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An open label randomized clinical trial comparing the safety and effectiveness of one, two or three weekly pentamidine isethionate doses (seven milligrams per kilogram) in the treatment of cutaneous leishmaniasis in the Amazon Region

PLoS Neglected Tropical Diseases News - 31 October 2018 - 9:00pm

by Ellen Priscilla Nunes Gadelha, Rajendranath Ramasawmy, Bruna da Costa Oliveira, Nágila Moraes Rocha, Jorge Augusto de Oliveira Guerra, George Allan Villa Rouco da Silva, Tirza Gabrielle Ramos de Mesquita, Carolina Chrusciak Talhari Cortez, Anette Chrusciak Talhari

Background

American Cutaneous Leishmaniasis (ACL), a vector borne disease, is caused by various species of Leishmania and in the Amazonas, Leishmania guyanensis is predominant. The recommended drugs for treatment of cutaneous leishmaniasis (CL) in Brazil are pentavalent antimonials, pentamidine isethionate (PI) and amphotericin B. Pentamidine was initially used as metanolsulfonate or mesylate (Lomidine) at a dose of 4 mg/kg/daily, containing 2.3mg of base. This drug was withdrawn from the market in the eighties, and currently is available as PI. The PI dose required to achieve an equivalent dose of pentamidine base is 7 mg/kg, rather than the 4 mg/kg that is currently recommended in Brazil.

Objectives

The aim of this study was to evaluate the efficacy and safety of PI in a single dose, two or three doses of 7 mg/kg body weight, intramuscularly, with an interval of seven days between each dose.

Materials and methods

This study was conducted as a controlled, randomized, open–label clinical trial for a total number of 159 patients with CL. Individuals aged 16–64 years with one to six lesions of confirmed CL based on amastigotes visualization in direct examination of Giemsa stained of dermal scraping from the border of the lesion with no previous treatment for CL and no abnormal values for liver enzymes were eligible to participate in the study. Patients with history of diabetes, cardiac, renal, and hepatic disease as well as pregnant women were excluded. Cure was defined as complete healing in the diameters of the ulcers and lesions skin six months after the end of the treatment.

Results

From November 2013 to December 2015, 159 patients were screened and allocated in three groups for treatment with PI: i) 53 patients were treated with a single dose intramuscularly injection of 7 mg/kg body weight; ii) 53 received two doses of 7 mg/kg within an interval of seven days; and iii) 53 were treated with three doses of 7mg/kg with an interval of seven days between each dose. In 120 patients, L. guyanensis was identified. A cure rate of 45%, 81.1% and 96.2% were observed in the first, second and third group, respectively. The cure in the three PI dose group was higher compared to the single-dose (p<0.0001) and two-dose groups (p = 0.03). No serious adverse events occurred.

Conclusion

The present study shows that PI is a safe drug and its efficacy varied with the number of doses. The administration of PI in patients with ACL, predominantly caused by L. guyanensis, was mostly efficient in three or two doses of 7 mg/kg.

Trial registration

ClinicalTrials.gov NCT02919605

Participatory survey of Rift Valley fever in nomadic pastoral communities of North-central Nigeria: The associated risk pathways and factors

PLoS Neglected Tropical Diseases News - 30 October 2018 - 9:00pm

by Nma Bida Alhaji, Olutayo Olajide Babalobi, Yiltawe Wungak, Hussaini Gulak Ularamu

Background

Rift Valley fever (RVF) is an emerging neglected mosquito-borne viral zoonotic disease of domestic animals and humans, with potential for global expansion. The objectives of this study were: to assess perceived relative burden and seasonality of RVF in nomadic cattle herds and validate the burden with sero-prevalence impact; and assess perceived risk factors associated with the disease and risk pathways for RVF virus in nomadic pastoral herds of North-central Nigeria using pastoralists’ existing veterinary knowledge.

Methods

Participatory Epidemiology (PE) survey was conducted in Fulani nomadic pastoral communities domiciled in Niger State between January and December 2015. A cross-sectional sero-prevalence investigation was also carried out in nomadic pastoral cattle herds to validate outcomes of PE. A total of nine nomadic pastoral communities were purposively selected for qualitative impact assessment using Participatory Rural Appraisal tools, while 97 cattle randomly sampled from 15 purposively selected nomadic herds and had their sera analyzed using c-ELISA. Kendall’s Coefficient of Concordance W statistics and OpenEpi 2.3.1 were used for statistical analyses.

Results

Mean proportional piles (relative burden) of RVF (Gabi-gabiF) was 8.3%, and nomads agreement on the burden was strong (W = 0.6855) and statistically significant (P<0.001). This was validated by 11.3% (11/97; 95% CI: 6.1–18.9) sero-positivity (quantitative impact). Mean matrix scores of prominent clinical signs associated with RVF were fever (3.1), anorexia (2.1), abortion (4.1), nasal discharge (3.3), neurological disorder (8.4), diarrhoea (3.2), and sudden death (4.4), with strong agreement (W = 0.6687) and statistically significant (p<0.001). Mean proportional piles of pastoralists’ perceived risk factors identified to influenced RVF occurrence were: availability of mosquitoes (18 piles, 17.6%), high cattle density (16 piles, 15.9%) and high rainfall (12 piles, 12.2%). Agreement on the risk factors was strong (W = 0.8372) and statistically significant (p<0.01). Mean matrix scores for the Entry pathway of RVF virus into the nomadic pastoral herds were: presence of RVFV infected mosquitoes (tiny biting flies) (7.9), presence of infected cattle in herds (8.4), and contacts of herd with infected wild animals at grazing (10.1). Mean matrix scores for the Spread pathway of RVF virus in herds were bites of infected mosquitoes (5.1), contacts with infected aborted fetuses/fluids (7.8), and contaminated pasture with aborted fetuses/fluids (9.7). Agreement on risk pathways was strong (W = 0.6922) and statistically significant (p<0.03). Key informants scored RVF to occurred more in Damina or late rainy season (5.3), followed by Kaka or early dry season (3.3), with strong agreement (W = 0.8719) and statistically significant (P<0.01). This study highlighted the significant existing knowledge level about RVF contained in nomadic pastoralists.

Conclusions

The use of PE approach is needful in active surveillance of livestock diseases in pastoral communities domiciled in highly remote areas. RVF surveillance system, control and prevention programmes that take the identified risk factors and pathways into consideration will be beneficial to the livestock industry in Nigeria, and indeed Africa. An ‘OneHealth’ approach is needed to improve efficiency of RVF research, surveillance, prevention and control systems, so as to assure food security and public health in developing countries.

<i>SODB1</i> is essential for <i>Leishmania major</i> infection of Macrophages and Pathogenesis in Mice

PLoS Neglected Tropical Diseases News - 29 October 2018 - 9:00pm

by Bennett J. Davenport, Casey G. Martin, Stephen M. Beverley, David J. Orlicky, Andres Vazquez-Torres, Thomas E. Morrison

Leishmania species are sand fly-transmitted protozoan parasites that cause leishmaniasis, neglected tropical diseases that affect millions of people. Leishmania amastigotes must overcome a variety of host defenses, including reactive oxygen species (ROS) produced by the NADPH oxidase. Leishmania species encode three superoxide dismutases (SODs): the mitochondrial SODA and two glycosomal SODs (SODB1 and SODB2). SODs are metalloenzymes that function in antioxidant defense by converting superoxide to oxygen and hydrogen peroxide. Here, we investigated a role for SODB1 in Leishmania infection of macrophages and virulence in mice. We found that a single allele deletion of SODB1 (SODB1/⊗sodb1) had minimal effects on the replication of axenically-grown L. major promastigotes or differentiation to infective metacyclic promastigotes. Disruption of a single SODB1 allele also did not affect L. donovani differentiation to amastigotes induced axenically, or the replication of axenically-grown L. donovani promastigotes and amastigotes. In contrast, the persistence of SODB1/⊗sodb1 L. major in WT macrophages was impaired, and the development of cutaneous lesions in SODB1/⊗sodb1 L. major-infected C57BL/6 and BALB/c mice was strongly reduced. The reduced disease severity in mice was associated with reduced burdens of SODB1/⊗sodb1 L. major parasites in the foot at late, but not early times post-inoculation, as well as an impaired capacity to disseminate from the site of inoculation. Collectively, these data suggest that SODB1 is critical for L. major persistence in macrophages and virulence in mice.

Clinical and microscopic predictors of <i>Entamoeba histolytica</i> intestinal infection in travelers and migrants diagnosed with <i>Entamoeba histolytica/dispar</i> infection

PLoS Neglected Tropical Diseases News - 29 October 2018 - 9:00pm

by Steven Van Den Broucke, Jacob Verschueren, Marjan Van Esbroeck, Emmanuel Bottieau, Jef Van den Ende

Background

Amebiasis is a protozoal infection caused by Entamoeba histolytica, while the morphologically indistinguishable E. dispar is considered as non-pathogenic. Polymerase chain reaction (PCR) assays are necessary to differentiate both species. The most common clinical presentations of E. histolytica disease are amebic colitis and amebic liver abscess, but asymptomatic infection is also possible. We assessed the frequency and pattern of clinical symptoms and microscopic features in travelers/migrants associated with E. histolytica intestinal infection and compared them to those found in individuals with E. dispar infection.

Methods

We conducted a retrospective study at the travel clinic of the Institute of Tropical Medicine, Antwerp, Belgium on travelers/migrants found from 2006 to 2016 positive for Entamoeba histolytica/dispar through antigen detection and/or through microscopy confirmed by PCR. All files of individuals with a positive PCR for E. histolytica (= cases) and a random selection of an equal number of Entamoeba dispar carriers (= controls) were reviewed. We calculated the sensitivity, specificity and likelihood ratios (LRs) of clinical symptoms (blood in stool, mucus in stool, watery diarrhea, abdominal cramps, fever or any of these 5 symptoms) and of microscopic features (presence of trophozoites in direct and in sodium acetate-acetic acid-formalin (SAF)-fixed stool smears) to discriminate between E. histolytica and E. dispar infection.

Results

Of all stool samples positive for Entamoeba histolytica/dispar for which PCR was performed (n = 810), 30 (3.7%) were true E. histolytica infections, of which 39% were asymptomatic. Sensitivity, specificity and positive LRs were 30%, 100% and 300 (p 0.007) for presence of blood in stool; 22%, 100% and 222 (p 0.03) for mucus in stool; 44%, 90% and 4.7 (p 0.009) for cramps and 14%, 97% and 4.8 (p = 0.02) for trophozoites in direct smears. For watery diarrhea, fever and for trophozoites in SAF fixated smears results were non-significant.

Conclusions

E. histolytica infection was demonstrated in a small proportion of travelers/migrants with evidence of Entamoeba histolytica/dispar infection. In this group, history of blood and mucus in stool and cramps had good to strong confirming power (LR+) for actual E. histolytica infection. Trophozoites were also predictive for true E. histolytica infection but in direct smears only.

Development of reverse genetics systems and investigation of host response antagonism and reassortment potential for Cache Valley and Kairi viruses, two emerging orthobunyaviruses of the Americas

PLoS Neglected Tropical Diseases News - 29 October 2018 - 9:00pm

by James I. Dunlop, Agnieszka M. Szemiel, Aitor Navarro, Gavin S. Wilkie, Lily Tong, Sejal Modha, Daniel Mair, Vattipally B. Sreenu, Ana Da Silva Filipe, Ping Li, Yan-Jang S. Huang, Benjamin Brennan, Joseph Hughes, Dana L. Vanlandingham, Stephen Higgs, Richard M. Elliott, Alain Kohl

Orthobunyaviruses such as Cache Valley virus (CVV) and Kairi virus (KRIV) are important animal pathogens. Periodic outbreaks of CVV have resulted in the significant loss of lambs on North American farms, whilst KRIV has mainly been detected in South and Central America with little overlap in geographical range. Vaccines or treatments for these viruses are unavailable. One approach to develop novel vaccine candidates is based on the use of reverse genetics to produce attenuated viruses that elicit immune responses but cannot revert to full virulence. The full genomes of both viruses were sequenced to obtain up to date genome sequence information. Following sequencing, minigenome systems and reverse genetics systems for both CVV and KRIV were developed. Both CVV and KRIV showed a wide in vitro cell host range, with BHK-21 cells a suitable host cell line for virus propagation and titration. To develop attenuated viruses, the open reading frames of the NSs proteins were disrupted. The recombinant viruses with no NSs protein expression induced the production of type I interferon (IFN), indicating that for both viruses NSs functions as an IFN antagonist and that such attenuated viruses could form the basis for attenuated viral vaccines. To assess the potential for reassortment between CVV and KRIV, which could be relevant during vaccination campaigns in areas of overlap, we attempted to produce M segment reassortants by reverse genetics. We were unable to obtain such viruses, suggesting that it is an unlikely event.

Seroprevalence for the tick-borne relapsing fever spirochete <i>Borrelia turicatae</i> among small and medium sized mammals of Texas

PLoS Neglected Tropical Diseases News - 29 October 2018 - 9:00pm

by Brittany A. Armstrong, Alexander Kneubehl, Aparna Krishnavajhala, Hannah K. Wilder, William Boyle, Edward Wozniak, Carson Phillips, Kristen Hollywood, Kristy O. Murray, Taylor G. Donaldson, Pete D. Teel, Ken Waldrup, Job E. Lopez

Background

In low elevation arid regions throughout the Southern United States, Borrelia turicatae is the principal agent of tick-borne relapsing fever. However, endemic foci and the vertebrate hosts involved in the ecology of B. turicatae remain undefined. Experimental infection studies suggest that small and medium sized mammals likely maintain B. turicatae in nature, while the tick vector is a long-lived reservoir.

Methodology/principal findings

Serum samples from wild caught rodents, raccoons, and wild and domestic canids from 23 counties in Texas were screened for prior exposure to B. turicatae. Serological assays were performed using B. turicatae protein lysates and recombinant Borrelia immunogenic protein A (rBipA), a diagnostic protein that is unique to RF spirochetes and may be a species-specific antigen.

Conclusions/significance

Serological responses to B. turicatae were detected from 24 coyotes, one gray fox, two raccoons, and one rodent from six counties in Texas. These studies indicate that wild canids and raccoons were exposed to B. turicatae and are likely involved in the pathogen’s ecology. Additionally, more work should focus on evaluating rodent exposure to B. turicatae and the role of these small mammals in the pathogen’s maintenance in nature.

A simian-adenovirus-vectored rabies vaccine suitable for thermostabilisation and clinical development for low-cost single-dose pre-exposure prophylaxis

PLoS Neglected Tropical Diseases News - 29 October 2018 - 9:00pm

by Chuan Wang, Pawan Dulal, Xiangyang Zhou, Zhiquan Xiang, Hooman Goharriz, Ashley Banyard, Nicky Green, Livia Brunner, Roland Ventura, Nicolas Collin, Simon J. Draper, Adrian V. S. Hill, Rebecca Ashfield, Anthony R. Fooks, Hildegund C. Ertl, Alexander D. Douglas

Background

Estimates of current global rabies mortality range from 26,000 to 59,000 deaths per annum. Although pre-exposure prophylaxis using inactivated rabies virus vaccines (IRVs) is effective, it requires two to three doses and is regarded as being too expensive and impractical for inclusion in routine childhood immunization programmes.

Methodology/ Principal findings

Here we report the development of a simian-adenovirus-vectored rabies vaccine intended to enable cost-effective population-wide pre-exposure prophylaxis against rabies. ChAdOx2 RabG uses the chimpanzee adenovirus serotype 68 (AdC68) backbone previously shown to achieve pre-exposure protection against rabies in non-human primates. ChAdOx2 differs from AdC68 in that it contains the human adenovirus serotype 5 (AdHu5) E4 orf6/7 region in place of the AdC68 equivalents, enhancing ease of manufacturing in cell lines which provide AdHu5 E1 proteins in trans.We show that immunogenicity of ChAdOx2 RabG in mice is comparable to that of AdC68 RabG and other adenovirus serotypes expressing rabies virus glycoprotein. High titers of rabies virus neutralizing antibody (VNA) are elicited after a single dose. The relationship between levels of VNA activity and rabies virus glycoprotein monomer-binding antibody differs after immunization with adenovirus-vectored vaccines and IRV vaccines, suggesting routes to further enhancement of the efficacy of the adenovirus-vectored candidates. We also demonstrate that ChAdOx2 RabG can be thermostabilised using a low-cost method suitable for clinical bio-manufacture and ambient-temperature distribution in tropical climates. Finally, we show that a dose-sparing effect can be achieved by formulating ChAdOx2 RabG with a simple chemical adjuvant. This approach could lower the cost of ChAdOx2 RabG and other adenovirus-vectored vaccines.

Conclusions/ Significance

ChAdOx2 RabG may prove to be a useful tool to reduce the human rabies death toll. We have secured funding for Good Manufacturing Practice- compliant bio-manufacture and Phase I clinical trial of this candidate.

Designed mono- and di-covalent inhibitors trap modeled functional motions for <i>Trypanosoma cruzi</i> proline racemase in crystallography

PLoS Neglected Tropical Diseases News - 29 October 2018 - 9:00pm

by Patricia de Aguiar Amaral, Delphine Autheman, Guilherme Dias de Melo, Nicolas Gouault, Jean-François Cupif, Sophie Goyard, Patricia Dutra, Nicolas Coatnoan, Alain Cosson, Damien Monet, Frederick Saul, Ahmed Haouz, Philippe Uriac, Arnaud Blondel, Paola Minoprio

Chagas disease, caused by Trypanosoma cruzi, affects millions of people in South America and no satisfactory therapy exists, especially for its life threatening chronic phase. We targeted the Proline Racemase of T. cruzi, which is present in all stages of the parasite life cycle, to discover new inhibitors against this disease. The first published crystal structures of the enzyme revealed that the catalytic site is too small to allow any relevant drug design. In previous work, to break through the chemical space afforded to virtual screening and drug design, we generated intermediate models between the open (ligand free) and closed (ligand bound) forms of the enzyme. In the present work, we co-crystallized the enzyme with the selected inhibitors and found that they were covalently bound to the catalytic cysteine residues in the active site, thus explaining why these compounds act as irreversible inhibitors. These results led us to the design of a novel, more potent specific inhibitor, NG-P27. Co-crystallization of this new inhibitor with the enzyme allowed us to confirm the predicted protein functional motions and further characterize the chemical mechanism. Hence, the catalytic Cys300 sulfur atom of the enzyme attacks the C2 carbon of the inhibitor in a coupled, regiospecific—stereospecific Michael reaction with trans-addition of a proton on the C3 carbon. Strikingly, the six different conformations of the catalytic site in the crystal structures reported in this work had key similarities to our intermediate models previously genrated by inference of the protein functional motions. These crystal structures span a conformational interval covering roughly the first quarter of the opening mechanism, demonstrating the relevance of modeling approaches to break through chemical space in drug design.

Spatial-temporal clustering analysis of yaws on Lihir Island, Papua New Guinea to enhance planning and implementation of eradication programs

PLoS Neglected Tropical Diseases News - 29 October 2018 - 9:00pm

by Eric Q. Mooring, Oriol Mitjà, Megan B. Murray

Background

In the global program for the eradication of yaws, assessments of the prevalence of the disease are used to decide where to initiate mass treatment. However, the smallest administrative unit that should be used as the basis for making decisions is not clear. We investigated spatial and temporal clustering of yaws to help inform the choice of implementation unit.

Methodology/Principal findings

We analyzed 11 years of passive surveillance data on incident yaws cases (n = 1448) from Lihir Island, Papua New Guinea. After adjusting for age, sex, and trends in health-seeking, we detected three non-overlapping spatial-temporal clusters (p < 1 × 10−17, p = 1.4 × 10−14, p = 1.4 × 10−8). These lasted from 28 to 47 months in duration and each encompassed between 4 and 6 villages. We also assessed spatial clustering of prevalent yaws cases (n = 532) that had been detected in 7 biannual active case finding surveys beginning in 2013. We identified 1 statistically significant cluster in each survey. We considered the possibility that schools that serve multiple villages might be loci of transmission, but we found no evidence that incident cases of yaws among 8- to 14-year-olds clustered within primary school attendance areas (p = 0.6846).

Conclusions/Significance

These clusters likely reflect transmission of yaws across village boundaries; villages may be epidemiologically linked to a degree such that mass drug administration may be more effectively implemented at a spatial scale larger than the individual village.

Spatial prediction of risk areas for vector transmission of <i>Trypanosoma cruzi</i> in the State of Paraná, southern Brazil

PLoS Neglected Tropical Diseases News - 26 October 2018 - 9:00pm

by Andréia Mantovani Ferro e Silva, Thadeu Sobral-Souza, Maurício Humberto Vancine, Renata Lara Muylaert, Ana Paula de Abreu, Sandra Marisa Pelloso, Maria Dalva de Barros Carvalho, Luciano de Andrade, Milton Cezar Ribeiro, Max Jean de Ornelas Toledo

After obtaining certification of the absence of transmission of the Trypanosoma cruzi by Triatoma infestans in 2006, other native species of protozoan vectors have been found in human dwellings within municipalities of the State of Paraná, Southern Brazil. However, the spatial distribution of T. cruzi vectors and how climatic and landscape combined variables explain the distribution are still poorly understood. The goal of this study was to predict the potential distribution of T. cruzi vectors as a proxy for Chagas disease transmission risk using Ecological Niche Models (ENMs) based on climatic and landscape variables. We hypothesize that ENM based on both climate and landscape variables are more powerful than climate-only or landscape-only models, and that this will be true independent of vector species. A total of 2,662 records of triatomines of five species were obtained by community-based entomological surveillance from 2007 to 2013. The species with the highest number of specimens was Panstrongylus megistus (73%; n = 1,943), followed by Panstrongylus geniculatus (15.4%; 411), Rhodnius neglectus (6.0%; 159), Triatoma sordida (4.5%; 119) and Rhodnius prolixus (1.1%; 30). Of the total, 71.9% were captured at the intradomicile. T. cruzi infection was observed in 19.7% of the 2,472 examined insects. ENMs were generated based on selected climate and landscape variables with 1 km2 spatial resolution. Zonal statistics were used for classifying the municipalities as to the risk of occurrence of synanthropic triatomines. The integrated analysis of the climate and landscape suitability on triatomines geographical distribution was powerful on generating good predictive models. Moreover, this showed that some municipalities in the northwest, north and northeast of the Paraná state have a higher risk of T. cruzi vector transmission. This occurs because those regions present high climatic and landscape suitability values for occurrence of their vectors. The frequent invasion of houses by infected triatomines clearly indicates a greater risk of transmission of T. cruzi to the inhabitants. More public health attention should be given in the northern areas of the State of Paraná, which presents high climate and landscape suitabilities for the disease vectors. In conclusion, our results–through spatial analysis and predictive maps–showed to be effective in identifying areas of potential distribution and, consequently, in the definition of strategic areas and actions to prevent new cases of Chagas' disease, reinforcing the need for continuous and robust surveillance in these areas.

Inhibition of histone methyltransferase EZH2 in <i>Schistosoma mansoni in vitro</i> by GSK343 reduces egg laying and decreases the expression of genes implicated in DNA replication and noncoding RNA metabolism

PLoS Neglected Tropical Diseases News - 26 October 2018 - 9:00pm

by Adriana S. A. Pereira, Murilo S. Amaral, Elton J. R. Vasconcelos, David S. Pires, Huma Asif, Lucas F. daSilva, David A. Morales-Vicente, Vitor C. Carneiro, Claudia B. Angeli, Giuseppe Palmisano, Marcelo R. Fantappie, Raymond J. Pierce, João C. Setubal, Sergio Verjovski-Almeida

Background

The possibility of emergence of praziquantel-resistant Schistosoma parasites and the lack of other effective drugs demand the discovery of new schistosomicidal agents. In this context the study of compounds that target histone-modifying enzymes is extremely promising. Our aim was to investigate the effect of inhibition of EZH2, a histone methyltransferase that is involved in chromatin remodeling processes and gene expression control; we tested different developmental forms of Schistosoma mansoni using GKS343, a selective inhibitor of EZH2 in human cells.

Methodology/Principal findings

Adult male and female worms and schistosomula were treated with different concentrations of GSK343 for up to two days in vitro. Western blotting showed a decrease in the H3K27me3 histone mark in all three developmental forms. Motility, mortality, pairing and egg laying were employed as schistosomicidal parameters for adult worms. Schistosomula viability was evaluated with propidium iodide staining and ATP quantification. Adult worms showed decreased motility when exposed to GSK343. Also, an approximate 40% reduction of egg laying by GSK343-treated females was observed when compared with controls (0.1% DMSO). Scanning electron microscopy showed the formation of bulges and bubbles throughout the dorsal region of GSK343-treated adult worms. In schistosomula the body was extremely contracted with the presence of numerous folds, and growth was markedly slowed. RNA-seq was applied to identify the metabolic pathways affected by GSK343 sublethal doses. GSK343-treated adult worms showed significantly altered expression of genes related to transmembrane transport, cellular homeostasis and egg development. In females, genes related to DNA replication and noncoding RNA metabolism processes were downregulated. Schistosomula showed altered expression of genes related to cell adhesion and membrane synthesis pathways.

Conclusions/Significance

The results indicated that GSK343 presents in vitro activities against S. mansoni, and the characterization of EZH2 as a new potential molecular target establishes EZH2 inhibitors as part of a promising new group of compounds that could be used for the development of schistosomicidal agents.

High accuracy of an ELISA test based in a flagella antigen of <i>Leishmania</i> in serodiagnosis of canine visceral leishmaniasis with potential to improve the control measures in Brazil – A Phase II study

PLoS Neglected Tropical Diseases News - 26 October 2018 - 9:00pm

by Lairton Souza Borja, Lívia Brito Coelho, Matheus Silva de Jesus, Artur Trancoso Lopo de Queiroz, Paola Alejandra Fiorani Celedon, Nilson Ivo Tonin Zachin, Edimilson Domingos Silva, Antônio Gomes Pinto Ferreira, Marco Aurélio Krieger, Patrícia Sampaio Tavares Veras, Deborah Bittencourt Mothé Fraga

Background

Canine Visceral leishmaniasis (CVL) is a serious public health problem, thus for its control, the Ministry of Health in Brazil recommends the rapid diagnosis and euthanasia of seropositive dogs in endemic areas. Therefore, our group had previously selected six recombinant proteins (rLci1, rLci2, rLci4, rLci5, rLci8, and rLci12) due to their high potential for CVL diagnostic testing. The present study aims to produce an immunodiagnostic test using the aforementioned antigens, to improve the performance of the diagnosis of CVL recommended by Brazilian Ministry of Health.

Methodology/Principal findings

To evaluate the recombinant proteins in the serological assays, positive and negative samples were selected based on parasitological test (culture) and molecular test (qPCR) of splenic aspirate. Initially, we selected 135 dog serum samples, 73 positives (symptomatic and asymptomatic) and 62 negatives to screen recombinant proteins on ELISA platform. Then, for rLci5 ELISA validation, 361 serum samples collected in a cross-sectional study were selected, being 183 positives (symptomatic and asymptomatic) and 178 negatives. In the screening of the recombinant proteins, rLci5 was the only protein to present a performance statistically higher than the performance presented by EIE-LVC test, presenting 96% (IC 95%; 85–99%) vs. 83% (IC 95%; 69–92%) of sensitivity for symptomatic dogs, 71% (IC 95%; 49–97%) vs. 54% (IC 95%; 33–74%) for asymptomatic dogs and 94% (IC 95%; 83–99%) vs, 88% (IC 95%; 76–95% of specificity. Thus, the rLci5 protein was selected to compose a final ELISA test. Validation of rLci5 ELISA showed 87% (IC 81–91%) of sensitivity, 94% (IC 95%; 90–97%) of specificity and 90% accuracy. Testing the EIE-LVC with the same validation panel, we observed a lower performance when compared to ELISA rLci5 (sensitivity of 67% (IC 95%; 59–74%), specificity of 87% (IC 95%; 81–92%), and accuracy of 77%). Finally, the performance of current CVL diagnostic protocol recommended by Brazilian Ministry of Health, using DPP-LVC as screening test and EIE-LVC as confirmatory test, was compared with a modified protocol, replacing EIE-LVC by rLci5 ELISA. The current protocol presented a sensitivity of 59% (IC 95%; 52–66%), specificity of 98% (IC 95%; 95–99%) and accuracy of 80% (IC 95%; 76–84%), while the modified protocol presented a sensitivity of 71% (IC 95%; 63–77%), specificity of 99% (IC 95%; 97–100%) and accuracy of 86% (IC 95%; 83–89%).

Conclusion

Thus, we concluded that rLci5 ELISA is a promising test to replace EIE-LVC test and increase the diagnostic performance of CVL in Brazil.

Uncharted territory of the epidemiological burden of cutaneous leishmaniasis in sub-Saharan Africa—A systematic review

PLoS Neglected Tropical Diseases News - 25 October 2018 - 9:00pm

by Temmy Sunyoto, Kristien Verdonck, Sayda el Safi, Julien Potet, Albert Picado, Marleen Boelaert

Introduction

Cutaneous leishmaniasis (CL) is the most frequent form of leishmaniasis, with 0.7 to 1.2 million cases per year globally. However, the burden of CL is poorly documented in some regions. We carried out this review to synthesize knowledge on the epidemiological burden of CL in sub-Saharan Africa.

Methods

We systematically searched PubMed, CABI Global health, Africa Index Medicus databases for publications on CL and its burden. There were no restrictions on language/publication date. Case series with less than ten patients, species identification studies, reviews, non-human, and non-CL focused studies were excluded. Findings were extracted and described. The review was conducted following PRISMA guidelines; the protocol was registered in PROSPERO (42016036272).

Results

From 289 identified records, 54 met eligibility criteria and were included in the synthesis. CL was reported from 13 of the 48 sub-Saharan African countries (3 eastern, nine western and one from southern Africa). More than half of the records (30/54; 56%) were from western Africa, notably Senegal, Burkina Faso and Mali. All studies were observational: 29 were descriptive case series (total 13,257 cases), and 24 followed a cross-sectional design. The majority (78%) of the studies were carried out before the year 2000. Forty-two studies mentioned the parasite species, but was either assumed or attributed on the historical account. Regional differences in clinical manifestations were reported. We found high variability across methodologies, leading to difficulties to compare or combine data. The prevalence in hospital settings among suspected cases ranged between 0.1 and 14.2%. At the community level, CL prevalence varied widely between studies. Outbreaks of thousands of cases occurred in Ethiopia, Ghana, and Sudan. Polymorphism of CL in HIV-infected people is a concern. Key information gaps in CL burden here include population-based CL prevalence/incidence, risk factors, and its socio-economic burden.

Conclusion

The evidence on CL epidemiology in sub-Saharan Africa is scanty. The CL frequency and severity are poorly identified. There is a need for population-based studies to define the CL burden better. Endemic countries should consider research and action to improve burden estimation and essential control measures including diagnosis and treatment capacity.

Revisiting human T-cell lymphotropic virus types 1 and 2 infections among rural population in Gabon, central Africa thirty years after the first analysis

PLoS Neglected Tropical Diseases News - 25 October 2018 - 9:00pm

by Melanie Caron, Guillaume Besson, Cindy Padilla, Maria Makuwa, Dieudonne Nkoghe, Eric Leroy, Mirdad Kazanji

HTLV-1 infection is considered as highly endemic in central Africa. Thirty years ago, a first epidemiological study was performed in Gabon, central Africa, and revealed that the prevalence varied from 5.0 to 10.5%. To evaluate current distribution of HTLVs in Gabon, 4.381 samples were collected from rural population living in 220 villages distributed within the 9 provinces of country. HTLVs prevalence was determined using two ELISA tests and positive results were confirmed by Western Blot. The overall HTLV-1 seroprevalence was of 7.3% among the rural Gabonese population; with 5.4% for men and 9.0% for women. Prevalence of HTLV-1 differed by province, ranging from 2.3% to 12.5% into the rain forest. Being a woman older than 51 years represented a high risk for HTLV-1 acquisition. Hospitalization, operation/surgery, transfusion and medical abortion or fever, arthritis and abdominal pain are also significant risk factors. In addition, 0.1% of samples were found as HTLV-2 positive, while 12.0% had an indeterminate HTLV serological pattern. HTLV-3 and HTLV-4 were not found. Phylogenetic analysis was performed on 87 samples and demonstrated that HTLV-1 present in Gabon belongs mostly to subtype B, however the rare subtype D was also found. Altogether, our results demonstrate that almost thirty years after the first epidemiological study prevention of HTLVs infection is still an issue in Gabon.

SIV/SHIV-Zika co-infection does not alter disease pathogenesis in adult non-pregnant rhesus macaque model

PLoS Neglected Tropical Diseases News - 25 October 2018 - 9:00pm

by Mehdi R. M. Bidokhti, Debashis Dutta, Lepakshe S. V. Madduri, Shawna M. Woollard, Robert Norgren Jr., Luis Giavedoni, Siddappa N. Byrareddy

Due to the large geographical overlap of populations exposed to Zika virus (ZIKV) and human immunodeficiency virus (HIV), understanding the disease pathogenesis of co-infection is urgently needed. This warrants the development of an animal model for HIV-ZIKV co-infection. In this study, we used adult non-pregnant macaques that were chronically infected with simian immunodeficiency virus/chimeric simian human immunodeficiency virus (SIV/SHIV) and then inoculated with ZIKV. Plasma viral loads of both SIV/SHIV and ZIKV co-infected animals revealed no significant changes as compared to animals that were infected with ZIKV alone or as compared to SIV/SHIV infected animals prior to ZIKV inoculation. ZIKV tissue clearance of co-infected animals was similar to animals that were infected with ZIKV alone. Furthermore, in co-infected macaques, there was no statistically significant difference in plasma cytokines/chemokines levels as compared to prior to ZIKV inoculation. Collectively, these findings suggest that co-infection may not alter disease pathogenesis, thus warranting larger HIV-ZIKV epidemiological studies in order to validate these findings.

From recognition to action: A strategic approach to foster sustainable collaborations for rabies elimination

PLoS Neglected Tropical Diseases News - 25 October 2018 - 9:00pm

by Rany Octaria, Stephanie J. Salyer, Jesse Blanton, Emily G. Pieracci, Peninah Munyua, Max Millien, Louis Nel, Ryan M. Wallace

Knowledge, attitude and practices of snakebite management amongest health workers in Cameroon: Need for continuous training and capacity building

PLoS Neglected Tropical Diseases News - 25 October 2018 - 9:00pm

by Fabien Taieb, Timothée Dub, Yoann Madec, Laura Tondeur, Jean Philippe Chippaux, Matthew Lebreton, Raphael Medang, Françoise Ngnedjou Nwabufo Foute, Désiré Tchoffo, Julien Potet, Gabriel Alcoba, Eric Comte, Ellen M. Einterz, Armand S. Nkwescheu

Background

Snakebite has only recently been recognized as a neglected tropical disease by the WHO. Knowledge regarding snakebites and its care is poor both at the population level, and at the health care staff level. The goal of this study was to describe the level of knowledge and clinical practice regarding snakebite among health care staff from Cameroon.

Methods

A two-day training dedicated to snakebite and its care was organized in 2015 in Yaoundé, capital city of Cameroon. A total of 98 health care staff from all over Cameroon attended the training. Prior to and after the training, an evaluation quantified the attendees’ level of knowledge. Pre- and post-training evaluations were compared to assess knowledge improvement.

Results

Overall, prior to the training knowledge regarding snakebite and care was poor, and wrong beliefs that “pierre noire” or tourniquet were useful in case of snakebite were common. Knowledge was statistically improved after the training.

Conclusion

Trainings dedicated to all type of health care staff towards snakebite to improve care are needed, this training must take into consideration the context and the targeted population.

The recently identified flavivirus Bamaga virus is transmitted horizontally by <i>Culex</i> mosquitoes and interferes with West Nile virus replication <i>in vitro</i> and transmission <i>in vivo</i>

PLoS Neglected Tropical Diseases News - 24 October 2018 - 9:00pm

by Agathe M. G. Colmant, Sonja Hall-Mendelin, Scott A. Ritchie, Helle Bielefeldt-Ohmann, Jessica J. Harrison, Natalee D. Newton, Caitlin A. O’Brien, Chris Cazier, Cheryl A. Johansen, Jody Hobson-Peters, Roy A. Hall, Andrew F. van den Hurk

Arthropod-borne flaviviruses such as yellow fever (YFV), Zika and dengue viruses continue to cause significant human disease globally. These viruses are transmitted by mosquitoes when a female imbibes an infected blood-meal from a viremic vertebrate host and expectorates the virus into a subsequent host. Bamaga virus (BgV) is a flavivirus recently discovered in Culex sitiens subgroup mosquitoes collected from Cape York Peninsula, Australia. This virus phylogenetically clusters with the YFV group, but is potentially restricted in most vertebrates. However, high levels of replication in an opossum cell line (OK) indicate a potential association with marsupials. To ascertain whether BgV could be horizontally transmitted by mosquitoes, the vector competence of two members of the Cx. sitiens subgroup, Cx. annulirostris and Cx. sitiens, for BgV was investigated. Eleven to thirteen days after imbibing an infectious blood-meal, infection rates were 11.3% and 18.8% for Cx. annulirostris and Cx. sitiens, respectively. Cx. annulirostris transmitted the virus at low levels (5.6% had BgV-positive saliva overall); Cx. sitiens did not transmit the virus. When mosquitoes were injected intrathoracially with BgV, the infection and transmission rates were 100% and 82%, respectively, for both species. These results provided evidence for the first time that BgV can be transmitted horizontally by Cx. annulirostris, the primary vector of pathogenic zoonotic flaviviruses in Australia. We also assessed whether BgV could interfere with replication in vitro, and infection and transmission in vivo of super-infecting pathogenic Culex-associated flaviviruses. BgV significantly reduced growth of Murray Valley encephalitis and West Nile (WNV) viruses in vitro. While prior infection with BgV by injection did not inhibit WNV super-infection of Cx. annulirostris, significantly fewer BgV-infected mosquitoes could transmit WNV than mock-injected mosquitoes. Overall, these data contribute to our understanding of flavivirus ecology, modes of transmission by Australian mosquitoes and mechanisms for super-infection interference.

Spatial heterogeneity of hemorrhagic fever with renal syndrome is driven by environmental factors and rodent community composition

PLoS Neglected Tropical Diseases News - 24 October 2018 - 9:00pm

by Hong Xiao, Xin Tong, Lidong Gao, Shixiong Hu, Hua Tan, Zheng Y. X. Huang, Guogang Zhang, Qiqi Yang, Xinyao Li, Ru Huang, Shilu Tong, Huaiyu Tian

Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne disease caused mainly by two hantaviruses in China: Hantaan virus and Seoul virus. Environmental factors can significantly affect the risk of contracting hantavirus infections, primarily through their effects on rodent population dynamics and human-rodent contact. We aimed to clarify the environmental risk factors favoring rodent-to-human transmission to provide scientific evidence for developing effective HFRS prevention and control strategies. The 10-year (2006–2015) field surveillance data from the rodent hosts for hantavirus, the epidemiological and environmental data extracted from satellite images and meteorological stations, rodent-to-human transmission rates and impacts of the environment on rodent community composition were used to quantify the relationships among environmental factors, rodent species and HFRS occurrence. The study included 709 cases of HFRS. Rodent species in Chenzhou, a hantavirus hotspot, comprise mainly Rattus norvegicus, Mus musculus, R. flavipectus and some other species (R. losea and Microtus fortis calamorum). The rodent species played different roles across the various land types we examined, but all of them were associated with transmission risks. Some species were associated with HFRS occurrence risk in forest and water bodies. R. norvegicus and R. flavipectus were associated with risk of HFRS incidence in grassland, whereas M. musculus and R. flavipectus were associated with this risk in built-on land. The rodent community composition was also associated with environmental variability. The predictive risk models based on these significant factors were validated by a good-fit model, where: cultivated land was predicted to represent the highest risk for HFRS incidence, which accords with the statistics for HFRS cases in 2014–2015. The spatial heterogeneity of HFRS disease may be influenced by rodent community composition, which is associated with local environmental conditions. Therefore, future work should focus on preventing HFRS is moist, warm environments.

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