Identification of clinically approved small molecules that inhibit growth and affect transcript levels of developmentally regulated genes in the African trypanosome

by Madison Elle Walsh, Eleanor Mary Naudzius, Savanah Jessica Diaz, Theodore William Wismar, Mikhail Martchenko Shilman, Danae SchulzTrypanosoma brucei are unicellular parasites endemic to Sub-Saharan Africa that cause fatal disease in humans and animals. Infection with these parasites is caused by the bite of the tsetse fly vector, and parasites living extracellularly in the blood of infected animals evade the host immune system through antigenic variation. Existing drugs for Human and Animal African Trypanosomiasis are difficult to administer and can have serious side effects. Resistance to some drugs is also increasing, creating an urgent need for alternative trypanosomiasis therapeutics. We screened a library of 1,585 U.S. or foreign-approved drugs and identified 154 compounds that inhibit trypanosome growth. As all of these compounds have already undergone testing for human toxicity, they represent good candidates for repurposing as trypanosome therapeutics. In addition to identifying drugs that inhibit trypanosome growth, we wished to identify small molecules that can induce bloodstream form parasites to differentiate into forms adapted for the insect vector. These insect stage parasites lack the immune evasion mechanisms prevalent in bloodstream forms, making them vulnerable to the host immune system. To identify drugs that increase transcript levels of an invariant, insect-stage specific surface protein called procyclin, we engineered bloodstream reporter parasites th...
Source: PLoS Neglected Tropical Diseases - Category: Tropical Medicine Authors: Source Type: research

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Optimisation of template preparation and laboratory evaluation of the Loopamp™ Trypanosoma brucei kit for detection of parasite DNA in blood. Exp Parasitol. 2020 Feb 28;:107844 Authors: Matovu E, Katiti D, Kitibwa A, Kazibwe A, Kato CD, Biéler S, Ndung'u JM Abstract The Loopamp™ Trypanosoma brucei Detection Kit is the latest addition of molecular techniques for amplification of parasite DNA in biological materials. We have evaluated the kit on a number of preparations of crude templates from the blood of experimentally infected rodents, to provide the best option that can be extrapo...
Source: Experimental Parasitology - Category: Parasitology Authors: Tags: Exp Parasitol Source Type: research
Immunological Human African Trypanosomiasis (HAT) studies often exclude malaria, although both infections overlap in specific endemic areas. During this co-infection, it is not known whether this parasitic int...
Source: Allergy, Asthma and Clinical Immunology - Category: Allergy & Immunology Authors: Tags: Research Source Type: research
Abstract Neglected Tropical Diseases (NTDs) comprise of a group of seventeen infectious conditions endemic in many developing countries. Among these diseases are three of protozoan origin, namely leishmaniasis, Chagas disease, and African trypanosomiasis, caused by the parasites Leishmania spp., Trypanosoma cruzi, and Trypanosoma brucei respectively. These diseases have their own unique challenges which are associated with the development of effective prevention and treatment methods. Collectively, these parasitic diseases cause more deaths worldwide than all other NTDs combined. Moreover, many current therapies for these ...
Source: Journal of Venomous Animals and Toxins including Tropical Diseases - Category: Tropical Medicine Source Type: research
ConclusionsThis is the first imported rhodesiense HAT case reported in China. This case alerts clinical and public health workers to be aware of HAT in travelers, and expatriates and migrants who have visited at-risk areas in Africa.
Source: Infectious Diseases of Poverty - Category: Infectious Diseases Source Type: research
Conclusions/SignificanceA recent study in the Soroti and Kaberamaido focus in Central Uganda found that theAPOL1 G2 allele was strongly associated with protection against Tbr HAT (odds ratio = 0.2, 95% CI: 0.07 to 0.48, p = 0.0001). However, in our study no effect of G2 on Tbr HAT was found, despite being well powered to find a similar sized effect (OR = 0.9281, 95% CI: 0.482 to 1.788, p = 0.8035). It is possible that the G2 allele is protective from Tbr in the Soroti/Kabermaido focus but not in the Iganga district of Busoga, which differ in ethnicity and infection history. Mechanisms underlying HAT infection outcome and v...
Source: PLoS Neglected Tropical Diseases - Category: Tropical Medicine Authors: Source Type: research
Conclusion and recommendationCoping strategies outlined in this study impacted negatively on the affected households leading to further food insecurity and impoverishment. Calculation of the true burden of disease needs to go beyond incidence, mortality and morbidity rates to capture socio-economic variables entailed in seeking treatment and coping strategies of HAT affected households.
Source: PLoS Neglected Tropical Diseases - Category: Tropical Medicine Authors: Source Type: research
ConclusionOur data show that host genes are involved in modulatingTrypanosoma brucei gambiense infection outcome in infected individuals from Guinea withIL6 rs1818879 being associated with a lower risk of progressing to active HAT. These results enhance our understanding of host-parasite interactions and, ultimately, may lead to the development of new control tools.
Source: PLoS Neglected Tropical Diseases - Category: Tropical Medicine Authors: Source Type: research
Publication date: Available online 30 June 2017 Source:The Lancet Author(s): Philippe Büscher, Giuliano Cecchi, Vincent Jamonneau, Gerardo Priotto Human African trypanosomiasis (sleeping sickness) is a parasitic infection that almost invariably progresses to death unless treated. Human African trypanosomiasis caused devastating epidemics during the 20th century. Thanks to sustained and coordinated efforts over the past 15 years, the number of reported cases has fallen to an historically low level. Fewer than 3000 cases were reported in 2015, and the disease is targeted for elimination by WHO. Despite these recent suc...
Source: The Lancet - Category: General Medicine Source Type: research
Human African trypanosomiasis (sleeping sickness) is a parasitic infection that almost invariably progresses to death unless treated. Human African trypanosomiasis caused devastating epidemics during the 20th century. Thanks to sustained and coordinated efforts over the past 15 years, the number of reported cases has fallen to an historically low level. Fewer than 3000 cases were reported in 2015, and the disease is targeted for elimination by WHO. Despite these recent successes, the disease is still endemic in parts of sub-Saharan Africa, where it is a considerable burden on rural communities, most notably in central Africa.
Source: LANCET - Category: General Medicine Authors: Tags: Seminar Source Type: research
Publication date: Available online 1 June 2017 Source:Pharmacology & Therapeutics Author(s): Leonardo G. Ferreira, Adriano D. Andricopulo Chagas disease and human African trypanosomiasis are endemic conditions in Latin America and Africa, respectively, for which no effective and safe therapy is available. Efforts in drug discovery have focused on several enzymes from these protozoans, among which cysteine proteases have been validated as molecular targets for pharmacological intervention. These enzymes are expressed during the entire life cycle of trypanosomatid parasites and are essential to many biological processes...
Source: Pharmacology and Therapeutics - Category: Drugs & Pharmacology Source Type: research
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