Pharma to farmer: field challenges of optimizing trypanocide use in African animal trypanosomiasis

Richards, Shauna; Morrison, Liam J.; Torr, Stephen J.; Barrett, Michael P.; Manangwa, Oliver; Mramba, Furaha; Auty, Harriet

doi:10.1016/j.pt.2021.04.007

Cited by 27 publications

(28 citation statements)

References 64 publications

(151 reference statements)

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“…Veterinary services are expensive and often not accessible to or are not accessed by many livestock owners in rural or remote regions of sub-Saharan Africa. This means that diagnosis is often subjective and based on clinical signs that are not pathognomonic, resulting in farmers often misdiagnosing AT and/or administering unnecessary drug doses for treatment ( 19 ). It would be extremely desirable to develop a rapid and cost-effective diagnostic test that can be used in a field setting before deciding on a trypanocidal treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Since field-applicable diagnostic methods have relatively poor accuracy and veterinary support is not always available, disease control largely focuses on chemotherapy or chemoprophylaxis following presumptive diagnosis ( 18 , 19 ). However, there are only four available trypanocidal drugs [diminazene aceturate, homidium salts and isometamidium chloride are the most widely used for cattle, sheep and goat infections, and quinapyramine salts for T. b. evansi infections, particularly in equids ( 3 )], to which resistance is becoming increasingly common due to inappropriate use; this is compounded by the fact that no new trypanocidal actives have been approved in the last 60 years ( 3 , 19 ). Vector control is also deployed as a control measure, but this is difficult to achieve successfully due to the range and mobility of the tsetse fly; indeed, sustainable removal has been achieved in less than 2% of the infested territory ( 20 ).…”

Section: Introductionmentioning

confidence: 99%

“…Vector control is also deployed as a control measure, but this is difficult to achieve successfully due to the range and mobility of the tsetse fly; indeed, sustainable removal has been achieved in less than 2% of the infested territory ( 20 ). Better diagnostics are essential to ensure the efficacy of the few available trypanocides is preserved through effective and sustainable use ( 19 ). In addition, better estimates of disease prevalence through more accurate diagnosis would represent a first step toward establishing appropriate and sustainable control activities ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

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Comparative Sensitivity and Specificity of the 7SL sRNA Diagnostic Test for Animal Trypanosomiasis

et al. 2022

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Animal trypanosomiasis (AT) is a significant livestock disease, affecting millions of animals across Sub-Saharan Africa, Central and South America, and Asia, and is caused by the protozoan parasites Trypanosoma brucei, Trypanosoma vivax, and Trypanosoma congolense, with the largest economic impact in cattle. There is over-reliance on presumptive chemotherapy due to inadequate existing diagnostic tests, highlighting the need for improved AT diagnostics. A small RNA species, the 7SL sRNA, is excreted/secreted by trypanosomes in infected animals, and has been previously shown to reliably diagnose active infection. We sought to explore key properties of 7SL sRNA RT-qPCR assays; namely, assessing the potential for cross-reaction with the widespread and benign Trypanosoma theileri, directly comparing assay performance against currently available diagnostic methods, quantitatively assessing specificity and sensitivity, and assessing the rate of decay of 7SL sRNA post-treatment. Results showed that the 7SL sRNA RT-qPCR assays specific for T. brucei, T. vivax, and T. congolense performed better than microscopy and DNA PCR in detecting infection. The 7SL sRNA signal was undetectable or significantly reduced by 96-h post treatment; at 1 × curative dose there was no detectable signal in 5/5 cattle infected with T. congolense, and in 3/5 cattle infected with T. vivax, with the signal being reduced 14,630-fold in the remaining two T. vivax cattle. Additionally, the assays did not cross-react with T. theileri. Finally, by using a large panel of validated infected and uninfected samples, the species-specific assays are shown to be highly sensitive and specific by receiver operating characteristic (ROC) analysis, with 100% sensitivity (95% CI, 96.44–100%) and 100% specificity (95% CI, 96.53–100%), 96.73% (95% CI, 95.54–99.96%) and 99.19% specificity (95% CI, 92.58–99.60%), and 93.42% (95% CI, 85.51–97.16% %) and 82.43% specificity (95% CI, 72.23–89.44% %) for the T brucei, T. congolense and T. vivax assays, respectively, under the conditions used. These findings indicate that the 7SL sRNA has many attributes that would be required for a potential diagnostic marker of AT: no cross-reaction with T. theileri, high specificity and sensitivity, early infection detection, continued signal even in the absence of detectable parasitaemia in blood, and clear discrimination between infected and treated animals.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparative Sensitivity and Specificity of the 7SL sRNA Diagnostic Test for Animal Trypanosomiasis

et al. 2022

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“…AAT is one of the most important livestock diseases across sub-Saharan Africa and accounts for livestock deaths in excess of 3 million annually, with up to 120 million cattle at risk [2][3][4]. Current methods of disease control centre around chemotherapy and prophylaxis (reviewed in [3]), but the very few available veterinary trypanocidal drugs have been used extensively for decades, resulting in resistance and inadequate protection [5][6][7][8]. In contrast to T. brucei [9], the resistance mechanisms of T. congolense are still poorly understood [10].…”

Section: Introductionmentioning

confidence: 99%

Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition

et al. 2021

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Animal African Trypanosomiasis (AAT) is a debilitating livestock disease prevalent across sub-Saharan Africa, a main cause of which is the protozoan parasite Trypanosoma congolense. In comparison to the well-studied T. brucei, there is a major paucity of knowledge regarding the biology of T. congolense. Here, we use a combination of omics technologies and novel genetic tools to characterise core metabolism in T. congolense mammalian-infective bloodstream-form parasites, and test whether metabolic differences compared to T. brucei impact upon sensitivity to metabolic inhibition. Like the bloodstream stage of T. brucei, glycolysis plays a major part in T. congolense energy metabolism. However, the rate of glucose uptake is significantly lower in bloodstream stage T. congolense, with cells remaining viable when cultured in concentrations as low as 2 mM. Instead of pyruvate, the primary glycolytic endpoints are succinate, malate and acetate. Transcriptomics analysis showed higher levels of transcripts associated with the mitochondrial pyruvate dehydrogenase complex, acetate generation, and the glycosomal succinate shunt in T. congolense, compared to T. brucei. Stable-isotope labelling of glucose enabled the comparison of carbon usage between T. brucei and T. congolense, highlighting differences in nucleotide and saturated fatty acid metabolism. To validate the metabolic similarities and differences, both species were treated with metabolic inhibitors, confirming that electron transport chain activity is not essential in T. congolense. However, the parasite exhibits increased sensitivity to inhibition of mitochondrial pyruvate import, compared to T. brucei. Strikingly, T. congolense exhibited significant resistance to inhibitors of fatty acid synthesis, including a 780-fold higher EC50 for the lipase and fatty acid synthase inhibitor Orlistat, compared to T. brucei. These data highlight that bloodstream form T. congolense diverges from T. brucei in key areas of metabolism, with several features that are intermediate between bloodstream- and insect-stage T. brucei. These results have implications for drug development, mechanisms of drug resistance and host-pathogen interactions.

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“…The human infections are fatal without treatment and affect across 36 countries in sub-Sahara African area, and majority of the reported cases (>95%) were caused by the sub-species T. brucei gambiense ( Kennedy, 2019 ; WHO). In addition, nagana has been a burden for economic development by affecting domestic animals ( Richards et al, 2021 ). More than 20 million people are currently infected with T. cruzi or Leishmania , leading to over 30 thousand deaths each year.…”

Section: Introductionmentioning

confidence: 99%

Novel Trypanocidal Inhibitors that Block Glycosome Biogenesis by Targeting PEX3–PEX19 Interaction

Li¹,

Gaussmann²,

Tippler³

et al. 2021

Front. Cell Dev. Biol.

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Human pathogenic trypanosomatid parasites harbor a unique form of peroxisomes termed glycosomes that are essential for parasite viability. We and others previously identified and characterized the essential Trypanosoma brucei ortholog TbPEX3, which is the membrane-docking factor for the cytosolic receptor PEX19 bound to the glycosomal membrane proteins. Knockdown of TbPEX3 expression leads to mislocalization of glycosomal membrane and matrix proteins, and subsequent cell death. As an early step in glycosome biogenesis, the PEX3–PEX19 interaction is an attractive drug target. We established a high-throughput assay for TbPEX3–TbPEX19 interaction and screened a compound library for small-molecule inhibitors. Hits from the screen were further validated using an in vitro ELISA assay. We identified three compounds, which exhibit significant trypanocidal activity but show no apparent toxicity to human cells. Furthermore, we show that these compounds lead to mislocalization of glycosomal proteins, which is toxic to the trypanosomes. Moreover, NMR-based experiments indicate that the inhibitors bind to PEX3. The inhibitors interfering with glycosomal biogenesis by targeting the TbPEX3–TbPEX19 interaction serve as starting points for further optimization and anti-trypanosomal drug development.

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Pharma to farmer: field challenges of optimizing trypanocide use in African animal trypanosomiasis

Cited by 27 publications

References 64 publications

Comparative Sensitivity and Specificity of the 7SL sRNA Diagnostic Test for Animal Trypanosomiasis

Comparative Sensitivity and Specificity of the 7SL sRNA Diagnostic Test for Animal Trypanosomiasis

Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition

Novel Trypanocidal Inhibitors that Block Glycosome Biogenesis by Targeting PEX3–PEX19 Interaction

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