Chagas disease, Inhibitor, Trypanosoma, Trypanosoma cruzi

30

Chagas disease is a deadly infection caused by the protozoan parasite Trypanosoma cruzi. Afflicting ∼8 million people in Latin America, it is now becoming a serious global health problem proliferating beyond the traditional geographical borders, mainly due to human/vector migration. Because the disease is endemic in low resource areas, industrial drug development has been lethargic. The chronic form remains incurable, there are no vaccines, and two existing drugs for the acute form are toxic and have low efficacy. Here we report the efficacy of a small molecule VNI, including evidence of its effectiveness against chronic Chagas. VNI is a potent experimental inhibitor of T. cruzi sterol 14α-demethylase. Non-toxic and highly selective, it displays promising pharmacokinetics and cures, with 100% survival, the acute and chronic T. cruzi infection in mice when administered orally at 25 mg/kg for 30 days.

Concepts: Pharmacology, Medicine, Disease, Infectious disease, Chagas disease, Trypanosoma, Trypanosoma cruzi, Carlos Chagas

28

The highly motile and versatile protozoan pathogen Trypanosoma brucei undergoes a complex life cycle in the tsetse fly. Here we introduce the host insect as an expedient model environment for microswimmer research, as it allows examination of microbial motion within a diversified, secluded and yet microscopically tractable space. During their week-long journey through the different microenvironments of the fly´s interior organs, the incessantly swimming trypanosomes cross various barriers and confined surroundings, with concurrently occurring major changes of parasite cell architecture. Multicolour light sheet fluorescence microscopy provided information about tsetse tissue topology with unprecedented resolution and allowed the first 3D analysis of the infection process. High-speed fluorescence microscopy illuminated the versatile behaviour of trypanosome developmental stages, ranging from solitary motion and near-wall swimming to collective motility in synchronised swarms and in confinement. We correlate the microenvironments and trypanosome morphologies to high-speed motility data, which paves the way for cross-disciplinary microswimmer research in a naturally evolved environment.

Concepts: Immune system, Bacteria, Biology, Trypanosoma brucei, African trypanosomiasis, Trypanosoma, Microscopy, Trypanosomiasis

28

For comparative evaluation, a real time PCR assay was standardized by using TaqMan primer and probe targeting the internal transcribed spacer 1 (ITS-1) region of rRNA for Trypanosoma evansi and sensitivity was evaluated by using DNA, extracted from diethyleamino ethane cellulose purified trypanosomes and trypanosomes infected whole blood of mice. The minimum detection limit for purified trypanosomal DNA was 0.01ng (∼0.33 genomic DNA of T. evansi) whereas for whole blood the minimum detection limit was 0.1ng (∼6.12 genomic DNA). T. evansi infected mice blood samples were collected at different interval post infection and were analysed by conventional parasitological methods (CPT) viz. wet blood smear, thin blood smear, thick blood smear, quantitative buffy coat and real time PCR and found that TaqMan assay was two fold sensitive than CPT in case of in vivo infectivity in mice and gave positive signal at 36h post infection where as QBC and blood smear examination was able to detect at 60h and 72h post infection respectively. A total 109 (80 cattle and 29 buffaloes) blood samples were collected from in and around Ludhiana district and analysed by CPT and real time PCR. The overall prevalence of T. evansi by CPT in cattle and buffaloes was 2.75 per cent. The prevalence rate was 2.5 per cent in cattle and 3.45 per cent in buffaloes. By real time PCR overall prevalence was 12.84 per cent in cattle and buffaloes, with a prevalence rate of 12.50 per cent in cattle and 13.79 per cent in buffaloes.

Concepts: DNA, Time, Polymerase chain reaction, Blood, Trypanosoma, Euglenozoa, Trypanosoma evansi, Buffy coat