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Immunogenicity and efficacy following sequential parenterally-administered doses of <i>Salmonella</i> Enteritidis COPS:FliC glycoconjugates in infant and adult mice

PLoS Neglected Tropical Diseases News - 23 May 2018 - 9:00pm

by Scott M. Baliban, Brittany Curtis, Deanna Toema, Sharon M. Tennant, Myron M. Levine, Marcela F. Pasetti, Raphael Simon

In sub-Saharan Africa, invasive nontyphoidal Salmonella (iNTS) infections with serovars S. Enteritidis, S. Typhimurium and I 4,[5],12:i:- are widespread in children < 5 years old. Development of an efficacious vaccine would provide an important public health tool to prevent iNTS disease in this population. Glycoconjugates of S. Enteritidis core and O-polysaccharide (COPS) coupled to the homologous serovar phase 1 flagellin protein (FliC) were previously shown to be immunogenic and protected adult mice against death following challenge with a virulent Malian S. Enteritidis blood isolate. This study extends these observations to immunization of mice in early life and also assesses protection with partial and full regimens. Anti-COPS and anti-FliC serum IgG titers were assessed in infant and adult mice after immunization with 1, 2 or 3 doses of S. Enteritidis COPS:FliC alone or co-formulated with aluminum hydroxide or monophosphoryl lipid A (MPL) adjuvants. S. Enteritidis COPS:FliC was immunogenic in both age groups, although the immune responses were quantitatively lower in infants. Kinetics of antibody production were similar for the native and adjuvanted formulations after three doses; conjugates formulated with MPL elicited significantly increased anti-COPS IgG titers in adult but not infant mice. Nevertheless, robust protection against S. Enteritidis challenge was seen for all three formulations when three doses were given either during infancy or as adults. We further found that significant protection could be achieved with two COPS:FliC doses, despite elicitation of modest serum anti-COPS IgG antibody titers. These findings guide potential immunization strategies that may be translated to develop a human pediatric iNTS vaccine for sub-Saharan Africa.

Cost-effectiveness of dog rabies vaccination programs in East Africa

PLoS Neglected Tropical Diseases News - 23 May 2018 - 9:00pm

by Rebekah H. Borse, Charisma Y. Atkins, Manoj Gambhir, Eduardo A. Undurraga, Jesse D. Blanton, Emily B. Kahn, Jessie L. Dyer, Charles E. Rupprecht, Martin I. Meltzer

Background

Dog rabies annually causes 24,000–70,000 deaths globally. We built a spreadsheet tool, RabiesEcon, to aid public health officials to estimate the cost-effectiveness of dog rabies vaccination programs in East Africa.

Methods

RabiesEcon uses a mathematical model of dog-dog and dog-human rabies transmission to estimate dog rabies cases averted, the cost per human rabies death averted and cost per year of life gained (YLG) due to dog vaccination programs (US 2015 dollars). We used an East African human population of 1 million (approximately 2/3 living in urban setting, 1/3 rural). We considered, using data from the literature, three vaccination options; no vaccination, annual vaccination of 50% of dogs and 20% of dogs vaccinated semi-annually. We assessed 2 transmission scenarios: low (1.2 dogs infected per infectious dog) and high (1.7 dogs infected). We also examined the impact of annually vaccinating 70% of all dogs (World Health Organization recommendation for dog rabies elimination).

Results

Without dog vaccination, over 10 years there would a total of be approximately 44,000–65,000 rabid dogs and 2,100–2,900 human deaths. Annually vaccinating 50% of dogs results in 10-year reductions of 97% and 75% in rabid dogs (low and high transmissions scenarios, respectively), approximately 2,000–1,600 human deaths averted, and an undiscounted cost-effectiveness of $451-$385 per life saved. Semi-annual vaccination of 20% of dogs results in in 10-year reductions of 94% and 78% in rabid dogs, and approximately 2,000–1,900 human deaths averted, and cost $404-$305 per life saved. In the low transmission scenario, vaccinating either 50% or 70% of dogs eliminated dog rabies. Results were most sensitive to dog birth rate and the initial rate of dog-to-dog transmission (Ro).

Conclusions

Dog rabies vaccination programs can control, and potentially eliminate, dog rabies. The frequency and coverage of vaccination programs, along with the level of dog rabies transmission, can affect the cost-effectiveness of such programs. RabiesEcon can aid both the planning and assessment of dog rabies vaccination programs.

The human-snail transmission environment shapes long term schistosomiasis control outcomes: Implications for improving the accuracy of predictive modeling

PLoS Neglected Tropical Diseases News - 21 May 2018 - 9:00pm

by David Gurarie, Nathan C. Lo, Martial L. Ndeffo-Mbah, David P. Durham, Charles H. King

Introduction

Schistosomiasis is a chronic parasitic trematode disease that affects over 240 million people worldwide. The Schistosoma lifecycle is complex, involving transmission via specific intermediate-host freshwater snails. Predictive mathematical models of Schistosoma transmission have often chosen to simplify or ignore the details of environmental human-snail interaction in their analyses. Schistosome transmission models now aim to provide better precision for policy planning of elimination of transmission. This heightens the importance of including the environmental complexity of vector-pathogen interaction in order to make more accurate projections.

Methodology and principal findings

We propose a nonlinear snail force of infection (FOI) that takes into account an intermediate larval stage (miracidium) and snail biology. We focused, in particular, on the effects of snail force of infection (FOI) on the impact of mass drug administration (MDA) in human communities. The proposed (modified) model was compared to a conventional model in terms of their predictions. A longitudinal dataset generated in Kenya field studies was used for model calibration and validation. For each sample community, we calibrated modified and conventional model systems, then used them to model outcomes for a range of MDA regimens. In most cases, the modified model predicted more vigorous post-MDA rebound, with faster relapse to baseline levels of infection. The effect was pronounced in higher risk communities. When compared to observed data, only the modified system was able to successfully predict persistent rebound of Schistosoma infection.

Conclusion and significance

The observed impact of varying location-specific snail inputs sheds light on the diverse MDA response patterns noted in operational research on schistosomiasis control, such as the recent SCORE project. Efficiency of human-to-snail transmission is likely to be much higher than predicted by standard models, which, in practice, will make local elimination by implementation of MDA alone highly unlikely, even over a multi-decade period.

Development of a toolkit for <i>piggyBac</i>-mediated integrative transfection of the human filarial parasite <i>Brugia malayi</i>

PLoS Neglected Tropical Diseases News - 21 May 2018 - 9:00pm

by Canhui Liu, Amruta S. Mhashilkar, Johan Chabanon, Shulin Xu, Sara Lustigman, John H. Adams, Thomas R. Unnasch

Background

The human filarial parasites cause diseases that are among the most important causes of morbidity in the developing world. The elimination programs targeting these infections rely on a limited number of drugs, making the identification of new chemotherapeutic agents a high priority. The study of these parasites has lagged due to the lack of reverse genetic methods.

Methodology/Principal findings

We report a novel co-culture method that results in developmentally competent infective larvae of one of the human filarial parasites (Brugia malayi) and describe a method to efficiently transfect the larval stages of this parasite. We describe the production of constructs that result in integrative transfection using the piggyBac transposon system, and a selectable marker that can be used to identify transgenic parasites. We describe the production and use of dual reporter plasmids containing both a secreted luciferase selectable marker and fluorescent protein reporters that will be useful to study temporal and spatial patterns of gene expression.

Conclusions/Significance

The methods and constructs reported here will permit the efficient production of integrated transgenic filarial parasite lines, allowing reverse genetic technologies to be applied to all life cycle stages of the parasite.

Regulation of midgut cell proliferation impacts <i>Aedes aegypti</i> susceptibility to dengue virus

PLoS Neglected Tropical Diseases News - 21 May 2018 - 9:00pm

by Mabel L. Taracena, Vanessa Bottino-Rojas, Octavio A. C. Talyuli, Ana Beatriz Walter-Nuno, José Henrique M. Oliveira, Yesseinia I. Angleró-Rodriguez, Michael B. Wells, George Dimopoulos, Pedro L. Oliveira, Gabriela O. Paiva-Silva

Aedes aegypti is the vector of some of the most important vector-borne diseases like dengue, chikungunya, zika and yellow fever, affecting millions of people worldwide. The cellular processes that follow a blood meal in the mosquito midgut are directly associated with pathogen transmission. We studied the homeostatic response of the midgut against oxidative stress, as well as bacterial and dengue virus (DENV) infections, focusing on the proliferative ability of the intestinal stem cells (ISC). Inhibition of the peritrophic matrix (PM) formation led to an increase in reactive oxygen species (ROS) production by the epithelial cells in response to contact with the resident microbiota, suggesting that maintenance of low levels of ROS in the intestinal lumen is key to keep ISCs division in balance. We show that dengue virus infection induces midgut cell division in both DENV susceptible (Rockefeller) and refractory (Orlando) mosquito strains. However, the susceptible strain delays the activation of the regeneration process compared with the refractory strain. Impairment of the Delta/Notch signaling, by silencing the Notch ligand Delta using RNAi, significantly increased the susceptibility of the refractory strains to DENV infection of the midgut. We propose that this cell replenishment is essential to control viral infection in the mosquito. Our study demonstrates that the intestinal epithelium of the blood fed mosquito is able to respond and defend against different challenges, including virus infection. In addition, we provide unprecedented evidence that the activation of a cellular regenerative program in the midgut is important for the determination of the mosquito vectorial competence.

Molecular, immunological and neurophysiological evaluations for early diagnosis of neural impairment in seropositive leprosy household contacts

PLoS Neglected Tropical Diseases News - 21 May 2018 - 9:00pm

by Diogo Fernandes dos Santos, Matheus Rocha Mendonça, Douglas Eulálio Antunes, Elaine Fávaro Pípi Sabino, Raquel Campos Pereira, Luiz Ricardo Goulart, Isabela Maria Bernardes Goulart

Background

Household contacts constitute the highest risk group for leprosy development, and despite significant progress in the disease control, early diagnosis remains the primary goals for leprosy management programs.

Methods

We have recruited 175 seropositive and 35 seronegative household contacts from 2014 to 2016, who were subjected to an extensive protocol that included clinical, molecular (peripheral blood qPCR, slit-skin smear qPCR, skin biopsy qPCR) and electroneuromyographic evaluations.

Results/Principal findings

The positivity of peripheral blood qPCR of seropositive contacts was 40.6% (71/175) whereas only 8.6% (3/35) were qPCR positive in seronegative contacts (p = 0.0003). For the slit-skin smear, only 4% (7/175) of seropositive contacts presented positive bacilloscopy, whereas the qPCR detected 47.4% (83/175) positivity in this group compared with only 17.1% (6/35) in seronegative contacts (p = 0.0009). In the ENMG evaluation of contacts, 31.4% (55/175) of seropositives presented some neural impairment, and 13.3% (4/35) in seronegatives (p = 0.0163). The presence of neural thickening conferred a 2.94-fold higher chance of ENMG abnormality (p = 0.0031). Seropositive contacts presented a 4.04-fold higher chance of neural impairment (p = 0.0206). The peripheral blood qPCR positivity presented odds 2.08-fold higher towards neural impairment (OR, 2.08; p = 0.028). Contrarily, the presence of at least one BCG vaccine scar demonstrated 2.44-fold greater protection against neural impairment (OR = 0.41; p = 0.044).

Conclusions/Sgnificance

ELISA anti-PGL-I is the most important test in determining the increased chance of neural impairment in asymptomatic leprosy household contacts. The combination of the two assays (ELISA anti-PGL-I and peripheral blood qPCR) and the presence of BCG scar may identify individuals with higher chances of developing leprosy neuropathy, corroborating with the early diagnosis and treatment.

Dissecting the phyloepidemiology of <i>Trypanosoma cruzi</i> I (TcI) in Brazil by the use of high resolution genetic markers

PLoS Neglected Tropical Diseases News - 21 May 2018 - 9:00pm

by Fabiola Roman, Samanta das Chagas Xavier, Louisa A. Messenger, Márcio G. Pavan, Michael A. Miles, Ana María Jansen, Matthew Yeo

Background

Trypanosoma cruzi, the causal agent of Chagas disease, is monophyletic but genetically heterogeneous. It is currently represented by six genetic lineages (Discrete Typing Units, DTUs) designated TcI-TcVI. TcI is the most geographically widespread and genetically heterogeneous lineage, this as is evidenced by a wide range of genetic markers applied to isolates spanning a vast geographic range in Latin America.

Methodology/Principal findings

In total, 78 TcI isolated from hosts and vectors distributed in 5 different biomes of Brazil, were analyzed using 6 nuclear housekeeping genes, 25 microsatellite loci and one mitochondrial marker. Nuclear markers reveal substantial genetic diversity, significant gene flow between biomes, incongruence in phylogenies, and haplotypic analysis indicative of intra-DTU genetic exchange. Phylogenetic reconstructions based on mitochondrial and nuclear loci were incongruent, and consistent with introgression. Structure analysis of microsatellite data reveals that, amongst biomes, the Amazon is the most genetically diverse and experiences the lowest level of gene flow. Investigation of population structure based on the host species/genus, indicated that Didelphis marsupialis might play a role as the main disperser of TcI.

Conclusions/Significance

The present work considers a large TcI sample from different hosts and vectors spanning multiple ecologically diverse biomes in Brazil. Importantly, we combine fast and slow evolving markers to contribute to the epizootiological understanding of TcI in five distinct Brazilian biomes. This constitutes the first instance in which MLST analysis was combined with the use of MLMT and maxicircle markers to evaluate the genetic diversity of TcI isolates in Brazil. Our results demonstrate the existence of substantial genetic diversity and the occurrence of introgression events. We provide evidence of genetic exchange in TcI isolates from Brazil and of the relative isolation of TcI in the Amazon biome. We observe the absence of strict associations with TcI genotypes to geographic areas and/or host species.

Molecular detection of <i>Mycobacterium ulcerans</i> in the environment and its relationship with Buruli ulcer occurrence in Zio and Yoto districts of maritime region in Togo

PLoS Neglected Tropical Diseases News - 21 May 2018 - 9:00pm

by Issaka Maman, Tchadjobo Tchacondo, Abiba Banla Kere, Marcus Beissner, Kossi Badziklou, Ekanao Tedihou, Edith Nyaku, Komi Amekuse, Franz Xaver Wiedemann, Damintoti Simplice Karou, Gisela Bretzel

Background

Buruli Ulcer (BU) is a neglected tropical skin infection caused by Mycobacterium ulcerans. Residence near aquatic areas has been identified as an important source of transmission of M. ulcerans with increased risk of contracting Buruli ulcer. However, the reservoir and the mode of transmission are not yet well known. The aim of this study was to identify the presence of M. ulcerans in the environment and its relationship with Buruli ulcer occurrence in Zio and Yoto districts of the maritime region in south Togo.

Methods

A total of 219 environmental samples including soil (n = 119), water (n = 65), biofilms/plants (n = 29) and animals’ feces (n = 6) were collected in 17 villages of Zio and Yoto districts of the maritime region in Togo. DNA of M. ulcerans including IS2404 and IS2606 insertions sequences and mycolactone ketoreductase-B gene (KR-B) was detected using real time PCR amplification (qPCR) technique. In parallel, clinical samples of patients were tested to establish a comparison of the genetic profile of M. ulcerans between the two types of samples. A calibration curve was generated for IS2404 from a synthetic gene of M. ulcerans Transposase pMUM001, the plasmid of virulence.

Results

In the absence of inhibition of the qPCR, 6/219 (2.7%) samples were tested positive for M. ulcerans DNA containing three sequences (IS2404/IS2606/KR-B). Positive samples of M. ulcerans were consisting of biofilms/plants (3/29; 10.3%), water (1/65; 1.7%) and soil (2/119; 1.5%). Comparative analysis between DNA detected in environmental and clinical samples from BU patients showed the same genetic profile of M. ulcerans in the same environment. All these samples were collected in the environment of Haho and Zio rivers in the maritime region.

Conclusion

This study confirms the presence of M. ulcerans in the environment of the Zio and Yoto districts of the maritime region of Togo. This may explain partially, the high rates of Buruli ulcer patients in this region. Also, water, plants and soil along the rivers could be possible reservoirs of the bacterium. Therefore, Haho and Zio rivers could be potential sources of infection with M. ulcerans in humans in these districts.

<i>In vivo</i> and <i>in vitro</i> studies of Cry5B and nicotinic acetylcholine receptor agonist anthelmintics reveal a powerful and unique combination therapy against intestinal nematode parasites

PLoS Neglected Tropical Diseases News - 18 May 2018 - 9:00pm

by Yan Hu, Melanie Miller, Bo Zhang, Thanh-Thanh Nguyen, Martin K. Nielsen, Raffi V. Aroian

Background

The soil-transmitted nematodes (STNs) or helminths (hookworms, whipworms, large roundworms) infect the intestines of ~1.5 billion of the poorest peoples and are leading causes of morbidity worldwide. Only one class of anthelmintic or anti-nematode drugs, the benzimidazoles, is currently used in mass drug administrations, which is a dangerous situation. New anti-nematode drugs are urgently needed. Bacillus thuringiensis crystal protein Cry5B is a powerful, promising new candidate. Drug combinations, when properly made, are ideal for treating infectious diseases. Although there are some clinical trials using drug combinations against STNs, little quantitative and systemic work has been performed to define the characteristics of these combinations in vivo.

Methodology/Principal findings

Working with the hookworm Ancylostoma ceylanicum-hamster infection system, we establish a laboratory paradigm for studying anti-nematode combinations in vivo using Cry5B and the nicotinic acetylcholine receptor (nAChR) agonists tribendimidine and pyrantel pamoate. We demonstrate that Cry5B strongly synergizes in vivo with both tribendimidine and pyrantel at specific dose ratios against hookworm infections. For example, whereas 1 mg/kg Cry5B and 1 mg/kg tribendimidine individually resulted in only a 0%-6% reduction in hookworm burdens, the combination of the two resulted in a 41% reduction (P = 0.020). Furthermore, when mixed at synergistic ratios, these combinations eradicate hookworm infections at doses where the individual doses do not. Using cyathostomin nematode parasites of horses, we find based on inhibitory concentration 50% values that a strongylid parasite population doubly resistant to nAChR agonists and benzimidazoles is more susceptible or “hypersusceptible” to Cry5B than a cyathostomin population not resistant to nAChR agonists, consistent with previous Caenhorhabditis elegans results.

Conclusions/Significance

Our study provides a powerful means by which anthelmintic combination therapies can be examined in vivo in the laboratory. In addition, we demonstrate that Cry5B and nAChR agonists have excellent combinatorial properties—Cry5B combined with nAChR agonists gives rise to potent cures that are predicted to be recalcitrant to the development of parasite resistance. These drug combinations highlight bright spots in new anthelmintic development for human and veterinary animal intestinal nematode infections.

<i>Ts</i>-Hsp70 induces protective immunity against <i>Trichinella spiralis</i> infection in mouse by activating dendritic cells through TLR2 and TLR4

PLoS Neglected Tropical Diseases News - 18 May 2018 - 9:00pm

by Rui Zhang, Qing Sun, Yi Chen, Ximeng Sun, Yuan Gu, Zhang Zhao, Yuli Cheng, Limei Zhao, Jingjing Huang, Bin Zhan, Xinping Zhu

Background

Trichinellosis is a serious food-borne parasitic zoonosis worldwide. In the effort to develop vaccine against Trichinella infection, we have identified Trichinella spiralis Heat shock protein 70 (Ts-Hsp70) elicits partial protective immunity against T. spiralis infection via activating dendritic cells (DCs) in our previous study. This study aims to investigate whether DCs were activated by Ts-Hsp70 through TLR2 and/or TLR4 pathways.

Methods and findings

After blocking with anti-TLR2 and TLR4 antibodies, the binding of Ts-Hsp70 to DCs was significantly reduced. The reduced binding effects were also found in TLR2 and TLR4 knockout (TLR2-/- and TLR4-/-) DCs. The expression of TLR2 and TLR4 on DCs was upregulated after treatment with Ts-Hsp70 in vitro. These results suggest that Ts-Hsp70 is able to directly bind to TLR2 and TLR4 on the surface of mouse bone morrow-derived DCs. In addition, the expression of the co-stimulatory molecules (CD80, CD83) on Ts-Hsp70-induced DCs was reduced in TLR2-/- and TLR4-/- mice. More evidence showed that Ts-Hsp70 reduced its activation on TLR2/4 knockout DCs to subsequently activate the naïve T-cells. Furthermore, Ts-Hsp70 elicited protective immunity against T. spiralis infection was reduced in TLR2-/- and TLR4-/- mice correlating with the reduced humoral and cellular immune responses.

Conclusion

This study demonstrates that Ts-Hsp70 activates DCs through TLR2 and TLR4, and TLR2 and TLR4 play important roles in Ts-Hsp70-induced DCs activation and immune responses.

Skin disease prevalence study in schoolchildren in rural Côte d'Ivoire: Implications for integration of neglected skin diseases (skin NTDs)

PLoS Neglected Tropical Diseases News - 17 May 2018 - 9:00pm

by Rie Roselyne Yotsu, Kouamé Kouadio, Bamba Vagamon, Konan N’guessan, Amari Jules Akpa, Aubin Yao, Julien Aké, Rigobert Abbet Abbet, Barbine Tchamba Agbor Agbor, Roger Bedimo, Norihisa Ishii, L. Claire Fuller, Roderick Hay, Oriol Mitjà, Henning Drechsler, Kingsley Asiedu

Background

Early detection of several skin-related neglected tropical diseases (skin NTDs)–including leprosy, Buruli ulcer, yaws, and scabies- may be achieved through school surveys, but such an approach has seldom been tested systematically on a large scale in endemic countries. Additionally, a better understanding of the spectrum of skin diseases and the at-risk populations to be encountered during such surveys is necessary to facilitate the process.

Methods

We performed a school skin survey for selected NTDs and the spectrum of skin diseases, among primary schoolchildren aged 5 to 15 in Côte d’Ivoire, West Africa. This 2-phase survey took place in 49 schools from 16 villages in the Adzopé health district from November 2015 to January 2016. The first phase involved a rapid visual examination of the skin by local community healthcare workers (village nurses) to identify any skin abnormality. In a second phase, a specialized medical team including dermatologists performed a total skin examination of all screened students with any skin lesion and provided treatment where necessary.

Results

Of a total of 13,019 children, 3,504 screened positive for skin lesions and were listed for the next stage examination. The medical team examined 1,138 of these children. The overall prevalence of skin diseases was 25.6% (95% CI: 24.3–26.9%). The predominant diagnoses were fungal infections (n = 858, prevalence: 22.3%), followed by inflammatory skin diseases (n = 265, prevalence: 6.9%). Skin diseases were more common in boys and in children living along the main road with heavy traffic. One case of multi-bacillary type leprosy was detected early, along with 36 cases of scabies. Our survey was met with very good community acceptance.

Conclusion

We carried out the first large-scale integrated, two-phase pediatric multi-skin NTD survey in rural Côte d’Ivoire, effectively reaching a large population. We found a high prevalence of skin diseases in children, but only limited number of skin NTDs. With the lessons learned, we plan to expand the project to a wider area to further explore its potential to better integrate skin NTD screening in the public health agenda.

Mosquito saliva alone has profound effects on the human immune system

PLoS Neglected Tropical Diseases News - 17 May 2018 - 9:00pm

by Megan B. Vogt, Anismrita Lahon, Ravi P. Arya, Alexander R. Kneubehl, Jennifer L. Spencer Clinton, Silke Paust, Rebecca Rico-Hesse

Mosquito saliva is a very complex concoction of >100 proteins, many of which have unknown functions. The effects of mosquito saliva proteins injected into our skin during blood feeding have been studied mainly in mouse models of injection or biting, with many of these systems producing results that may not be relevant to human disease. Here, we describe the numerous effects that mosquito bites have on human immune cells in mice engrafted with human hematopoietic stem cells. We used flow cytometry and multiplex cytokine bead array assays, with detailed statistical analyses, to detect small but significant variations in immune cell functions after 4 mosquitoes fed on humanized mice footpads. After preliminary analyses, at different early times after biting, we focused on assessing innate immune and subsequent cellular responses at 6 hours, 24 hours and 7 days after mosquito bites. We detected both Th1 and Th2 human immune responses, and delayed effects on cytokine levels in the blood, and immune cell compositions in the skin and bone marrow, up to 7 days post-bites. These are the first measurements of this kind, with human immune responses in whole animals, bitten by living mosquitoes, versus previous studies using incomplete mouse models and salivary gland extracts or needle injected saliva. The results have major implications for the study of hematophagous insect saliva, its effects on the human immune system, with or without pathogen transmission, and the possibility of determining which of these proteins to target for vaccination, in attempts to block transmission of numerous tropical diseases.

Efficacy of ivermectin mass-drug administration to control scabies in asylum seekers in the Netherlands: A retrospective cohort study between January 2014 – March 2016

PLoS Neglected Tropical Diseases News - 17 May 2018 - 9:00pm

by Dorien T. Beeres, Sofanne J. Ravensbergen, Annelies Heidema, Darren Cornish, Machiel Vonk, Leonie D. Wijnholds, Jessica J. H. Hendriks, Johanneke Kleinnijenhuis, Till F. Omansen, Ymkje Stienstra

Scabies is a skin infestation with the mite Sarcoptes scabiei causing itch and rash and is a major risk factor for bacterial skin infections and severe complications. Here, we evaluated the treatment outcome of 2866 asylum seekers who received (preventive) scabies treatment before and during a scabies intervention programme (SIP) in the main reception centre in the Netherlands between January 2014 and March 2016. A SIP was introduced in the main national reception centre based on frequent observations of scabies and its complications amongst Eritrean and Ethiopian asylum seekers in the Netherlands. On arrival, all asylum seekers from Eritrea or Ethiopia were checked for clinical scabies signs and received ivermectin/permethrin either as prevention or treatment. A retrospective cohort study was conducted to compare the reinfestations and complications of scabies in asylum seekers who entered the Netherlands before and during the intervention and who received ivermectin/permethrin. In total, 2866 asylum seekers received treatment during the study period (January 2014 –March 2016) of which 1359 (47.4%) had clinical signs of scabies. During the programme, most of the asylum seekers with scabies were already diagnosed on arrival as part of the SIP screening (580 (64.7%) of the 897). Asylum seekers with more than one scabies episode reduced from 42.0% (194/462) before the programme to 27.2% (243/897) during the programme (RR = 0.64, 95% CI = 0.55–0.75). Development of scabies complications later in the asylum procedure reduced from 12.3% (57/462) to 4.6% (41/897). A scabies prevention and treatment programme at start of the asylum procedure was feasible and effective in the Netherlands; patients were diagnosed early and risk of reinfestations and complications reduced. To achieve a further decrease of scabies, implementation of the programme in multiple asylum centres may be needed.

Ethics of randomized trials in a public health emergency

PLoS Neglected Tropical Diseases News - 17 May 2018 - 9:00pm

by Alex John London, Olayemi O. Omotade, Michelle M. Mello, Gerald T. Keusch

Silencing of RpATG6 impaired the yolk accumulation and the biogenesis of the yolk organelles in the insect vector <i>R</i>. <i>prolixus</i>

PLoS Neglected Tropical Diseases News - 16 May 2018 - 9:00pm

by Priscila H. Vieira, Larissa Bomfim, Georgia C. Atella, Hatisaburo Masuda, Isabela Ramos

In oviparous animals, the egg yolk is synthesized by the mother in a major metabolic challenge, where the different yolk components are secreted to the hemolymph and delivered to the oocytes mostly by endocytosis. The yolk macromolecules are then stored in a wide range of endocytic-originated vesicles which are collectively referred to as yolk organelles and occupy most of the mature oocytes cytoplasm. After fertilization, the contents of these organelles are degraded in a regulated manner to supply the embryo cells with fundamental molecules for de novo synthesis. Yolk accumulation and its regulated degradation are therefore crucial for successful development, however, most of the molecular mechanisms involved in the biogenesis, sorting and degradation of targeted yolk organelles are still poorly understood. ATG6 is part of two PI3P-kinase complexes that can regulate the recruitment of the endocytic or the autophagy machineries. Here, we investigate the role of RpATG6 in the endocytosis of the yolk macromolecules and in the biogenesis of the yolk organelles in the insect vector Rhodnius prolixus. We found that vitellogenic females express high levels of RpATG6 in the ovaries, when compared to the levels detected in the midgut and fat body. RNAi silencing of RpATG6 resulted in yolk proteins accumulated in the vitellogenic hemolymph, as a consequence of poor uptake by the oocytes. Accordingly, the silenced oocytes are unviable, white (contrasting to the control pink oocytes), smaller (62% of the control oocyte volume) and accumulate only 40% of the yolk proteins, 80% of the TAG and 50% of the polymer polyphosphate quantified in control oocytes. The cortex of silenced oocytes present atypical smaller vesicles indicating that the yolk organelles were not properly formed and/or sorted, which was supported by the lack of endocytic vesicles near the plasma membrane of silenced oocytes as seen by TEM. Altogether, we found that RpATG6 is central for the mechanisms of yolk accumulation, emerging as an important target for further investigations on oogenesis and, therefore, reproduction of this vector.

A secreted Heat shock protein 90 of <i>Trichomonas vaginalis</i>

PLoS Neglected Tropical Diseases News - 16 May 2018 - 9:00pm

by Meetali Singh, Divya Beri, Rishi Kumar Nageshan, Leena Chavaan, Darshak Gadara, Mukta Poojary, Suraj Subramaniam, Utpal Tatu

Trichomonas vaginalis is a causative agent of Trichomoniasis, a leading non-viral sexually transmitted disease worldwide. In the current study, we show Heat shock protein 90 is essential for its growth. Upon genomics analysis of the parasite, it was found to possess seven ORFs which could potentially encode Hsp90 isoforms. We identified a cytosolic Hsp90 homolog, four homologs which can align to truncated cytosolic Hsp90 gene products along with two Grp94 homologs (ER isoform of Hsp90). However, both Grp94 orthologs lacked an ER retention motif. In cancer cells, it is very well established that Hsp90 is secreted and regulates key clients involved in metastases, migration, and invasion. Since Trichomonas Grp94 lacks ER retention motif, we examined the possibility of its secretion. By using cell biology and biochemical approaches we show that the Grp94 isoform of Hsp90 is secreted by the parasite by the classical ER-Golgi pathway. This is the first report of a genome encoded secreted Hsp90 in a clinically important parasitic protozoan.

Adverse events following single dose treatment of lymphatic filariasis: Observations from a review of the literature

PLoS Neglected Tropical Diseases News - 16 May 2018 - 9:00pm

by Philip J. Budge, Carly Herbert, Britt Andersen, Gary J. Weil

Background

WHO’s Global Programme to Eliminate Lymphatic Filariasis (LF) uses mass drug administration (MDA) of anthelmintic medications to interrupt LF transmission in endemic areas. Recently, a single dose combination of ivermectin (IVM), diethylcarbamazine (DEC), and albendazole (ALB) was shown to be markedly more effective than the standard two-drug regimens (DEC or IVM, plus ALB) for achieving long-term clearance of microfilaremia.

Objective and methods

To provide context for the results of a large-scale, international safety trial of MDA using triple drug therapy, we searched Ovid Medline for studies published from 1985–2017 that reported adverse events (AEs) following treatment of LF with IVM, DEC, ALB, or any combination of these medications. Studies that reported AE rates by treatment group were included.

Findings

We reviewed 162 published manuscripts, 55 of which met inclusion criteria. Among these, 34 were clinic or hospital-based clinical trials, and 21 were community-based studies. Reported AE rates varied widely. The median AE rate following DEC or IVM treatment was greater than 60% among microfilaremic participants and less than 10% in persons without microfilaremia. The most common AEs reported were fever, headache, myalgia or arthralgia, fatigue, and malaise.

Interpretation

Mild to moderate systemic AEs related to death of microfilariae are common following LF treatment. Post-treatment AEs are transient and rarely severe or serious. Comparison of AE rates from different community studies is difficult due to inconsistent AE reporting, varied infection rates, and varied intensity of follow-up. A more uniform approach for assessing and reporting AEs in LF community treatment studies would be helpful.

A systematic review of human and animal leptospirosis in the Pacific Islands reveals pathogen and reservoir diversity

PLoS Neglected Tropical Diseases News - 14 May 2018 - 9:00pm

by Vanina Guernier, Cyrille Goarant, Jackie Benschop, Colleen L. Lau

Background

The Pacific Islands have environmental conditions highly favourable for transmission of leptospirosis, a neglected zoonosis with highest incidence in the tropics, and Oceania in particular. Recent reports confirm the emergence and outbreaks of leptospirosis in the Pacific Islands, but the epidemiology and drivers of transmission of human and animal leptospirosis are poorly documented, especially in the more isolated and less developed islands.

Methodology/Principal findings

We conducted a systematic review of human and animal leptospirosis within 25 Pacific Islands (PIs) in Polynesia, Melanesia, Micronesia, as well as Easter Island and Hawaii. We performed a literature search using four international databases for articles published between January 1947 and June 2017. We further included grey literature available on the internet. We identified 148 studies describing leptospirosis epidemiology, but the number of studies varied significantly between PIs. No data were available from four PIs. Human leptospirosis has been reported from 13 PIs, with 63% of all studies conducted in Hawaii, French Polynesia and New Caledonia. Animal leptospirosis has been investigated in 19 PIs and from 14 host species, mainly pigs (18% of studies), cattle (16%) and dogs (11%). Only 13 studies provided information on both human and animal leptospirosis from the same location. Serology results were highly diverse in the region, both in humans and animals.

Conclusions/Significance

Our study suggests that, as in other tropical regions, leptospirosis is widespread in the PIs while showing some epidemiological heterogeneity. Data are scarce or absent from many PIs. Rodents, cattle, pigs and dogs are all likely to be important carriers, but the relative importance of each animal species in human infection needs to be clarified. Epidemiological surveys with appropriate sampling design, pathogen typing and data analysis are needed to improve our understanding of transmission patterns and to develop effective intervention strategies.

The mass use of deltamethrin collars to control and prevent canine visceral leishmaniasis: A field effectiveness study in a highly endemic area

PLoS Neglected Tropical Diseases News - 14 May 2018 - 9:00pm

by Bruna Martins Macedo Leite, Manuela da Silva Solcà, Liliane Celestino Sales Santos, Lívia Brito Coelho, Leila Denise Alves Ferreira Amorim, Lucas Edel Donato, Sandra Maria de Souza Passos, Adriana Oliveira de Almeida, Patrícia Sampaio Tavares Veras, Deborah Bittencourt Mothé Fraga

Background

Visceral leishmaniasis (VL) is a zoonosis of great importance. Limitations in current VL control measures compromise efficacy, indicating the need to implement new strategies. The aim of this study was to evaluate the effectiveness of the mass use of deltamethrin-impregnated collars in dogs as a public health measure to control and prevent canine visceral leishmaniasis (CVL).

Methodology

An interventional study was implemented in two endemic areas in the district of Monte Gordo (Bahia-Brazil): an intervention area, in which VL seronegative dogs were collared, and a control area in which only conventional CVL control measures were applied. At baseline, seropositive dogs were removed and seronegative dogs were included. Dogs were then reevaluated every 7–8 months for almost two years. At each time point, dogs in the intervention area that remained seronegative received new collars and newly identified seronegative dogs were included and collared. The local zoonosis control authorities were notified of any dogs that tested seropositive in both areas, which were subsequently marked for euthanasia as mandated by the Brazilian Ministry of Health.

Principal findings

In the first serological survey, seroprevalence was similar in both areas. At the second evaluation, significant reductions in seroprevalence were seen in both areas, while seroprevalence in the intervention area reduced to 6.0% during the final evaluation versus an increase of 11.0% in the control area. This significant increase and the estimated relative risk (RR = 0.55) indicated protection against CVL in the intervention area. Although CVL incidence did not differ significantly between the areas, an increased tendency was observed in the control area, which could be due to low seroconversion rates throughout the study or a high loss to follow-up.

Conclusions/Significance

Although our evaluation of the effectiveness of deltamethrin-impregnated collars as a community-wide public health control measure was inconclusive, this measure likely provides protection over time. In endemic areas of Brazil, this strategy represents an operational challenge for local zoonosis control authorities, indicating the need for adjustments, including improved collar design.

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