The Hidden Hand of Asymptomatic Infection Hinders Control of Neglected Tropical Diseases: A Modeling Analysis.

BACKGROUND: Neglected tropical diseases are responsible for considerable morbidity and mortality in low-income populations. International efforts have reduced their global burden, but transmission is persistent and case-finding-based interventions rarely target asymptomatic individuals. METHODS: We develop a generic mathematical modeling framework for analyzing the dynamics of visceral leishmaniasis in the Indian sub-continent (VL), gambiense sleeping sickness (gHAT), and Chagas disease and use it to assess the possible contribution of asymptomatics who later develop disease (pre-symptomatics) and those who do not (non-symptomatics) to the maintenance of infection. Plausible interventions, including active screening, vector control, and reduced time to detection, are simulated for the three diseases. RESULTS: We found that the high asymptomatic contribution to transmission for Chagas and gHAT and the apparently high basic reproductive number of VL may undermine long-term control. However, the ability to treat some asymptomatics for Chagas and gHAT should make them more controllable, albeit over relatively long time periods due to the slow dynamics of these diseases. For VL, the toxicity of available therapeutics means the asymptomatic population cannot currently be treated, but combining treatment of symptomatics and vector control could yield a quick reduction in transmission. CONCLUSIONS: Despite the uncertainty in natural history, it appears there is already a relatively good toolbox of interventions to eliminate gHAT, and it is likely that Chagas will need improvements to diagnostics and their use to better target pre-symptomatics. The situation for VL is less clear, and model predictions could be improved by additional empirical data. However, interventions may have to improve to successfully eliminate this disease.

The elimination of human African trypanosomiasis: Monitoring progress towards the 2021-2030 WHO road map targets.

BACKGROUND: Human African trypanosomiasis (HAT) is a neglected tropical disease that usually occurs in rural areas in sub-Saharan Africa. It caused devastating epidemics during the 20th century. Sustained, coordinated efforts by different stakeholders working with national sleeping sickness control programmes (NSSCPs) succeeded in controlling the disease and reducing the number of cases to historically low levels. In 2012, WHO targeted the elimination of the disease as a public health problem by 2020. This goal has been reached and a new ambitious target was stated in the WHO road map for NTDs 2021-2030 and endorsed by the 73rd World Health Assembly: the elimination of gambiense HAT transmission (i.e. reducing the number of reported cases to zero). The interruption of transmission was not considered as an achievable goal for rhodesiense HAT, as it would require vast veterinary interventions rather than actions at the public health level. METHODOLOGY/PRINCIPAL FINDINGS: Data reported to WHO by NSSCPs were harmonized, verified, georeferenced and included in the atlas of HAT. A total of 802 cases were reported in 2021 and 837 in 2022. This is below the target for elimination as a public health problem at the global level (< 2000 HAT cases/year); 94% of the cases were caused by infection with T. b. gambiense. The areas reporting ≥ 1 HAT case/10 000 inhabitants/year in 2018-2022 cover a surface of 73 134 km2, with only 3013 km2 at very high or high risk. This represents a reduction of 90% from the baseline figure for 2000-2004, the target set for the elimination of HAT as a public health problem. For the surveillance of the disease, 4.5 million people were screened for gambiense HAT with serological tests in 2021-2022, 3.6 million through active screening and 0.9 million by passive screening. In 2021 and 2022 the elimination of HAT as a public health problem was validated in Benin, Uganda, Equatorial Guinea and Ghana for gambiense HAT and in Rwanda for rhodesiense HAT. To reach the next goal of elimination of transmission of gambiense HAT, countries have to report zero cases of human infection with T. b. gambiense for a period of at least 5 consecutive years. The criteria and procedures to verify elimination of transmission have been recently published by WHO. CONCLUSIONS/SIGNIFICANCE: HAT elimination as a public health problem has been reached at global level, with seven countries already validated as having reached this goal. This achievement was made possible by the work of NSSCPs, supported by different public and private partners, and coordinated by WHO. The new challenging goal now is to reach zero cases by 2030. To reach this goal is crucial to maintain the engagement and support of donors and stakeholders and to keep the involvement and coordination of all partners. Along with the focus on elimination of transmission of gambiense HAT, it is important not to neglect rhodesiense HAT, which is targeted for elimination as a public health problem in the WHO road map for NTDs 2021-2030.

The cost of tsetse control using 'Tiny Targets' in the sleeping sickness endemic forest area of Bonon in Côte d'Ivoire: Implications for comparing costs across different settings.

BACKGROUND: Work to control the gambiense form of human African trypanosomiasis (gHAT), or sleeping sickness, is now directed towards ending transmission of the parasite by 2030. In order to supplement gHAT case-finding and treatment, since 2011 tsetse control has been implemented using Tiny Targets in a number of gHAT foci. As this intervention is extended to new foci, it is vital to understand the costs involved. Costs have already been analysed for the foci of Arua in Uganda and Mandoul in Chad. This paper examines the costs of controlling Glossina palpalis palpalis in the focus of Bonon in Côte d'Ivoire from 2016 to 2017. METHODOLOGY/PRINCIPAL FINDINGS: Some 2000 targets were placed throughout the main gHAT transmission area of 130 km2 at a density of 14.9 per km2. The average annual cost was USD 0.5 per person protected, USD 31.6 per target deployed of which 12% was the cost of the target itself, or USD 471.2 per km2 protected. Broken down by activity, 54% was for deployment and maintenance of targets, 34% for tsetse surveys/monitoring and 12% for sensitising populations. CONCLUSIONS/SIGNIFICANCE: The cost of tsetse control per km2 of the gHAT focus protected in Bonon was more expensive than in Chad or Uganda, while the cost per km2 treated, that is the area where the targets were actually deployed, was cheaper. Per person protected, the Bonon cost fell between the two, with Uganda cheaper and Chad more expensive. In Bonon, targets were deployed throughout the protected area, because G. p. palpalis was present everywhere, whereas in Chad and Uganda G. fuscipes fuscipes was found only the riverine fringing vegetation. Thus, differences between gHAT foci, in terms of tsetse ecology and human geography, impact on the cost-effectiveness of tsetse control. It also demonstrates the need to take into account both the area treated and protected alongside other impact indicators, such as the cost per person protected.

Occurrence, diversity and distribution of Trypanosoma infections in cattle around the Akagera National Park, Rwanda.

BACKGROUND: African Trypanosomiases threaten the life of both humans and animals. Trypanosomes are transmitted by tsetse and other biting flies. In Rwanda, the African Animal Trypanosomiasis (AAT) endemic area is mainly around the tsetse-infested Akagera National Park (NP). The study aimed to identify Trypanosoma species circulating in cattle, their genetic diversity and distribution around the Akagera NP. METHODOLOGY: A cross-sectional study was carried out in four districts, where 1,037 cattle blood samples were collected. The presence of trypanosomes was determined by microscopy, immunological rapid test VerY Diag and PCR coupled with High-Resolution Melt (HRM) analysis. A parametric test (ANOVA) was used to compare the mean Packed cell Volume (PCV) and trypanosomes occurrence. The Cohen Kappa test was used to compare the level of agreement between the diagnostic methods. FINDINGS: The overall prevalence of trypanosome infections was 5.6%, 7.1% and 18.7% by thin smear, Buffy coat technique and PCR/HRM respectively. Microscopy showed a low sensitivity while a low specificity was shown by the rapid test (VerY Diag). Trypanosoma (T.) congolense was found at a prevalence of 10.7%, T. vivax 5.2%, T. brucei brucei 2% and T. evansi 0.7% by PCR/HRM. This is the first report of T.evansi in cattle in Rwanda. The non-pathogenic T. theileri was also detected. Lower trypanosome infections were observed in Ankole x Friesian breeds than indigenous Ankole. No human-infective T. brucei rhodesiense was detected. There was no significant difference between the mean PCV of infected and non-infected animals (p>0.162). CONCLUSIONS: Our study sheds light on the species of animal infective trypanosomes around the Akagera NP, including both pathogenic and non-pathogenic trypanosomes. The PCV estimation is not always an indication of trypanosome infection and the mechanical transmission should not be overlooked. The study confirms that the area around the Akagera NP is affected by AAT, and should, therefore, be targeted by the control activities. AAT impact assessment on cattle production and information on the use of trypanocides are needed to help policymakers prioritise target areas and optimize intervention strategies. Ultimately, these studies will allow Rwanda to advance in the Progressive Control Pathway (PCP) to reduce or eliminate the burden of AAT.

Apparent density, trypanosome infection rates and host preference of tsetse flies in the sleeping sickness endemic focus of northwestern Uganda.

BACKGROUND: African trypanosomiasis, caused by protozoa of the genus Trypanosoma and transmitted by the tsetse fly, is a serious parasitic disease of humans and animals. Reliable data on the vector distribution, feeding preference and the trypanosome species they carry is pertinent to planning sustainable control strategies. METHODOLOGY: We deployed 109 biconical traps in 10 villages in two districts of northwestern Uganda to obtain information on the apparent density, trypanosome infection status and blood meal sources of tsetse flies. A subset (272) of the collected samples was analyzed for detection of trypanosomes species and sub-species using a nested PCR protocol based on primers amplifying the Internal Transcribed Spacer (ITS) region of ribosomal DNA. 34 blood-engorged adult tsetse midguts were analyzed for blood meal sources by sequencing of the mitochondrial cytochrome c oxidase 1 (COI) and cytochrome b (cytb) genes. RESULTS: We captured a total of 622 Glossina fuscipes fuscipes tsetse flies (269 males and 353 females) in the two districts with apparent density (AD) ranging from 0.6 to 3.7 flies/trap/day (FTD). 10.7% (29/272) of the flies were infected with one or more trypanosome species. Infection rate was not significantly associated with district of origin (Generalized linear model (GLM), χ2 = 0.018, P = 0.895, df = 1, n = 272) and sex of the fly (χ2 = 1.723, P = 0.189, df = 1, n = 272). However, trypanosome infection was highly significantly associated with the fly's age based on wing fray category (χ2 = 22.374, P < 0.001, df = 1, n = 272), being higher among the very old than the young tsetse. Nested PCR revealed several species of trypanosomes: T. vivax (6.62%), T. congolense (2.57%), T. brucei and T. simiae each at 0.73%. Blood meal analyses revealed five principal vertebrate hosts, namely, cattle (Bos taurus), humans (Homo sapiens), Nile monitor lizard (Varanus niloticus), African mud turtle (Pelusios chapini) and the African Savanna elephant (Loxodonta africana). CONCLUSION: We found an infection rate of 10.8% in the tsetse sampled, with all infections attributed to trypanosome species that are causative agents for AAT. However, more verification of this finding using large-scale passive and active screening of human and tsetse samples should be done. Cattle and humans appear to be the most important tsetse hosts in the region and should be considered in the design of control interventions.

Modelling the impact of fexinidazole use on human African trypanosomiasis (HAT) transmission in the Democratic Republic of the Congo.

Gambiense human African trypanosomiasis is a deadly disease that has been declining in incidence since the start of the Century, primarily due to increased screening, diagnosis and treatment of infected people. The main treatment regimen currently in use requires a lumbar puncture as part of the diagnostic process to determine disease stage and hospital admission for drug administration. Fexinidazole is a new oral treatment for stage 1 and non-severe stage 2 human African trypanosomiasis. The World Health Organization has recently incorporated fexinidazole into its treatment guidelines for human African trypanosomiasis. The treatment does not require hospital admission or a lumbar puncture for all patients, which is likely to ease access for patients; however, it does require concomitant food intake, which is likely to reduce adherence. Here, we use a mathematical model calibrated to case and screening data from Mushie territory, in the Democratic Republic of the Congo, to explore the potential negative impact of poor compliance to an oral treatment, and potential gains to be made from increases in the rate at which patients seek treatment. We find that reductions in compliance in treatment of stage 1 cases are projected to result in the largest increase in further transmission of the disease, with failing to cure stage 2 cases also posing a smaller concern. Reductions in compliance may be offset by increases in the rate at which cases are passively detected. Efforts should therefore be made to ensure good adherence for stage 1 patients to treatment with fexinidazole and to improve access to care.

Modelling to explore the potential impact of asymptomatic human infections on transmission and dynamics of African sleeping sickness.

Gambiense human African trypanosomiasis (gHAT, sleeping sickness) is one of several neglected tropical diseases (NTDs) where there is evidence of asymptomatic human infection but there is uncertainty of the role it plays in transmission and maintenance. To explore possible consequences of asymptomatic infections, particularly in the context of elimination of transmission-a goal set to be achieved by 2030-we propose a novel dynamic transmission model to account for the asymptomatic population. This extends an established framework, basing infection progression on a number of experimental and observation gHAT studies. Asymptomatic gHAT infections include those in people with blood-dwelling trypanosomes, but no discernible symptoms, or those with parasites only detectable in skin. Given current protocols, asymptomatic infection with blood parasites may be diagnosed and treated, based on observable parasitaemia, in contrast to many other diseases for which treatment (and/or diagnosis) may be based on symptomatic infection. We construct a model in which exposed people can either progress to either asymptomatic skin-only parasite infection, which would not be diagnosed through active screening algorithms, or blood-parasite infection, which is likely to be diagnosed if tested. We add extra parameters to the baseline model including different self-cure, recovery, transmission and detection rates for skin-only or blood infections. Performing sensitivity analysis suggests all the new parameters introduced in the asymptomatic model can impact the infection dynamics substantially. Among them, the proportion of exposures resulting in initial skin or blood infection appears the most influential parameter. For some plausible parameterisations, an initial fall in infection prevalence due to interventions could subsequently stagnate even under continued screening due to the formation of a new, lower endemic equilibrium. Excluding this scenario, our results still highlight the possibility for asymptomatic infection to slow down progress towards elimination of transmission. Location-specific model fitting will be needed to determine if and where this could pose a threat.

Satellite-based modelling of potential tsetse (Glossina pallidipes) breeding and foraging sites using teneral and non-teneral fly occurrence data.

BACKGROUND: African trypanosomiasis, which is mainly transmitted by tsetse flies (Glossina spp.), is a threat to public health and a significant hindrance to animal production. Tools that can reduce tsetse densities and interrupt disease transmission exist, but their large-scale deployment is limited by high implementation costs. This is in part limited by the absence of knowledge of breeding sites and dispersal data, and tools that can predict these in the absence of ground-truthing. METHODS: In Kenya, tsetse collections were carried out in 261 randomized points within Shimba Hills National Reserve (SHNR) and villages up to 5 km from the reserve boundary between 2017 and 2019. Considering their limited dispersal rate, we used in situ observations of newly emerged flies that had not had a blood meal (teneral) as a proxy for active breeding locations. We fitted commonly used species distribution models linking teneral and non-teneral tsetse presence with satellite-derived vegetation cover type fractions, greenness, temperature, and soil texture and moisture indices separately for the wet and dry season. Model performance was assessed with area under curve (AUC) statistics, while the maximum sum of sensitivity and specificity was used to classify suitable breeding or foraging sites. RESULTS: Glossina pallidipes flies were caught in 47% of the 261 traps, with teneral flies accounting for 37% of these traps. Fitted models were more accurate for the teneral flies (AUC = 0.83) as compared to the non-teneral (AUC = 0.73). The probability of teneral fly occurrence increased with woodland fractions but decreased with cropland fractions. During the wet season, the likelihood of teneral flies occurring decreased as silt content increased. Adult tsetse flies were less likely to be trapped in areas with average land surface temperatures below 24 °C. The models predicted that 63% of the potential tsetse breeding area was within the SHNR, but also indicated potential breeding pockets outside the reserve. CONCLUSION: Modelling tsetse occurrence data disaggregated by life stages with time series of satellite-derived variables enabled the spatial characterization of potential breeding and foraging sites for G. pallidipes. Our models provide insight into tsetse bionomics and aid in characterising tsetse infestations and thus prioritizing control areas.

A gene expression panel for estimating age in males and females of the sleeping sickness vector Glossina morsitans.

Many vector-borne diseases are controlled by methods that kill the insect vectors responsible for disease transmission. Recording the age structure of vector populations provides information on mortality rates and vectorial capacity, and should form part of the detailed monitoring that occurs in the wake of control programmes, yet tools for obtaining estimates of individual age remain limited. We investigate the potential of using markers of gene expression to predict age in tsetse flies, which are the vectors of deadly and economically damaging African trypanosomiases. We use RNAseq to identify candidate expression markers, and test these markers using qPCR in laboratory-reared Glossina morsitans morsitans of known age. Measuring the expression of six genes was sufficient to obtain a prediction of age with root mean squared error of less than 8 days, while just two genes were sufficient to classify flies into age categories of ≤15 and >15 days old. Further testing of these markers in field-caught samples and in other species will determine the accuracy of these markers in the field.

An Overview on Target-Based Drug Design against Kinetoplastid Protozoan Infections: Human African Trypanosomiasis, Chagas Disease and Leishmaniases.

The protozoan diseases Human African Trypanosomiasis (HAT), Chagas disease (CD), and leishmaniases span worldwide and therefore their impact is a universal concern. The present regimen against kinetoplastid protozoan infections is poor and insufficient. Target-based design expands the horizon of drug design and development and offers novel chemical entities and potential drug candidates to the therapeutic arsenal against the aforementioned neglected diseases. In this review, we report the most promising targets of the main kinetoplastid parasites, as well as their corresponding inhibitors. This overview is part of the Special Issue, entitled "Advances of Medicinal Chemistry against Kinetoplastid Protozoa (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) Infections: Drug Design, Synthesis and Pharmacology".

The potential economic benefits of controlling trypanosomiasis using waterbuck repellent blend in sub-Saharan Africa.

Trypanosomiasis is a significant productivity-limiting livestock disease in sub-Saharan Africa, contributing to poverty and food insecurity. In this paper, we estimate the potential economic gains from adopting Waterbuck Repellent Blend (WRB). The WRB is a new technology that pushes trypanosomiasis-transmitting tsetse fly away from animals, improving animals' health and increasing meat and milk productivity. We estimate the benefits of WRB on the production of meat and milk using the economic surplus approach. We obtained data from an expert elicitation survey, secondary and experimental sources. Our findings show that the adoption of WRB in 5 to 50% of the animal population would generate an economic surplus of US$ 78-869 million per annum for African 18 countries. The estimated benefit-cost ratio (9:1) further justifies an investment in WRB. The technology's potential benefits are likely to be underestimated since our estimates did not include the indirect benefits of the technology adoption, such as the increase in the quantity and quality of animals' draught power services and human and environmental health effects. These benefits suggest that investing in WRB can contribute to nutrition security and sustainable development goals.

Diversity of tsetse flies and trypanosome species circulating in the area of Lake Iro in southeastern Chad.

BACKGROUND: African trypanosomiases are vector-borne diseases that affect humans and livestock in sub-Saharan Africa. Although data have been collected on tsetse fauna as well as trypanosome infections in tsetse flies and mammals in foci of sleeping sickness in Chad, the situation of tsetse fly-transmitted trypanosomes remains unknown in several tsetse-infested areas of Chad. This study was designed to fill this epidemiological knowledge gap by determining the tsetse fauna as well as the trypanosomes infecting tsetse flies in the area of Lake Iro in southeastern Chad. METHODS: Tsetse flies were trapped along the Salamat River using biconical traps. The proboscis and tsetse body were removed from each fly. DNA was extracted from the proboscis using proteinase K and phosphate buffer and from the tsetse body using Chelex 5%. Tsetse flies were identified by amplifying and sequencing the cytochrome c oxydase I gene of each tsetse fly. Trypanosome species were detected by amplifying and sequencing the internal transcribed spacer 1 of infecting trypanosomes. RESULTS: A total of 617 tsetse flies were trapped; the apparent density of flies per trap per day was 2. 6. Of the trapped flies, 359 were randomly selected for the molecular identification and for the detection of infecting trypanosomes. Glossina morsitans submorsitans (96.1%) was the dominant tsetse fly species followed by G. fuscipes fuscipes (3.1%) and G. tachinoides (0.8%). Four trypanosome species, including Trypanosoma vivax, T. simiae, T. godfreyi and T. congolense savannah, were detected. Both single infection (56.7%) and mixed infections of trypanosomes (4.6%) were detected in G. m. submorsitans. The single infection included T. simiae (20.5%), T. congolense savannah (16.43%), T. vivax (11.7%) and T. godfreyi (9.8%). The trypanosome infection rate was 61.4% in G. m. submorsitans, 72.7% in G. f. fuscipes and 66.6% in G. tachinoides. Trypanosome infections were more prevalent in tsetse bodies (40.6%) than in the proboscis (16.3%). CONCLUSION: This study revealed the presence of different tsetse species and a diversity of trypanosomes pathogenic to livestock in the area of Lake Iro. The results highlight the risks and constraints that animal African trypanosomiasis pose to livestock breeding and the importance of assessing trypanosome infections in livestock in this area.

Strengthening data collection for neglected tropical diseases: What data are needed for models to better inform tailored intervention programmes?

Locally tailored interventions for neglected tropical diseases (NTDs) are becoming increasingly important for ensuring that the World Health Organization (WHO) goals for control and elimination are reached. Mathematical models, such as those developed by the NTD Modelling Consortium, are able to offer recommendations on interventions but remain constrained by the data currently available. Data collection for NTDs needs to be strengthened as better data are required to indirectly inform transmission in an area. Addressing specific data needs will improve our modelling recommendations, enabling more accurate tailoring of interventions and assessment of their progress. In this collection, we discuss the data needs for several NTDs, specifically gambiense human African trypanosomiasis, lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminths (STH), trachoma, and visceral leishmaniasis. Similarities in the data needs for these NTDs highlight the potential for integration across these diseases and where possible, a wider spectrum of diseases.

Computational Identification of Master Regulators Influencing Trypanotolerance in Cattle.

African Animal Trypanosomiasis (AAT) is transmitted by the tsetse fly which carries pathogenic trypanosomes in its saliva, thus causing debilitating infection to livestock health. As the disease advances, a multistage progression process is observed based on the progressive clinical signs displayed in the host's body. Investigation of genes expressed with regular monotonic patterns (known as Monotonically Expressed Genes (MEGs)) and of their master regulators can provide important clue for the understanding of the molecular mechanisms underlying the AAT disease. For this purpose, we analysed MEGs for three tissues (liver, spleen and lymph node) of two cattle breeds, namely trypanosusceptible Boran and trypanotolerant N'Dama. Our analysis revealed cattle breed-specific master regulators which are highly related to distinguish the genetic programs in both cattle breeds. Especially the master regulators MYC and DBP found in this study, seem to influence the immune responses strongly, thereby susceptibility and trypanotolerance of Boran and N'Dama respectively. Furthermore, our pathway analysis also bolsters the crucial roles of these master regulators. Taken together, our findings provide novel insights into breed-specific master regulators which orchestrate the regulatory cascades influencing the level of trypanotolerance in cattle breeds and thus could be promising drug targets for future therapeutic interventions.

Quantifying epidemiological drivers of gambiense human African Trypanosomiasis across the Democratic Republic of Congo.

Gambiense human African trypanosomiasis (gHAT) is a virulent disease declining in burden but still endemic in West and Central Africa. Although it is targeted for elimination of transmission by 2030, there remain numerous questions about the drivers of infection and how these vary geographically. In this study we focus on the Democratic Republic of Congo (DRC), which accounted for 84% of the global case burden in 2016, to explore changes in transmission across the country and elucidate factors which may have contributed to the persistence of disease or success of interventions in different regions. We present a Bayesian fitting methodology, applied to 168 endemic health zones (∼100,000 population size), which allows for calibration of a mechanistic gHAT model to case data (from the World Health Organization HAT Atlas) in an adaptive and automated framework. It was found that the model needed to capture improvements in passive detection to match observed trends in the data within former Bandundu and Bas Congo provinces indicating these regions have substantially reduced time to detection. Health zones in these provinces generally had longer burn-in periods during fitting due to additional model parameters. Posterior probability distributions were found for a range of fitted parameters in each health zone; these included the basic reproduction number estimates for pre-1998 (R0) which was inferred to be between 1 and 1.14, in line with previous gHAT estimates, with higher median values typically in health zones with more case reporting in the 2000s. Previously, it was not clear whether a fall in active case finding in the period contributed to the declining case numbers. The modelling here accounts for variable screening and suggests that underlying transmission has also reduced greatly-on average 96% in former Equateur, 93% in former Bas Congo and 89% in former Bandundu-Equateur and Bandundu having had the highest case burdens in 2000. This analysis also sets out a framework to enable future predictions for the country.

Global distribution, host range and prevalence of Trypanosoma vivax: a systematic review and meta-analysis.

BACKGROUND: Trypanosomosis caused by Trypanosoma vivax is one of the diseases threatening the health and productivity of livestock in Africa and Latin America. Trypanosoma vivax is mainly transmitted by tsetse flies; however, the parasite has also acquired the ability to be transmitted mechanically by hematophagous dipterans. Understanding its distribution, host range and prevalence is a key step in local and global efforts to control the disease. METHODS: The study was conducted according to the methodological recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. A systematic literature search was conducted on three search engines, namely PubMed, Scopus and CAB Direct, to identify all publications reporting natural infection of T. vivax across the world. All the three search engines were screened using the search term Trypanosoma vivax without time and language restrictions. Publications on T. vivax that met our inclusion criteria were considered for systematic review and meta-analysis. RESULT: The study provides a global database of T. vivax, consisting of 899 records from 245 peer-reviewed articles in 41 countries. A total of 232, 6277 tests were performed on 97 different mammalian hosts, including a wide range of wild animals. Natural infections of T. vivax were recorded in 39 different African and Latin American countries and 47 mammalian host species. All the 245 articles were included into the qualitative analysis, while information from 186 cross-sectional studies was used in the quantitative analysis mainly to estimate the pooled prevalence. Pooled prevalence estimates of T. vivax in domestic buffalo, cattle, dog, dromedary camel, equine, pig, small ruminant and wild animals were 30.6%, 6.4%, 2.6%, 8.4%, 3.7%, 5.5%, 3.8% and 12.9%, respectively. Stratified according to the diagnostic method, the highest pooled prevalences were found with serological techniques in domesticated buffalo (57.6%) followed by equine (50.0%) and wild animals (49.3%). CONCLUSION: The study provides a comprehensive dataset on the geographical distribution and host range of T. vivax and demonstrates the potential of this parasite to invade other countries out of Africa and Latin America.

Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis.

Tsetse transmit African trypanosomiasis, which is a disease fatal to both humans and animals. A vaccine to protect against this disease does not exist so transmission control relies on eliminating tsetse populations. Although neurotoxic insecticides are the gold standard for insect control, they negatively impact the environment and reduce populations of insect pollinator species. Here we present a promising, environment-friendly alternative to current insecticides that targets the insect tyrosine metabolism pathway. A bloodmeal contains high levels of tyrosine, which is toxic to haematophagous insects if it is not degraded and eliminated. RNA interference (RNAi) of either the first two enzymes in the tyrosine degradation pathway (tyrosine aminotransferase (TAT) and 4-hydroxyphenylpyruvate dioxygenase (HPPD)) was lethal to tsetse. Furthermore, nitisinone (NTBC), an FDA-approved tyrosine catabolism inhibitor, killed tsetse regardless if the drug was orally or topically applied. However, oral administration of NTBC to bumblebees did not affect their survival. Using a novel mathematical model, we show that NTBC could reduce the transmission of African trypanosomiasis in sub-Saharan Africa, thus accelerating current disease elimination programmes.

Effect of zebra skin-derived compounds on field catches of the human African trypanosomiasis vector Glossina fuscipes fuscipes.

The riverine tsetse fly Glossina fuscipes fuscipes is a major vector of trypanosome pathogens causing African trypanosomiasis. This fly species uses a combination of olfactory and visual cues to locate its hosts. Previously, traps and targets baited with visual cues have been used in vector control, but the development of olfactory-based tools has been challenging. Recently, repellents have shown promise as olfactory-based tools in tsetse vector control. Here, we evaluated a three-component blend comprising 6-methyl-5-hepten-2-one, acetophenone and geranyl acetone (blend K), previously identified as a repellent for savannah tsetse flies in zebra skin odor, on G. f. fuscipes populations. Using a series of 6 × 6 randomized Latin square-designed experiments, G. f. fuscipes catches in biconical traps were monitored on four islands of Lake Victoria in western Kenya between July and September 2019, after the long rainy season. Traps were baited with blend K and individual components of this blend. The known tsetse repellent blend WRC (waterbuck repellent compounds) and trap alone were included as controls. Daily catch data in thirty-six replicate trials were analyzed using generalized linear model with negative binomial error structure using the package "MASS" in R. Treatment, day and site were set as predictor variables. Our results showed that, blend K significantly reduced G. f. fuscipes catches by 25.6% (P < 0.01) compared to the control trap alone but was not significantly different from WRC which reduced catches by 20.7% (P < 0.05). Of the individual compounds, geranyl acetone solely significantly reduced catches by 29.1% (P < 0.01) which did not differ from blend K or WRC. We conclude that geranyl acetone accounts for the repellent effect of blend K on the riverine tsetse fly, G. f. fuscipes, demonstrating the ecological importance of animal skin odors in the host-seeking behavior of medically-important tsetse fly vectors.

Mathematical modelling and control of African animal trypanosomosis with interacting populations in West Africa-Could biting flies be important in main taining the disease endemicity?

African animal trypanosomosis (AAT) is transmitted cyclically by tsetse flies and mechanically by biting flies (tabanids and stomoxyines) in West Africa. AAT caused by Trypanosoma congolense, T. vivax and T. brucei brucei is a major threat to the cattle industry. A mathematical model involving three vertebrate hosts (cattle, small ruminants and wildlife) and three vector flies (Tsetse flies, tabanids and stomoxyines) was described to identify elimination strategies. The basic reproduction number (R0) was obtained with respect to the growth rate of infected wildlife (reservoir hosts) present around the susceptible population using a next generation matrix technique. With the aid of suitable Lyapunov functions, stability analyses of disease-free and endemic equilibria were established. Simulation of the predictive model was presented by solving the system of ordinary differential equations to explore the behaviour of the model. An operational area in southwest Nigeria was simulated using generated pertinent data. The R0 < 1 in the formulated model indicates the elimination of AAT. The comprehensive use of insecticide treated targets and insecticide treated cattle (ITT/ITC) affected the feeding tsetse and other biting flies resulting in R0 < 1. The insecticide type, application timing and method, expertise and environmental conditions could affect the model stability. In areas with abundant biting flies and no tsetse flies, T. vivax showed R0 > 1 when infected wildlife hosts were present. High tsetse populations revealed R0 <1 for T. vivax when ITT and ITC were administered, either individually or together. Elimination of the transmitting vectors of AAT could cost a total of US$ 1,056,990 in southwest Nigeria. Hence, AAT in West Africa can only be controlled by strategically applying insecticides targeting all transmitting vectors, appropriate use of trypanocides, and institutionalising an appropriate barrier between the domestic and sylvatic areas.