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<i>PLOS Neglected Tropical Diseases</i>: Ten years of progress in neglected tropical disease control and elimination … More or less

PLoS Neglected Tropical Diseases News - 20 April 2017 - 9:00pm

by Peter Hotez, Serap Aksoy

This year PLOS Neglected Tropical Diseases (PLOS NTDs) celebrates its tenth anniversary following the publication of the first issue in 2007 [1]. When PLOS NTDs was founded, the framework of the neglected tropical diseases (NTDs) as an alternative to “other diseases” (as they were then referred to in the Millennium Development Goals) was just getting started—especially for Africa [2, 3]. In the decade since, PLOS NTDs has overseen enormous successes in NTD control and elimination. Here, we want to briefly review the ten year progress made towards the control or elimination of the diseases now identified by the WHO as NTDs. Many of the details are highlighted in PLOS NTDs papers cited here, but the summary information is based on the recently released Global Burden of Disease (GBD) Study 2015 (also launched with Gates Foundation support) that summarized past-decade changes in disease prevalence, mortality, or disability rates (from the years 2005 to 2015) [4–6], as well as the GBD Study 2013 that summarizes disease prevalence changes over a longer time horizon from 1990 to 2013 [7].

Glycosome biogenesis in trypanosomes and the de novo dilemma

PLoS Neglected Tropical Diseases News - 20 April 2017 - 9:00pm

by Sarah Bauer, Meredith T. Morris

Trypanosomatid parasites, including Trypanosoma and Leishmania, are the causative agents of lethal diseases threatening millions of people around the world. These organisms compartmentalize glycolysis in essential, specialized peroxisomes called glycosomes. Peroxisome proliferation can occur through growth and division of existing organelles and de novo biogenesis from the endoplasmic reticulum. The level that each pathway contributes is debated. Current evidence supports the concerted contribution of both mechanisms in an equilibrium that can vary depending on environmental conditions and metabolic requirements of the cell. Homologs of a number of peroxins, the proteins involved in peroxisome biogenesis and matrix protein import, have been identified in T. brucei. Based on these findings, it is widely accepted that glycosomes proliferate through growth and division of existing organelles; however, to our knowledge, a de novo mechanism of biogenesis has not been directly demonstrated. Here, we review recent findings that provide support for the existence of an endoplasmic reticulum (ER)-derived de novo pathway of glycosome biogenesis in T. brucei. Two studies recently identified PEX13.1, a peroxin involved in matrix protein import, in the ER of procyclic form T. brucei. In other eukaryotes, peroxins including PEX13 have been found in the ER of cells undergoing de novo biogenesis of peroxisomes. In addition, PEX16 and PEX19 have been characterized in T. brucei, both of which are important for de novo biogenesis in other eukaryotes. Because glycosomes are rapidly remodeled via autophagy during life cycle differentiation, de novo biogenesis could provide a method of restoring glycosome populations following turnover. Together, the findings we summarize provide support for the hypothesis that glycosome proliferation occurs through growth and division of pre-existing organelles and de novo biogenesis of new organelles from the ER and that the level each mechanism contributes is influenced by glucose availability.

The gut microbiota as a modulator of innate immunity during melioidosis

PLoS Neglected Tropical Diseases News - 19 April 2017 - 9:00pm

by Jacqueline M. Lankelma, Emma Birnie, Tassili A. F. Weehuizen, Brendon P. Scicluna, Clara Belzer, Riekelt H. Houtkooper, Joris J. T. H. Roelofs, Alex F. de Vos, Tom van der Poll, Andries E. Budding, W. Joost Wiersinga

Background

Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is an emerging cause of pneumonia-derived sepsis in the tropics. The gut microbiota supports local mucosal immunity and is increasingly recognized as a protective mediator in host defenses against systemic infection. Here, we aimed to characterize the composition and function of the intestinal microbiota during experimental melioidosis.

Methodology/Principal findings

C57BL/6 mice were infected intranasally with B. pseudomallei and sacrificed at different time points to assess bacterial loads and inflammation. In selected experiments, the gut microbiota was disrupted with broad-spectrum antibiotics prior to inoculation. Fecal bacterial composition was analyzed by means of IS-pro, a 16S-23S interspacer region-based profiling method. A marked shift in fecal bacterial composition was seen in all mice during systemic B. pseudomallei infection with a strong increase in Proteobacteria and decrease in Actinobacteria, with an increase in bacterial diversity. We found enhanced early dissemination of B. pseudomallei and systemic inflammation during experimental melioidosis in microbiota-disrupted mice compared with controls. Whole-genome transcriptional profiling of the lung identified several genes that were differentially expressed between mice with a normal or disrupted intestinal microbiota. Genes involved in acute phase signaling, including macrophage-related signaling pathways were significantly elevated in microbiota disrupted mice. Compared with controls, alveolar macrophages derived from antibiotic pretreated mice showed a diminished capacity to phagocytose B. pseudomallei. This might in part explain the observed protective effect of the gut microbiota in the host defense against pneumonia-derived melioidosis.

Conclusions/Significance

Taken together, these data identify the gut microbiota as a potential modulator of innate immunity during B. pseudomallei infection.

<i>Trypanosoma brucei</i> TbIF1 inhibits the essential F<sub>1</sub>-ATPase in the infectious form of the parasite

PLoS Neglected Tropical Diseases News - 17 April 2017 - 9:00pm

by Brian Panicucci, Ondřej Gahura, Alena Zíková

The mitochondrial (mt) FoF1-ATP synthase of the digenetic parasite, Trypanosoma brucei, generates ATP during the insect procyclic form (PF), but becomes a perpetual consumer of ATP in the mammalian bloodstream form (BF), which lacks a canonical respiratory chain. This unconventional dependence on FoF1-ATPase is required to maintain the essential mt membrane potential (Δψm). Normally, ATP hydrolysis by this rotary molecular motor is restricted to when eukaryotic cells experience sporadic hypoxic conditions, during which this compulsory function quickly depletes the cellular ATP pool. To protect against this cellular treason, the highly conserved inhibitory factor 1 (IF1) binds the enzyme in a manner that solely inhibits the hydrolytic activity. Intriguingly, we were able to identify the IF1 homolog in T. brucei (TbIF1), but determined that its expression in the mitochondrion is tightly regulated throughout the life cycle as it is only detected in PF cells. TbIF1 appears to primarily function as an emergency brake in PF cells, where it prevented the restoration of the Δψm by FoF1-ATPase when respiration was chemically inhibited. In vitro, TbIF1 overexpression specifically inhibits the hydrolytic activity but not the synthetic capability of the FoF1-ATP synthase in PF mitochondria. Furthermore, low μM amounts of recombinant TbIF1 achieve the same inhibition of total mt ATPase activity as the FoF1-ATPase specific inhibitors, azide and oligomycin. Therefore, even minimal ectopic expression of TbIF1 in BF cells proved lethal as the indispensable Δψm collapsed due to inhibited FoF1-ATPase. In summary, we provide evidence that T. brucei harbors a natural and potent unidirectional inhibitor of the vital FoF1-ATPase activity that can be exploited for future structure-based drug design.

Knockdown resistance mutations predict DDT resistance and pyrethroid tolerance in the visceral leishmaniasis vector <i>Phlebotomus argentipes</i>

PLoS Neglected Tropical Diseases News - 17 April 2017 - 9:00pm

by Bruno Gomes, Bidyut Purkait, Rinki Michelle Deb, Aarti Rama, Rudra Pratap Singh, Geraldine Marie Foster, Michael Coleman, Vijay Kumar, Mark Paine, Pradeep Das, David Weetman

Background

Indoor residual spraying (IRS) with DDT has been the primary strategy for control of the visceral leishmaniasis (VL) vector Phlebotomus argentipes in India but efficacy may be compromised by resistance. Synthetic pyrethroids are now being introduced for IRS, but with a shared target site, the para voltage-gated sodium channel (VGSC), mutations affecting both insecticide classes could provide cross-resistance and represent a threat to sustainable IRS-based disease control.

Methodology/Principal findings

A region of the Vgsc gene was sequenced in P. argentipes from the VL hotspot of Bihar, India. Two knockdown resistance (kdr) mutations were detected at codon 1014 (L1014F and L1014S), each common in mosquitoes, but previously unknown in phlebotomines. Both kdr mutations appear largely recessive, but as homozygotes (especially 1014F/F) or as 1014F/S heterozygotes exert a strong effect on DDT resistance, and significantly predict survivorship to class II pyrethroids in short-duration bioassays. The mutations are present at high frequency in wild P. argentipes populations from Bihar, with 1014F significantly more common in higher VL areas.

Conclusions/Significance

The Vgsc mutations detected appear to be a primary mechanism underlying DDT resistance in P. argentipes and a contributory factor in reduced pyrethroid susceptibility, suggesting a potential impact if P. argentipes are subjected to suboptimal levels of pyrethroid exposure, or additional resistance mechanisms evolve. The assays to detect kdr frequency changes provide a sensitive, high-throughput monitoring tool to detecting spatial and temporal variation in resistance in P. argentipes.

<i>Mycobacterium ulcerans</i> low infectious dose and mechanical transmission support insect bites and puncturing injuries in the spread of Buruli ulcer

PLoS Neglected Tropical Diseases News - 14 April 2017 - 9:00pm

by John R. Wallace, Kirstie M. Mangas, Jessica L. Porter, Renee Marcsisin, Sacha J. Pidot, Brian Howden, Till F. Omansen, Weiguang Zeng, Jason K. Axford, Paul D. R. Johnson, Timothy P. Stinear

Addressing the transmission enigma of the neglected disease Buruli ulcer (BU) is a World Health Organization priority. In Australia, we have observed an association between mosquitoes harboring the causative agent, Mycobacterium ulcerans, and BU. Here we tested a contaminated skin model of BU transmission by dipping the tails from healthy mice in cultures of the causative agent, Mycobacterium ulcerans. Tails were exposed to mosquito (Aedes notoscriptus and Aedes aegypti) blood feeding or punctured with sterile needles. Two of 12 of mice with M. ulcerans contaminated tails exposed to feeding A. notoscriptus mosquitoes developed BU. There were no mice exposed to A. aegypti that developed BU. Eighty-eight percent of mice (21/24) subjected to contaminated tail needle puncture developed BU. Mouse tails coated only in bacteria did not develop disease. A median incubation time of 12 weeks, consistent with data from human infections, was noted. We then specifically tested the M. ulcerans infectious dose-50 (ID50) in this contaminated skin surface infection model with needle puncture and observed an ID50 of 2.6 colony-forming units. We have uncovered a biologically plausible transmission mode of BU via natural or anthropogenic skin punctures.

Tiger on the prowl: Invasion history and spatio-temporal genetic structure of the Asian tiger mosquito <i>Aedes albopictus</i> (Skuse 1894) in the Indo-Pacific

PLoS Neglected Tropical Diseases News - 14 April 2017 - 9:00pm

by Andrew J. Maynard, Luke Ambrose, Robert D. Cooper, Weng K. Chow, Joseph B. Davis, Mutizwa O. Muzari, Andrew F. van den Hurk, Sonja Hall-Mendelin, Jeomhee M. Hasty, Thomas R. Burkot, Michael J. Bangs, Lisa J. Reimer, Charles Butafa, Neil F. Lobo, Din Syafruddin, Yan Naung Maung Maung, Rohani Ahmad, Nigel W. Beebe

Background

Within the last century, increases in human movement and globalization of trade have facilitated the establishment of several highly invasive mosquito species in new geographic locations with concurrent major environmental, economic and health consequences. The Asian tiger mosquito, Aedes albopictus, is an extremely invasive and aggressive daytime-biting mosquito that is a major public health threat throughout its expanding range.

Methodology/Principal findings

We used 13 nuclear microsatellite loci (on 911 individuals) and mitochondrial COI sequences to gain a better understanding of the historical and contemporary movements of Ae. albopictus in the Indo-Pacific region and to characterize its population structure. Approximate Bayesian computation (ABC) was employed to test competing historical routes of invasion of Ae. albopictus within the Southeast (SE) Asian/Australasian region. Our ABC results show that Ae. albopictus was most likely introduced to New Guinea via mainland Southeast Asia, before colonizing the Solomon Islands via either Papua New Guinea or SE Asia. The analysis also supported that the recent incursion into northern Australia’s Torres Strait Islands was seeded chiefly from Indonesia. For the first time documented in this invasive species, we provide evidence of a recently colonized population (the Torres Strait Islands) that has undergone rapid temporal changes in its genetic makeup, which could be the result of genetic drift or represent a secondary invasion from an unknown source.

Conclusions/Significance

There appears to be high spatial genetic structure and high gene flow between some geographically distant populations. The species' genetic structure in the region tends to favour a dispersal pattern driven mostly by human movements. Importantly, this study provides a more widespread sampling distribution of the species’ native range, revealing more spatial population structure than previously shown. Additionally, we present the most probable invasion history of this species in the Australasian region using ABC analysis.

Quantitative assessment of the impact of partially protective anti-schistosomiasis vaccines

PLoS Neglected Tropical Diseases News - 14 April 2017 - 9:00pm

by Ramzi A. Alsallaq, David Gurarie, Martial Ndeffo Mbah, Alison Galvani, Charles King

Background

Mass drug administration (MDA) of praziquantel has been the intervention of choice against schistosomiasis but with limited success in interrupting the transmission. The development of anti-Schistosoma vaccines is underway. Our objective is to quantify the population-level impact of anti-Schistosoma vaccines when administered alone and in combination with mass drug administration (MDA) and determine factors in vaccine design and public health implementation that optimize vaccination role in schistosomiasis control and elimination.

Methods and findings

We developed a deterministic compartmental model simulation of schistosomiasis transmission in a high-risk Kenyan community, including stratification by age, parasite burden, and vaccination status. The modeled schistosomiasis vaccines differed in terms of vaccine duration of protection (durability) and three biological efficacies. These are vaccine susceptibility effect (SE) of reducing person’s susceptibility to Schistosoma acquisition, vaccine mortality effect (ME) of reducing established worm burden and vaccine fecundity effect (FE) of reducing egg release by mature worms. We quantified the population-level impact of vaccination over two decades under diverse vaccination schemes (childhood vs. mass campaigns), with different age-targeting scenarios, different risk settings, and with combined intervention with MDA. We also assessed the sensitivity of our predictions to uncertainties in model parameters. Over two decades, our base case vaccine with 80% SE, FE, and ME efficacies, 10 years’ durability, provided by mass vaccination every 10 years, reduced host prevalence, mean intensity, incidence, and patent snail prevalence to 31%, 20 eggs/10-ml sample/person, 0.87 worm/person-year, and 0.74%, from endemic-state values of 71%, 152, 3.3, and 0.98%, respectively. Lower impact was found when coverage did not encompass all potential contaminators, and childhood-only vaccination schemes showed delayed and lower impact. In lower prevalence settings, the base case vaccine generated a proportionately smaller impact. A substantially larger vaccine program effect was generated when MDA + mass vaccination was provided every 5 years, which could be achieved by an MDA-only program only if drug was offered annually. Vaccine impact on schistosomiasis transmission was sensitive to a number of parameters including vaccine efficacies, human contact rates with water, human density, patent snails’ rate of patency and lifespan, and force of infection to snails.

Conclusions

To be successful a vaccine-based control strategy will need a moderately to highly effective formulation combined with early vaccination of potential contaminators and aggressive coverage in repeated rounds of mass vaccination. Compared to MDA-only program, vaccination combined with MDA accelerates and prolongs the impact by reducing the acquisition of new worms and reducing egg release from residual worms.

Controlling cholera in the Ouest Department of Haiti using oral vaccines

PLoS Neglected Tropical Diseases News - 14 April 2017 - 9:00pm

by Alexander Kirpich, Thomas A. Weppelmann, Yang Yang, John Glenn Morris Jr., Ira M. Longini Jr.

Following the 2010 cholera outbreak in Haiti, a plan was initiated to provide massive improvements to the sanitation and drinking water infrastructure in order to eliminate cholera from the island of Hispaniola by 2023. Six years and a half billion dollars later, there is little evidence that any substantial improvements have been implemented; with increasing evidence that cholera has become endemic. Thus, it is time to explore strategies to control cholera in Haiti using oral cholera vaccines (OCVs). The potential effects of mass administration of OCVs on cholera transmission were assessed using dynamic compartment models fit to cholera incidence data from the Ouest Department of Haiti. The results indicated that interventions using an OCV that was 60% effective could have eliminated cholera transmission by August 2012 if started five weeks after the initial outbreak. A range of analyses on the ability of OCV interventions started January 1, 2017 to eliminate cholera transmission by 2023 were performed by considering different combinations of vaccine efficacies, vaccine administration rates, and durations of protective immunity. With an average of 50 weeks for the waiting time to vaccination and an average duration of three years for the vaccine-induced immunity, all campaigns that used an OCV with a vaccine efficacy of at least 60% successfully eliminated cholera transmission by 2023. The results of this study suggest that even with a relatively wide range of vaccine efficacies, administration rates, and durations of protective immunity, future epidemics could be controlled at a relatively low cost using mass administration of OCVs in Haiti.

Histone deacetylase inhibition modulates histone acetylation at gene promoter regions and affects genome-wide gene transcription in <i>Schistosoma mansoni</i>

PLoS Neglected Tropical Diseases News - 13 April 2017 - 9:00pm

by Letícia Anderson, Monete Rajão Gomes, Lucas Ferreira daSilva, Adriana da Silva Andrade Pereira, Marina M. Mourão, Christophe Romier, Raymond Pierce, Sergio Verjovski-Almeida

Background

Schistosomiasis is a parasitic disease infecting hundreds of millions of people worldwide. Treatment depends on a single drug, praziquantel, which kills the Schistosoma spp parasite only at the adult stage. HDAC inhibitors (HDACi) such as Trichostatin A (TSA) induce parasite mortality in vitro (schistosomula and adult worms), however the downstream effects of histone hyperacetylation on the parasite are not known.

Methodology/Principal findings

TSA treatment of adult worms in vitro increased histone acetylation at H3K9ac and H3K14ac, which are transcription activation marks, not affecting the unrelated transcription repression mark H3K27me3. We investigated the effect of TSA HDACi on schistosomula gene expression at three different time points, finding a marked genome-wide change in the transcriptome profile. Gene transcription activity was correlated with changes on the chromatin acetylation mark at gene promoter regions. Moreover, combining expression data with ChIP-Seq public data for schistosomula, we found that differentially expressed genes having the H3K4me3 mark at their promoter region in general showed transcription activation upon HDACi treatment, compared with those without the mark, which showed transcription down-regulation. Affected genes are enriched for DNA replication processes, most of them being up-regulated. Twenty out of 22 genes encoding proteins involved in reducing reactive oxygen species accumulation were down-regulated. Dozens of genes encoding proteins with histone reader motifs were changed, including SmEED from the PRC2 complex. We targeted SmEZH2 methyltransferase PRC2 component with a new EZH2 inhibitor (GSK343) and showed a synergistic effect with TSA, significantly increasing schistosomula mortality.

Conclusions/Significance

Genome-wide gene expression analyses have identified important pathways and cellular functions that were affected and may explain the schistosomicidal effect of TSA HDACi. The change in expression of dozens of histone reader genes involved in regulation of the epigenetic program in S. mansoni can be used as a starting point to look for possible novel schistosomicidal targets.

Spatial relationship between <i>Taenia solium</i> tapeworm carriers and necropsy cyst burden in pigs

PLoS Neglected Tropical Diseases News - 13 April 2017 - 9:00pm

by Ian W. Pray, Viterbo Ayvar, Ricardo Gamboa, Claudio Muro, Luz M. Moyano, Victor Benavides, Robert H. Flecker, Hector H. Garcia, Seth E. O’Neal

Background

Taenia solium, a parasite that affects humans and pigs, is the leading cause of preventable epilepsy in the developing world. Geographic hotspots of pigs testing positive for serologic markers of T. solium exposure have been observed surrounding the locations of human tapeworm carriers. This clustered pattern of seropositivity in endemic areas formed the basis for geographically targeted control interventions, which have been effective at reducing transmission. In this study, we further explore the spatial relationship between human tapeworm carriers and infected pigs using necroscopic examination as a quantitative gold-standard diagnostic to detect viable T. solium cyst infection in pigs.

Methodology/Principal findings

We performed necroscopic examinations on pigs from 7 villages in northern Peru to determine the number of viable T. solium cysts in each pig. Participating humans in the study villages were tested for T. solium tapeworm infection (i.e., taeniasis) with an ELISA coproantigen assay, and the distances from each pig to its nearest human tapeworm carrier were calculated. We assessed the relationship between proximity to a tapeworm carrier and the prevalence of light, moderate, and heavy cyst burden in pigs. The prevalence of pig infection was greatest within 50 meters of a tapeworm carrier and decreased monotonically as distance increased. Pigs living less than 50 meters from a human tapeworm carrier were 4.6 times more likely to be infected with at least one cyst than more distant pigs. Heavier cyst burdens, however, were not more strongly associated with proximity to tapeworm carriers than light cyst burdens.

Conclusion/Significance

Our study shows that human tapeworm carriers and pigs with viable T. solium cyst infection are geographically correlated in endemic areas. This finding supports control strategies that treat humans and pigs based on their proximity to other infected individuals. We did not, however, find sufficient evidence that heavier cyst burdens in pigs would serve as improved targets for geographically focused control interventions.

Application of a household-based molecular xenomonitoring strategy to evaluate the lymphatic filariasis elimination program in Tamil Nadu, India

PLoS Neglected Tropical Diseases News - 13 April 2017 - 9:00pm

by Subramanian Swaminathan, Jambulingam Purushothaman, Brian K. Chu, Sadanandane Candasamy, Vasuki Venkatesan, Srividya Adinarayanan, AbdulKhader Mohamed Sathak M., Krishnamoorthy Kaliannagounder, Harikishan K. Raju, Sandra J. Laney, Steven A. Williams, Ralph H. Henderson

Background

The monitoring and evaluation of lymphatic filariasis (LF) has largely relied on the detection of antigenemia and antibodies in human populations. Molecular xenomonitoring (MX), the detection of parasite DNA/RNA in mosquitoes, may be an effective complementary method, particularly for detecting signals in low-level prevalence areas where Culex is the primary mosquito vector. This paper investigated the application of a household-based sampling method for MX in Tamil Nadu, India.

Methods

MX surveys were conducted in 2010 in two evaluation units (EUs): 1) a hotspot area, defined as sites with community microfilaria prevalence ≥1%, and 2) a larger area that also encompassed the hotspots. Households were systematically selected using a sampling interval proportional to the number of households in the EU. Mosquito pools were collected and analyzed by real-time polymerase chain reaction (qPCR). Two independent samples were taken in each EU to assess reproducibility of results. Follow-up surveys were conducted in 2012.

Results

In 2010, the proportion of positive pools in the hotspot EU was 49.3% compared to 23.4% in the overall EU. In 2012, pool positivity was significantly reduced to 24.3% and 6.5%, respectively (p<0.0001). Pool positivity based on independent samples taken from each EU in 2010 and 2012 were not significantly different except for the hotspot EU in 2012 (p = 0.009). The estimated prevalence of infection in mosquitoes, measured by PoolScreen, declined from 2.2–2.7% in 2010 to 0.6–1.2% in 2012 in the hotspot area and from 0.9–1.1% to 0.2–0.3% in the larger area.

Conclusions

The household-based sampling strategy for MX led to mostly reproducible results and supported the observed LF infection trends found in humans. MX has the potential to be a cost-effective, non-invasive monitoring and evaluation tool with sensitive detection of infection signals in low prevalence settings. Further investigation and application of this sampling strategy for MX are recommended to support its adoption as a standardized method for global LF elimination programs.

The superfamily keeps growing: Identification in trypanosomatids of RIBJ, the first riboflavin transporter family in protists

PLoS Neglected Tropical Diseases News - 13 April 2017 - 9:00pm

by Darío E. Balcazar, María Cristina Vanrell, Patricia S. Romano, Claudio A. Pereira, Fernando A. Goldbaum, Hernán R. Bonomi, Carolina Carrillo

Background

Trypanosomatid parasites represent a major health issue affecting hundreds of million people worldwide, with clinical treatments that are partially effective and/or very toxic. They are responsible for serious human and plant diseases including Trypanosoma cruzi (Chagas disease), Trypanosoma brucei (Sleeping sickness), Leishmania spp. (Leishmaniasis), and Phytomonas spp. (phytoparasites). Both, animals and trypanosomatids lack the biosynthetic riboflavin (vitamin B2) pathway, the vital precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) cofactors. While metazoans obtain riboflavin from the diet through RFVT/SLC52 transporters, the riboflavin transport mechanisms in trypanosomatids still remain unknown.

Methodology/Principal findings

Here, we show that riboflavin is imported with high affinity in Trypanosoma cruzi, Trypanosoma brucei, Leishmania (Leishmania) mexicana, Crithidia fasciculata and Phytomonas Jma using radiolabeled riboflavin transport assays. The vitamin is incorporated through a saturable carrier-mediated process. Effective competitive uptake occurs with riboflavin analogs roseoflavin, lumiflavin and lumichrome, and co-factor derivatives FMN and FAD. Moreover, important biological processes evaluated in T. cruzi (i.e. proliferation, metacyclogenesis and amastigote replication) are dependent on riboflavin availability. In addition, the riboflavin competitive analogs were found to interfere with parasite physiology on riboflavin-dependent processes. By means of bioinformatics analyses we identified a novel family of riboflavin transporters (RibJ) in trypanosomatids. Two RibJ members, TcRibJ and TbRibJ from T. cruzi and T. brucei respectively, were functionally characterized using homologous and/or heterologous expression systems.

Conclusions/Significance

The RibJ family represents the first riboflavin transporters found in protists and the third eukaryotic family known to date. The essentiality of riboflavin for trypanosomatids, and the structural/biochemical differences that RFVT/SLC52 and RibJ present, make the riboflavin transporter -and its downstream metabolism- a potential trypanocidal drug target.

Cholera returns to southern Vietnam in an outbreak associated with consuming unsafe water through iced tea: A matched case-control study

PLoS Neglected Tropical Diseases News - 13 April 2017 - 9:00pm

by Thuong V. Nguyen, Quang D. Pham, Quoc K. Do, Tai T. Diep, Hung C. Phan, Thang V. Ho, Hong T. Do, Lan T. Phan, Huu N. Tran

Background

After more than a decade of steadily declining notifications, the number of reported cholera cases has recently increased in Vietnam. We conducted a matched case-control study to investigate transmission of cholera during an outbreak in Ben Tre, southern Vietnam, and to explore the associated risk factors.

Methodology/Principal findings

Sixty of 71 diarrheal patients confirmed to be infected with cholera by culture and diagnosed between May 9 and August 3, 2010 in Ben Tre were consecutively recruited as case-patients. Case-patients were matched 1:4 to controls by commune, sex, and 5-year age group. Risk factors for cholera were examined by multivariable conditional logistic regression. In addition, environmental samples from villages containing case-patients were taken to identify contamination of food and water sources. The regression indicated that drinking iced tea (adjusted odds ratio (aOR) = 8.40, 95% confidence interval (CI): 1.84–39.25), not always boiling drinking water (aOR = 2.62, 95% CI: 1.03–6.67), having the main source of water for use being close to a toilet (aOR = 4.36, 95% CI: 1.37–13.88), living with people who had acute diarrhea (aOR = 13.72, 95% CI: 2.77–67.97), and little or no education (aOR = 4.89, 95% CI: 1.18–20.19) were significantly associated with increased risk of cholera. In contrast, drinking stored rainwater (aOR = 0.17, 95% CI: 0.04–0.63), eating cooked seafood (aOR = 0.27, 95% CI: 0.10–0.73), and eating steamed vegetables (aOR = 0.22, 95% CI: 0.07–0.70) were protective against cholera. Vibrio cholerae O1 Ogawa carrying ctxA was found in two of twenty-five river water samples and one of six wastewater samples.

Conclusions/Significance

The magnitude of the cholera outbreak in Ben Tre was lower than in other similar settings. This investigation identified several risk factors and underscored the importance of continued responses targeting cholera prevention in southern Vietnam. The association between drinking iced tea and cholera and the spread of V. cholerae O1, altered El Tor strains warrant further research. These findings might be affected by a number of limitations due to the inability to capture asymptomatic or mildly symptomatic infections, the possible underreporting of personal unhygienic behaviors, and the purposive selection of environmental samples.

Sustained effectiveness of weekly iron-folic acid supplementation and regular deworming over 6 years in women in rural Vietnam

PLoS Neglected Tropical Diseases News - 13 April 2017 - 9:00pm

by Gerard J. Casey, Ta T. Tinh, Nong T. Tien, Sarah Hanieh, Luca T. Cavalli-Sforza, Antonio Montresor, Beverley-Ann Biggs

Background

Weekly iron-folic acid (IFA) supplementation and regular deworming is effective for the prevention of iron deficiency and anaemia in women of child-bearing age. Between 2006 and 2013, a program of weekly IFA and biannual deworming was implemented in Yen Bai province, Vietnam. In this study we aimed to determine the effectiveness of the program in reducing anaemia and the prevalence of hookworm infection after 72 months (six years).

Methods

This prospective cohort study followed up a cohort of 389 women of child-bearing age from baseline until six years after the introduction of the weekly IFA (one tablet containing 200 mg ferrous sulphate, 0.4mg folic acid) and deworming (one 400mg tablet of albendazole given twice yearly) program (May 2006 to 2012). In each of the six surveys (baseline and five follow-up surveys) we measured haemoglobin and ferritin, and the burden of soil transmitted helminth (STH) infections, and in the 72 month survey we also administered a questionnaire to assess adherence and possible impediments to participating in the program.

Results

Two hundred and fifty six (65.8%) of the original 389 women enrolled in the cohort attended the final 72 month survey. Haemoglobin levels were 122 g/L [95% C.I. 120, 124] at baseline and increased to 135g/L [95% C.I. 133, 138] after 72 months. The prevalence of anaemia was 37.8% [95% C.I. 31.0, 44.7] at baseline and reduced to 14.3% [95% C.I. 9.5, 19.1]. Hookworm infection prevalence, 75.9% [95% C.I. 68.1, 83.8] at baseline, reduced to 10.2% [95% C.I. 5.4, 15.0] with no moderate or heavy intensity infections. Seventy-two percent of participants reported still taking at least 75% of the weekly supplements, and 85.0% had taken the most recent deworming treatment.

Discussion

Anaemia rates fell significantly during the six-year program, and STH infections were eliminated as a public health risk. Adherence was well maintained but long-term sustainability is challenging in the absence of ongoing external support.

The phosphatidylinositol-3-phosphate 5-kinase inhibitor apilimod blocks filoviral entry and infection

PLoS Neglected Tropical Diseases News - 12 April 2017 - 9:00pm

by Elizabeth A. Nelson, Julie Dyall, Thomas Hoenen, Alyson B. Barnes, Huanying Zhou, Janie Y. Liang, Julia Michelotti, William H. Dewey, Lisa Evans DeWald, Richard S. Bennett, Patrick J. Morris, Rajarshi Guha, Carleen Klumpp-Thomas, Crystal McKnight, Yu-Chi Chen, Xin Xu, Amy Wang, Emma Hughes, Scott Martin, Craig Thomas, Peter B. Jahrling, Lisa E. Hensley, Gene G. Olinger Jr., Judith M. White

Phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) is a lipid kinase involved in endosome maturation that emerged from a haploid genetic screen as being required for Ebola virus (EBOV) infection. Here we analyzed the effects of apilimod, a PIKfyve inhibitor that was reported to be well tolerated in humans in phase 2 clinical trials, for its effects on entry and infection of EBOV and Marburg virus (MARV). We first found that apilimod blocks infections by EBOV and MARV in Huh 7, Vero E6 and primary human macrophage cells, with notable potency in the macrophages (IC50, 10 nM). We next observed that similar doses of apilimod block EBOV-glycoprotein-virus like particle (VLP) entry and transcription-replication competent VLP infection, suggesting that the primary mode of action of apilimod is as an entry inhibitor, preventing release of the viral genome into the cytoplasm to initiate replication. After providing evidence that the anti-EBOV action of apilimod is via PIKfyve, we showed that it blocks trafficking of EBOV VLPs to endolysosomes containing Niemann-Pick C1 (NPC1), the intracellular receptor for EBOV. Concurrently apilimod caused VLPs to accumulate in early endosome antigen 1-positive endosomes. We did not detect any effects of apilimod on bulk endosome acidification, on the activity of cathepsins B and L, or on cholesterol export from endolysosomes. Hence by antagonizing PIKfyve, apilimod appears to block EBOV trafficking to its site of fusion and entry into the cytoplasm. Given the drug’s observed anti-filoviral activity, relatively unexplored mechanism of entry inhibition, and reported tolerability in humans, we propose that apilimod be further explored as part of a therapeutic regimen to treat filoviral infections.

Epidemiological analysis of <i>Leishmania tropica</i> strains and giemsa-stained smears from Syrian and Turkish leishmaniasis patients using Multilocus Microsatellite Typing (MLMT)

PLoS Neglected Tropical Diseases News - 12 April 2017 - 9:00pm

by Mehmet Karakuş, Abed Nasereddin, Hüseyin Onay, Emin Karaca, Ahmet Özkeklikçi, Charles L. Jaffe, Katrin Kuhls, Ahmet Özbilgin, Hatice Ertabaklar, Samiye Demir, Yusuf Özbel, Seray Töz

Turkey is located in an important geographical location, in terms of the epidemiology of vector-borne diseases, linking Asia and Europe. Cutaneous leishmaniasis (CL) is one of the endemic diseases in a Turkey and according to the Ministry Health of Turkey, 45% of CL patients originate from Şanlıurfa province located in southeastern Turkey. Herein, the epidemiological status of CL, caused by L. tropica, in Turkey was examined using multilocus microsatellite typing (MLMT) of strains obtained from Turkish and Syrian patients. A total of 38 cryopreserved strains and 20 Giemsa-stained smears were included in the present study. MLMT was performed using 12 highly specific microsatellite markers. Delta K (ΔK) calculation and Bayesian statistics were used to determine the population structure. Three main populations (POP A, B and C) were identified and further examination revealed the presence of three subpopulations for POP B and C. Combined analysis was performed using the data of previously typed L. tropica strains and Mediterranean and Şanlıurfa populations were identified. This finding suggests that the epidemiological status of L. tropica is more complicated than expected when compared to previous studies. A new population, comprised of Syrian L. tropica samples, was reported for the first time in Turkey, and the data presented here will provide new epidemiological information for further studies.

Prevalence, diversity, and host associations of <i>Bartonella</i> strains in bats from Georgia (Caucasus)

PLoS Neglected Tropical Diseases News - 11 April 2017 - 9:00pm

by Lela Urushadze, Ying Bai, Lynn Osikowicz, Clifton McKee, Ketevan Sidamonidze, Davit Putkaradze, Paata Imnadze, Andrei Kandaurov, Ivan Kuzmin, Michael Kosoy

Bartonella infections were investigated in seven species of bats from four regions of the Republic of Georgia. Of the 236 bats that were captured, 212 (90%) specimens were tested for Bartonella infection. Colonies identified as Bartonella were isolated from 105 (49.5%) of 212 bats Phylogenetic analysis based on sequence variation of the gltA gene differentiated 22 unique Bartonella genogroups. Genetic distances between these diverse genogroups were at the level of those observed between different Bartonella species described previously. Twenty-one reference strains from 19 representative genogroups were characterized using four additional genetic markers. Host specificity to bat genera or families was reported for several Bartonella genogroups. Some Bartonella genotypes found in bats clustered with those identified in dogs from Thailand and humans from Poland.

Acute Q fever in febrile patients in northwestern of Iran

PLoS Neglected Tropical Diseases News - 10 April 2017 - 9:00pm

by Saber Esmaeili, Farhad Golzar, Erfan Ayubi, Behrooz Naghili, Ehsan Mostafavi

Background

Q fever is an endemic disease in different parts of Iran. This study aimed to investigate the prevalence of acute Q fever disease among at-risk individuals in northwestern Iran.

Methodology

An etiological study was carried out in 2013 in Tabriz County. A total of 116 individuals who were in contact with livestock and had a nonspecific febrile illness were enrolled in the study. IgG phase II antibodies against Coxiella burnetii were detected using ELISA.

Principal findings

The prevalence of acute Q fever was 13.8% (95% confidence interval [CI]: 8.0, 21.0%). Headache (87.5%) and fatigue and weakness (81.3%) were the dominant clinical characteristics among patients whit acute Q fever. Acute lower respiratory tract infection and chills were poorly associated with acute Q fever. Furthermore, 32% (95% CI: 24, 41%) of participants had a history of previous exposure to Q fever agent (past infection). Consumption of unpasteurized dairy products was a weak risk factor for previous exposure to C. burnetii.

Conclusion

This study identified patients with acute Q fever in northwestern of Iran. The evidence from this study and previous studies conducted in different regions of Iran support this fact that Q fever is one of the important endemic zoonotic diseases in Iran and needs due attention by clinical physicians and health care system.

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