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Genomic analyses of African <i>Trypanozoon</i> strains to assess evolutionary relationships and identify markers for strain identification

29 September 2017 - 9:00pm

by Joshua Brian Richardson, Kuang-Yao Lee, Paul Mireji, John Enyaru, Mark Sistrom, Serap Aksoy, Hongyu Zhao, Adalgisa Caccone

African trypanosomes of the sub-genus Trypanozoon) are eukaryotic parasitesthat cause disease in either humans or livestock. The development of genomic resources can be of great use to those interested in studying and controlling the spread of these trypanosomes. Here we present a large comparative analysis of Trypanozoon whole genomes, 83 in total, including human and animal infective African trypanosomes: 21 T. brucei brucei, 22 T. b. gambiense, 35 T. b. rhodesiense and 4 T. evansi strains, of which 21 were from Uganda. We constructed a maximum likelihood phylogeny based on 162,210 single nucleotide polymorphisms (SNPs.) The three Trypanosoma brucei sub-species and Trypanosoma evansi are not monophyletic, confirming earlier studies that indicated high similarity among Trypanosoma “sub-species”. We also used discriminant analysis of principal components (DAPC) on the same set of SNPs, identifying seven genetic clusters. These clusters do not correspond well with existing taxonomic classifications, in agreement with the phylogenetic analysis. Geographic origin is reflected in both the phylogeny and clustering analysis. Finally, we used sparse linear discriminant analysis to rank SNPs by their informativeness in differentiating the strains in our data set. As few as 84 SNPs can completely distinguish the strains used in our study, and discriminant analysis was still able to detect genetic structure using as few as 10 SNPs. Our results reinforce earlier results of high genetic similarity between the African Trypanozoon. Despite this, a small subset of SNPs can be used to identify genetic markers that can be used for strain identification or other epidemiological investigations.

Use of rhodamine B to mark the body and seminal fluid of male <i>Aedes aegypti</i> for mark-release-recapture experiments and estimating efficacy of sterile male releases

28 September 2017 - 9:00pm

by Brian J. Johnson, Sara N. Mitchell, Christopher J. Paton, Jessica Stevenson, Kyran M. Staunton, Nigel Snoad, Nigel Beebe, Bradley White, Scott A. Ritchie

Background

Recent interest in male-based sterile insect technique (SIT) and incompatible insect technique (IIT) to control Aedes aegypti and Aedes albopictus populations has revealed the need for an economical, rapid diagnostic tool for determining dispersion and mating success of sterilized males in the wild. Previous reports from other insects indicated rhodamine B, a thiol-reactive fluorescent dye, administered via sugar-feeding can be used to stain the body tissue and seminal fluid of insects. Here, we report on the adaptation of this technique for male Ae. aegypti to allow for rapid assessment of competitiveness (mating success) during field releases.

Methodology/Principle findings

Marking was achieved by feeding males on 0.1, 0.2, 0.4 or 0.8% rhodamine B (w/v) in 50% honey solutions during free flight. All concentrations produced >95% transfer to females and successful body marking after 4 days of feeding, with 0.4 and 0.8% solutions producing the longest-lasting body marking. Importantly, rhodamine B marking had no effect on male mating competitiveness and proof-of-principle field releases demonstrated successful transfer of marked seminal fluid to females under field conditions and recapture of marked males.

Conclusions/Significance

These results reveal rhodamine B to be a potentially useful evaluation method for male-based SIT/IIT control strategies as well as a viable body marking technique for male-based mark-release-recapture experiments without the negative side-effects of traditional marking methods. As a standalone method for use in mating competitiveness assays, rhodamine B marking is less expensive than PCR (e.g. paternity analysis) and stable isotope semen labelling methods and less time-consuming than female fertility assays used to assess competitiveness of sterilised males.

The diversity of the Chagas parasite, <i>Trypanosoma cruzi</i>, infecting the main Central American vector, <i>Triatoma dimidiata</i>, from Mexico to Colombia

28 September 2017 - 9:00pm

by Patricia L. Dorn, Annie G. McClure, Meghan D. Gallaspy, Etienne Waleckx, Adrienne S. Woods, Maria Carlota Monroy, Lori Stevens

Little is known about the strains of Trypanosoma cruzi circulating in Central America and specifically in the most important vector in this region, Triatoma dimidiata. Approximately six million people are infected with T. cruzi, the causative agent of Chagas disease, which has the greatest negative economic impact and is responsible for ~12,000 deaths annually in Latin America. By international consensus, strains of T. cruzi are divided into six monophyletic clades called discrete typing units (DTUs TcI-VI) and a seventh DTU first identified in bats called TcBat. TcI shows the greatest geographic range and diversity. Identifying strains present and diversity within these strains is important as different strains and their genotypes may cause different pathologies and may circulate in different localities and transmission cycles, thus impacting control efforts, treatment and vaccine development. To determine parasite strains present in T. dimidiata across its geographic range from Mexico to Colombia, we isolated abdominal DNA from T. dimidiata and determined which specimens were infected with T. cruzi by PCR. Strains from infected insects were determined by comparing the sequence of the 18S rDNA and the spliced-leader intergenic region to typed strains in GenBank. Two DTUs were found: 94% of infected T. dimidiata contained TcI and 6% contained TcIV. TcI exhibited high genetic diversity. Geographic structure of TcI haplotypes was evident by Principal Component and Median-Joining Network analyses as well as a significant result in the Mantel test, indicating isolation by distance. There was little evidence of association with TcI haplotypes and host/vector or ecotope. This study provides new information about the strains circulating in the most important Chagas vector in Central America and reveals considerable variability within TcI as well as geographic structuring at this large geographic scale. The lack of association with particular vectors/hosts or ecotopes suggests the parasites are moving among vectors/hosts and ecotopes therefore a comprehensive approach, such as the Ecohealth approach that makes houses refractory to the vectors will be needed to successfully halt transmission of Chagas disease.

Global surgery and the neglected tropical diseases

28 September 2017 - 9:00pm

by Vivek Karun, Peter J. Hotez, Todd K. Rosengart

Impact of environmental factors on neglected emerging arboviral diseases

27 September 2017 - 9:00pm

by Camila Lorenz, Thiago S. Azevedo, Flávia Virginio, Breno S. Aguiar, Francisco Chiaravalloti-Neto, Lincoln Suesdek

Background

Brazil is a tropical country that is largely covered by rainforests and other natural ecosystems, which provide ideal conditions for the existence of many arboviruses. However, few analyses have examined the associations between environmental factors and arboviral diseases. Thus, based on the hypothesis of correlation between environment and epidemiology, the proposals of this study were (1) to obtain the probability of occurrence of Oropouche, Mayaro, Saint Louis and Rocio fevers in Brazil based on environmental conditions corresponding to the periods of occurrence of the outbreaks; (2) to describe the macroclimatic scenario in Brazil in the last 50 years, evaluating if there was any detectable tendency to increase temperatures and (3) to model future expansion of those arboviruses in Brazil based on future temperature projections.

Methodology/Principal findings

Our model assessed seven environmental factors (annual rainfall, annual temperature, elevation, seasonality of temperature, seasonality of precipitation, thermal amplitude, and daytime temperature variation) for their association with the occurrence of outbreaks in the last 50 years. Our results suggest that various environmental factors distinctly influence the distribution of each arbovirus, with temperature being the central determinant of disease distribution in all high-risk areas. These areas are subject to change, since the average temperature of some areas has increased significantly over the time.

Conclusions/Significance

This is the first spatio-temporal study of the Oropouche, Mayaro, Saint Louis, and Rocio arboviruses, and our results indicate that they may become increasingly important public health problems in Brazil. Thus, next studies and control programs should include these diseases and also take into consideration key environmental elements.

Immune status alters the probability of apparent illness due to dengue virus infection: Evidence from a pooled analysis across multiple cohort and cluster studies

27 September 2017 - 9:00pm

by Hannah E. Clapham, Derek A. T. Cummings, Michael A. Johansson

Dengue is an important vector-borne pathogen found across much of the world. Many factors complicate our understanding of the relationship between infection with one of the four dengue virus serotypes, and the observed incidence of disease. One of the factors is a large proportion of infections appear to result in no or few symptoms, while others result in severe infections. Estimates of the proportion of infections that result in no symptoms (inapparent) vary widely from 8% to 100%, depending on study and setting. To investigate the sources of variation of these estimates, we used a flexible framework to combine data from multiple cohort studies and cluster studies (follow-up around index cases). Building on previous observations that the immune status of individuals affects their probability of apparent disease, we estimated the probability of apparent disease among individuals with different exposure histories. In cohort studies mostly assessing infection in children, we estimated the proportion of infections that are apparent as 0.18 (95% Credible Interval, CI: 0.16, 0.20) for primary infections, 0.13 (95% CI: 0.05, 0.17) for individuals infected in the year following a first infection (cross-immune period), and 0.41 (95% CI: 0.36, 0.45) for those experiencing secondary infections after this first year. Estimates of the proportion of infections that are apparent from cluster studies were slightly higher than those from cohort studies for both primary and secondary infections, 0.22 (95% CI: 0.15, 0.29) and 0.57 (95% CI: 0.49, 0.68) respectively. We attempted to estimate the apparent proportion by serotype, but current published data were too limited to distinguish the presence or absence of serotype-specific differences. These estimates are critical for understanding dengue epidemiology. Most dengue data come from passive surveillance systems which not only miss most infections because they are asymptomatic and often underreported, but will also vary in sensitivity over time due to the interaction between previous incidence and the symptomatic proportion, as shown here. Nonetheless the underlying incidence of infection is critical to understanding susceptibility of the population and estimating the true burden of disease, key factors for effectively targeting interventions. The estimates shown here help clarify the link between past infection, observed disease, and current transmission intensity.

How much will it cost to eradicate lymphatic filariasis? An analysis of the financial and economic costs of intensified efforts against lymphatic filariasis

26 September 2017 - 9:00pm

by Randee J. Kastner, Elisa Sicuri, Christopher M. Stone, Gabriel Matwale, Ambrose Onapa, Fabrizio Tediosi

Introduction

Lymphatic filariasis (LF), a neglected tropical disease (NTD) preventable through mass drug administration (MDA), is one of six diseases deemed possibly eradicable. Previously we developed one LF elimination scenario, which assumes MDA scale-up to continue in all countries that have previously undertaken MDA. In contrast, our three previously developed eradication scenarios assume all LF endemic countries will undertake MDA at an average (eradication I), fast (eradication II), or instantaneous (eradication III) rate of scale-up. In this analysis we use a micro-costing model to project the financial and economic costs of each of these scenarios in order to provide evidence to decision makers about the investment required to eliminate and eradicate LF.

Methodology/Key findings

Costing was undertaken from a health system perspective, with all results expressed in 2012 US dollars (USD). A discount rate of 3% was applied to calculate the net present value of future costs. Prospective NTD budgets from LF endemic countries were reviewed to preliminarily determine activities and resources necessary to undertake a program to eliminate LF at a country level. In consultation with LF program experts, activities and resources were further reviewed and a refined list of activities and necessary resources, along with their associated quantities and costs, were determined and grouped into the following activities: advocacy and communication, capacity strengthening, coordination and strengthening partnerships, data management, ongoing surveillance, monitoring and supervision, drug delivery, and administration. The costs of mapping and undertaking transmission assessment surveys and the value of donated drugs and volunteer time were also accounted for. Using previously developed scenarios and deterministic estimates of MDA duration, the financial and economic costs of interrupting LF transmission under varying rates of MDA scale-up were then modelled using a micro-costing approach. The elimination scenario, which includes countries that previously undertook MDA, is estimated to cost 929 million USD (95% Credible Interval: 884m-972m). Proceeding to eradication is anticipated to require a higher financial investment, estimated at 1.24 billion USD (1.17bn-1.30bn) in the eradication III scenario (immediate scale-up), with eradication II (intensified scale-up) projected at 1.27 billion USD (1.21bn-1.33bn), and eradication I (slow scale-up) estimated at 1.29 billion USD (1.23bn-1.34bn). The economic costs of the eradication III scenario are estimated at approximately 7.57 billion USD (7.12bn-7.94bn), while the elimination scenario is projected to have an economic cost of 5.21 billion USD (4.91bn-5.45bn). Countries in the AFRO region will require the greatest investment to reach elimination or eradication, but also stand to gain the most in cost savings. Across all scenarios, capacity strengthening and advocacy and communication represent the greatest financial costs, whereas mapping, post-MDA surveillance, and administration comprise the least.

Conclusions/Significance

Though challenging to implement, our results indicate that financial and economic savings are greatest under the eradication III scenario. Thus, if eradication for LF is the objective, accelerated scale-up is projected to be the best investment.

Effects of schistosomiasis on susceptibility to HIV-1 infection and HIV-1 viral load at HIV-1 seroconversion: A nested case-control study

25 September 2017 - 9:00pm

by Jennifer A. Downs, Kathryn M. Dupnik, Govert J. van Dam, Mark Urassa, Peter Lutonja, Dieuwke Kornelis, Claudia J. de Dood, Pytsje Hoekstra, Chifundo Kanjala, Raphael Isingo, Robert N. Peck, Myung Hee Lee, Paul L. A. M. Corstjens, Jim Todd, John M. Changalucha, Warren D. Johnson Jr., Daniel W. Fitzgerald

Background

Schistosomiasis affects 218 million people worldwide, with most infections in Africa. Prevalence studies suggest that people with chronic schistosomiasis may have higher risk of HIV-1 acquisition and impaired ability to control HIV-1 replication once infected. We hypothesized that: (1) pre-existing schistosome infection may increase the odds of HIV-1 acquisition and that the effects may differ between men and women, and (2) individuals with active schistosome infection at the time of HIV-1 acquisition may have impaired immune control of HIV-1, resulting in higher HIV-1 viral loads at HIV-1 seroconversion.

Methology/Principal findings

We conducted a nested case-control study within a large population-based survey of HIV-1 transmission in Tanzania. A population of adults from seven villages was tested for HIV in 2007, 2010, and 2013 and dried blood spots were archived for future studies with participants’ consent. Approximately 40% of this population has Schistosoma mansoni infection, and 2% has S. haematobium.We tested for schistosome antigens in the pre- and post-HIV-1-seroconversion blood spots of people who acquired HIV-1. We also tested blood spots of matched controls who did not acquire HIV-1 and calculated the odds that a person with schistosomiasis would become HIV-1-infected compared to these matched controls. Analysis was stratified by gender.We compared 73 HIV-1 seroconverters with 265 controls. Women with schistosome infections had a higher odds of HIV-1 acquisition than those without (adjusted OR = 2.8 [1.2–6.6], p = 0.019). Schistosome-infected men did not have an increased odds of HIV-1 acquisition (adjusted OR = 0.7 [0.3–1.8], p = 0.42).We additionally compared HIV-1 RNA levels in the post-seroconversion blood spots in HIV-1 seroconverters with schistosomiasis versus those without who became HIV-infected in 2010, before antiretroviral therapy was widely available in the region. The median whole blood HIV-1 RNA level in the 15 HIV-1 seroconverters with schistosome infection was significantly higher than in the 22 without schistosomiasis: 4.4 [3.9–4.6] log10 copies/mL versus 3.7 [3.2–4.3], p = 0.017.

Conclusions/Significance

We confirm, in an area with endemic S. mansoni, that pre-existing schistosome infection increases odds of HIV-1 acquisition in women and raises HIV-1 viral load at the time of HIV-1 seroconversion. This is the first study to demonstrate the effect of schistosome infection on HIV-1 susceptibility and viral control, and to differentiate effects by gender. Validation studies will be needed at additional sites.

Impact of <i>Enterobius vermicularis</i> infection and mebendazole treatment on intestinal microbiota and host immune response

25 September 2017 - 9:00pm

by Chin-An Yang, Chao Liang, Chia-Li Lin, Chiung-Tzu Hsiao, Ching-Tien Peng, Hung-Chih Lin, Jan-Gowth Chang

Background

Previous studies on the association of enterobiasis and chronic inflammatory diseases have revealed contradictory results. The interaction of Enterobius vermicularis infection in particular with gut microbiota and induced immune responses has never been thoroughly examined.

Methodology/Findings

In order to answer the question of whether exposure to pinworm and mebendazole can shift the intestinal microbial composition and immune responses, we recruited 109 (30 pinworm-negative, 79 pinworm-infected) first and fourth grade primary school children in Taichung, Taiwan, for a gut microbiome study and an intestinal cytokine and SIgA analysis. In the pinworm-infected individuals, fecal samples were collected again at 2 weeks after administration of 100 mg mebendazole. Gut microbiota diversity increased after Enterobius infection, and it peaked after administration of mebendazole. At the phylum level, pinworm infection and mebendazole deworming were associated with a decreased relative abundance of Fusobacteria and an increased proportion of Actinobacteria. At the genus level, the relative abundance of the probiotic Bifidobacterium increased after enterobiasis and mebendazole treatment. The intestinal SIgA level was found to be lower in the pinworm-infected group, and was elevated in half of the mebendazole-treated group. A higher proportion of pre-treatment Salmonella spp. was associated with a non-increase in SIgA after mebendazole deworming treatment.

Conclusions/Significance

Childhood exposure to pinworm plus mebendazole is associated with increased bacterial diversity, an increased abundance of Actinobacteria including the probiotic Bifidobacterium, and a decreased proportion of Fusobacteria. The gut SIgA level was lower in the pinworm-infected group, and was increased in half of the individuals after mebendazole deworming treatment.

Quantitative multiplexed proteomics of <i>Taenia solium</i> cysts obtained from the skeletal muscle and central nervous system of pigs

25 September 2017 - 9:00pm

by José Navarrete-Perea, Marta Isasa, Joao A. Paulo, Ricardo Corral-Corral, Jeanette Flores-Bautista, Beatriz Hernández-Téllez, Raúl J. Bobes, Gladis Fragoso, Edda Sciutto, Xavier Soberón, Steven P. Gygi, Juan P. Laclette

In human and porcine cysticercosis caused by the tapeworm Taenia solium, the larval stage (cysts) can infest several tissues including the central nervous system (CNS) and the skeletal muscles (SM). The cyst’s proteomics changes associated with the tissue localization in the host tissues have been poorly studied. Quantitative multiplexed proteomics has the power to evaluate global proteome changes in response to different conditions. Here, using a TMT-multiplexed strategy we identified and quantified over 4,200 proteins in cysts obtained from the SM and CNS of pigs, of which 891 were host proteins. To our knowledge, this is the most extensive intermixing of host and parasite proteins reported for tapeworm infections.Several antigens in cysticercosis, i.e., GP50, paramyosin and a calcium-binding protein were enriched in skeletal muscle cysts. Our results suggested the occurrence of tissue-enriched antigen that could be useful in the improvement of the immunodiagnosis for cysticercosis. Using several algorithms for epitope detection, we selected 42 highly antigenic proteins enriched for each tissue localization of the cysts. Taking into account the fold changes and the antigen/epitope contents, we selected 10 proteins and produced synthetic peptides from the best epitopes. Nine peptides were recognized by serum antibodies of cysticercotic pigs, suggesting that those peptides are antigens. Mixtures of peptides derived from SM and CNS cysts yielded better results than mixtures of peptides derived from a single tissue location, however the identification of the ‘optimal’ tissue-enriched antigens remains to be discovered. Through machine learning technologies, we determined that a reliable immunodiagnostic test for porcine cysticercosis required at least five different antigenic determinants.

Assessment of sesquiterpene lactones isolated from <i>Mikania</i> plants species for their potential efficacy against <i>Trypanosoma cruzi</i> and <i>Leishmania</i> sp.

25 September 2017 - 9:00pm

by Laura C. Laurella, Natacha Cerny, Augusto E. Bivona, Andrés Sánchez Alberti, Gustavo Giberti, Emilio L. Malchiodi, Virginia S. Martino, Cesar A. Catalan, María Rosario Alonso, Silvia I. Cazorla, Valeria P. Sülsen

Four sesquiterpene lactones, mikanolide, deoxymikanolide, dihydromikanolide and scandenolide, were isolated by a bioassay-guided fractionation of Mikania variifolia and Mikania micrantha dichloromethane extracts. Mikanolide and deoxymikanolide were the major compounds in both extracts (2.2% and 0.4% for Mikania variifolia and 21.0% and 6.4% for Mikania micrantha respectively, calculated on extract dry weight). Mikanolide, deoxymikanolide and dihydromikanolide were active against Trypanosoma cruzi epimastigotes (50% inhibitory concentrations of 0.7, 0.08 and 2.5 μg/mL, for each compound respectively). These sesquiterpene lactones were also active against the bloodstream trypomastigotes (50% inhibitory concentrations for each compound were 2.1, 1.5 and 0.3 μg/mL, respectively) and against amastigotes (50% inhibitory concentrations for each compound were 4.5, 6.3 and 8.5 μg/mL, respectively). By contrast, scandenolide was not active on Trypanosoma cruzi. Besides, mikanolide and deoxymikanolide were also active on Leishmania braziliensis promastigotes (50% inhibitory concentrations of 5.1 and 11.5 μg/mL, respectively). The four sesquiterpene lactones were tested for their cytotoxicity on THP 1 cells. Deoxymikanolide presented the highest selectivity index for trypomastigotes (SI = 54) and amastigotes (SI = 12.5). In an in vivo model of Trypanosoma cruzi infection, deoxymikanolide was able to decrease the parasitemia and the weight loss associated to the acute phase of the parasite infection. More importantly, while 100% of control mice died by day 22 after receiving a lethal T. cruzi infection, 70% of deoxymikanolide-treated mice survived. We also observed that this compound increased TNF-α and IL-12 production by macrophages, which could contribute to control T. cruzi infection.

New insights into experimental visceral leishmaniasis: Real-time <i>in vivo</i> imaging of <i>Leishmania donovani</i> virulence

25 September 2017 - 9:00pm

by Guilherme D. Melo, Sophie Goyard, Hervé Lecoeur, Eline Rouault, Pascale Pescher, Laurence Fiette, Alexandre Boissonnas, Paola Minoprio, Thierry Lang

Trial registration

ClinicalTrials.gov 2013-0047.

Estimating the burden of scrub typhus: A systematic review

25 September 2017 - 9:00pm

by Ana Bonell, Yoel Lubell, Paul N. Newton, John A. Crump, Daniel H. Paris

Background

Scrub typhus is a vector-borne zoonotic disease that can be life-threatening. There are no licensed vaccines, or vector control efforts in place. Despite increasing awareness in endemic regions, the public health burden and global distribution of scrub typhus remains poorly known.

Methods

We systematically reviewed all literature from public health records, fever studies and reports available on the Ovid MEDLINE, Embase Classic + Embase and EconLit databases, to estimate the burden of scrub typhus since the year 2000.

Findings

In prospective fever studies from Asia, scrub typhus is a leading cause of treatable non-malarial febrile illness. Sero-epidemiological data also suggest that Orientia tsutsugamushi infection is common across Asia, with seroprevalence ranging from 9.3%–27.9% (median 22.2% IQR 18.6–25.7). A substantial apparent rise in minimum disease incidence (median 4.6/100,000/10 years, highest in China with 11.2/100,000/10 years) was reported through passive national surveillance systems in South Korea, Japan, China, and Thailand. Case fatality risks from areas of reduced drug-susceptibility are reported at 12.2% and 13.6% for South India and northern Thailand, respectively. Mortality reports vary widely around a median mortality of 6.0% for untreated and 1.4% for treated scrub typhus. Limited evidence suggests high mortality in complicated scrub typhus with CNS involvement (13.6% mortality), multi-organ dysfunction (24.1%) and high pregnancy miscarriage rates with poor neonatal outcomes.

Interpretation

Scrub typhus appears to be a truly neglected tropical disease mainly affecting rural populations, but increasingly also metropolitan areas. Rising minimum incidence rates have been reported over the past 8–10 years from countries with an established surveillance system. A wider distribution of scrub typhus beyond Asia is likely, based on reports from South America and Africa. Unfortunately, the quality and quantity of the available data on scrub typhus epidemiology is currently too limited for any economical, mathematical modeling or mapping approaches.

Visceral leishmaniasis and HIV/AIDS in Brazil: Are we aware enough?

25 September 2017 - 9:00pm

by Marcia Leite de Sousa-Gomes, Gustavo Adolfo Sierra Romero, Guilherme Loureiro Werneck

Background

The urbanization of visceral leishmaniasis (VL) and the concurrent movement of the HIV infection to rural areas in Brazil are possible mechanisms associated with an increased number of Leishmania/HIV coinfected people. This study aimed to describe the clinical and epidemiological profile of VL/HIV coinfected patients and compare this profile to non-coinfected VL patients.

Methods

Cases of VL/HIV coinfection were obtained through a probabilistic record linkage of databases of VL and AIDS cases from the Brazilian Ministry of Health.

Results

We retrieved 760 cases of VL/HIV coinfection, most prevalent in adult males, with incidence ranging from 0.01 to 0.07 cases, per 100.000 population, in 2001 and 2010, respectively. Case-fatality rates were 27.3% in 2001 and 23.2% in 2010. Weakness, weight loss, cough, other associated infections and haemorrhagic phenomena were more commonly found among coinfected patients, which had a fatality rate three times higher as compared to the non-coinfected group. The relapse proportion was two times greater among coinfected (6.3%) than non-coinfected (3.1%).

Conclusions

The results found herein contribute to the increase of knowledge of the epidemiological situation of VL/HIV coinfection in Brazil and reinforce the necessity of implementing specific strategies to improve early case detection and efficacious and less toxic treatment in order to achieve lower case-fatality rates.

Household costs of hospitalized dengue illness in semi-rural Thailand

22 September 2017 - 9:00pm

by Yesim Tozan, Pitcha Ratanawong, Maquines Odhiambo Sewe, Annelies Wilder-Smith, Pattamaporn Kittayapong

Background

Dengue-related illness is a leading cause of hospitalization and death in Thailand and other Southeast Asian countries, imposing a major economic burden on households, health systems, and governments. This study aims to assess the economic impact of hospitalized dengue cases on households in Chachoengsao province in eastern Thailand.

Methods

We conducted a prospective cost-of-illness study of hospitalized pediatric and adult dengue patients at three public hospitals. We examined all hospitalized dengue cases regardless of disease severity. Patients or their legal guardians were interviewed using a standard questionnaire to determine household-level medical and non-medical expenditures and income losses during the illness episode.

Results

Between March and September 2015, we recruited a total of 224 hospitalized patients (<5 years, 4%; 5–14 years, 20%, 15–24 years, 36%, 25–34 years, 15%; 35–44 years, 10%; 45+ years, 12%), who were clinically diagnosed with dengue. The total cost of a hospitalized dengue case was higher for adult patients than pediatric patients, and was US$153.6 and US$166.3 for pediatric DF and DHF patients, respectively, and US$171.2 and US$226.1 for adult DF and DHF patients, respectively. The financial burden on households increased with the severity of dengue illness.

Conclusions

Although 74% of the households reported that the patient received free medical care, hospitalized dengue illness cost approximately 19–23% of the monthly household income. These results indicated that dengue imposed a substantial financial burden on households in Thailand where a great majority of the population was covered by the Universal Coverage Scheme for health care.

Recombinant vaccines of a CD4<sup>+</sup> T-cell epitope promote efficient control of <i>Paracoccidioides brasiliensis</i> burden by restraining primary organ infection

22 September 2017 - 9:00pm

by Rodrigo Assunção Holanda, Julián Esteban Muñoz, Lucas Santos Dias, Leandro Buffoni Roque Silva, Julliana Ribeiro Alves Santos, Sthefany Pagliari, Érica Leandro Marciano Vieira, Tatiane Alves Paixão, Carlos Pelleschi Taborda, Daniel Assis Santos, Oscar Bruña-Romero

Paracoccidioidomycosis (PCM) is an infectious disease endemic to South America, caused by the thermally dimorphic fungi Paracoccidioides. Currently, there is no effective human vaccine that can be used in prophylactic or therapeutic regimes. We tested the hypothesis that the immunogenicity of the immunodominant CD4+ T-cell epitope (P10) of Paracoccidioides brasiliensis gp43 antigen might be significantly enhanced by using a hepatitis B virus-derived particle (VLP) as an antigen carrier. This chimera was administered to mice as a (His)6-purified protein (rPbT) or a replication-deficient human type 5 adenoviral vector (rAdPbT) in an immunoprophylaxis assay. The highly virulent Pb18 yeast strain was used to challenge our vaccine candidates. Fungal challenge evoked robust P10-specific memory CD4+ T cells secreting protective Th-1 cytokines in most groups of immunized mice. Furthermore, the highest level of fungal burden control was achieved when rAdPbT was inoculated in a homologous prime-boost regimen, with 10-fold less CFU recovering than in non-vaccinated mice. Systemic Pb18 spreading was only prevented when rAdPbT was previously inoculated. In summary, we present here VLP/P10 formulations as vaccine candidates against PCM, some of which have demonstrated for the first time their ability to prevent progression of this pernicious fungal disease, which represents a significant social burden in developing countries.

Molecular genomic characterization of tick- and human-derived severe fever with thrombocytopenia syndrome virus isolates from South Korea

22 September 2017 - 9:00pm

by Seok-Min Yun, Su-Jin Park, Sun-Whan Park, WooYoung Choi, Hye Won Jeong, Young-Ki Choi, Won-Ja Lee

Background

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne viral disease caused by the SFTS virus (SFTSV) from Bunyaviridae that is endemic in East Asia. However, the genetic and evolutionary characteristics shared between tick- and human-derived Korean SFTSV strains are still limited.

Methodology/Principal findings

In this study we identify, for the first time, the genome sequence of a tick (Haemaphysalis longicornis)-derived Korean SFTSV strain (designated as KAGWT) and compare this virus with recent human SFTSV isolates to identify the genetic variations and relationships among SFTSV strains. The genome of the KAGWT strain is consistent with the described genome of other members of the genus Phlebovirus with 6,368 nucleotides (nt), 3,378 nt, and 1,746 nt in the Large (L), Medium (M) and Small (S) segments, respectively. Compared with other completely sequenced human-derived Korean SFTSV strains, the KAGWT strain had highest sequence identities at the nucleotide and deduced amino acid level in each segment with the KAGWH3 strain which was isolated from SFTS patient within the same region, although there is one unique amino acid substitution in the Gn protein (A66S). Phylogenetic analyses of complete genome sequences revealed that at least four different genotypes of SFTSV are co-circulating in South Korea, and that the tick- and human-derived Korean SFTSV strains (genotype B) are closely related to one another. Although we could not detect reassortant, which are commonly observed in segmented viruses, further large-scale surveillance and detailed genomic analysis studies are needed to better understand the molecular epidemiology, genetic diversity, and evolution of SFTSV.

Conclusions/Significance

Full-length sequence analysis revealed a clear association between the genetic origins of tick- and human-derived SFTSV strains. While the most prevalent Korean SFTSV is genotype B, at least four different genotypes of SFTSV strains are co-circulating in South Korea. These findings provide information regarding the molecular epidemiology, genetic diversity, and evolution of SFTSV in East Asia.

Low antibody prevalence against <i>Bacillus cereus</i> biovar <i>anthracis</i> in Taï National Park, Côte d'Ivoire, indicates high rate of lethal infections in wildlife

21 September 2017 - 9:00pm

by Fee Zimmermann, Susanne M. Köhler, Kathrin Nowak, Susann Dupke, Anne Barduhn, Ariane Düx, Alexander Lang, Hélène M. De Nys, Jan F. Gogarten, Roland Grunow, Emmanuel Couacy-Hymann, Roman M. Wittig, Silke R. Klee, Fabian H. Leendertz

Bacillus cereus biovar anthracis (Bcbva) is a member of the B. cereus group which carries both B. anthracis virulence plasmids, causes anthrax-like disease in various wildlife species and was described in several sub-Saharan African rainforests. Long-term monitoring of carcasses in Taï National Park, Côte d’Ivoire, revealed continuous wildlife mortality due to Bcbva in a broad range of mammalian species. While non-lethal anthrax infections in wildlife have been described for B. anthracis, nothing is known about the odds of survival following an anthrax infection caused by Bcbva. To address this gap, we present the results of a serological study of anthrax in five wildlife species known to succumb to Bcbva in this ecosystem. Specific antibodies were only detected in two out of 15 wild red colobus monkeys (Procolobus badius) and one out of 10 black-and-white colobus monkeys (Colobus polykomos), but in none of 16 sooty mangabeys (Cercocebus atys), 9 chimpanzees (Pan troglodytes verus) and 9 Maxwell’s duikers (Cephalophus maxwellii). The combination of high mortality and low antibody detection rates indicates high virulence of this disease across these different mammalian species.

Evaluation of the pharmacokinetic-pharmacodynamic relationship of praziquantel in the <i>Schistosoma mansoni</i> mouse model

21 September 2017 - 9:00pm

by Nada Abla, Jennifer Keiser, Mireille Vargas, Natalie Reimers, Helmut Haas, Thomas Spangenberg

After more than 40 years of use, Praziquantel (PZQ) still remains the drug of choice for the treatment of intestinal and urogenital schistosomiasis. Its anti-parasitic activity resides primarily in the (R)-enantiomer. Hitherto neither the molecular target nor the pharmacokinetic-pharmacodynamic relationship have been fully elucidated. Here we investigated the efficacy and pharmacokinetics of PZQ in the Schistosoma mansoni mouse model to determine the key factors that drive its efficacy. Dose-response studies with racemic PZQ with or without addition of an irreversible pan-cytochrome P450 (CYP) inhibitor, 1-aminobenzotriazole (ABT), were performed. In addition, efficacy of PZQ in the presence of the CYP inducer, dexamethasone (DEX), was determined. Plasma samples were obtained by tail vein bleeding at 4 time points. The (R)-PZQ levels were determined using a LC-MS/MS method. Non-compartmental pharmacokinetic analysis was performed using PKsolver. In addition, experiments using an enhanced in vitro assay were conducted. We found that the use of ABT increased (R)-PZQ plasma exposures in the systemic circulation by ~10 to 20 fold but the latter were not predictive of efficacy. The use of DEX decreased plasma exposures of (R)-PZQ in the systemic circulation by ~10 fold without reducing efficacy. We extrapolated the (R)-PZQ concentrations in mouse portal vein / mesenteric veins from the systemic exposures and found that a free exposure of (R)-PZQ of ~ 20 μM*h in the portal vein was needed to obtain a worm burden reduction >60%. It is suggested that the high (R)-PZQ concentrations available before the hepatic first pass metabolism drive the efficacy against S. mansoni adult worms residing in the mesenteric veins. It is then possible that the current dosing regimen of 40 mg/kg in preventive chemotherapy programs may provide suboptimal concentrations in low-weight patients such as children, due to smaller total amounts of drug administered, and may consequently result in lower cure rates.

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