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Temperature modulates dengue virus epidemic growth rates through its effects on reproduction numbers and generation intervals

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

by Amir S. Siraj, Rachel J. Oidtman, John H. Huber, Moritz U. G. Kraemer, Oliver J. Brady, Michael A. Johansson, T. Alex Perkins

Epidemic growth rate, r, provides a more complete description of the potential for epidemics than the more commonly studied basic reproduction number, R0, yet the former has never been described as a function of temperature for dengue virus or other pathogens with temperature-sensitive transmission. The need to understand the drivers of epidemics of these pathogens is acute, with arthropod-borne virus epidemics becoming increasingly problematic. We addressed this need by developing temperature-dependent descriptions of the two components of r—R0 and the generation interval—to obtain a temperature-dependent description of r. Our results show that the generation interval is highly sensitive to temperature, decreasing twofold between 25 and 35°C and suggesting that dengue virus epidemics may accelerate as temperatures increase, not only because of more infections per generation but also because of faster generations. Under the empirical temperature relationships that we considered, we found that r peaked at a temperature threshold that was robust to uncertainty in model parameters that do not depend on temperature. Although the precise value of this temperature threshold could be refined following future studies of empirical temperature relationships, the framework we present for identifying such temperature thresholds offers a new way to classify regions in which dengue virus epidemic intensity could either increase or decrease under future climate change.

Evolution of anti-<i>Trypanosoma cruzi</i> antibody production in patients with chronic Chagas disease: Correlation between antibody titers and development of cardiac disease severity

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

by Ingebourg Georg, Alejandro Marcel Hasslocher-Moreno, Sergio Salles Xavier, Marcelo Teixeira de Holanda, Eric Henrique Roma, Maria da Gloria Bonecini-Almeida

Chagas disease is one of the most important endemic infections in Latin America affecting around 6–7 million people. About 30–50% of patients develop the cardiac form of the disease, which can lead to severe cardiac dysfunction and death. In this scenario, the identification of immunological markers of disease progression would be a valuable tool for early treatment and reduction of death rates. In this observational study, the production of anti-Trypanosoma cruzi antibodies through a retrospective longitudinal follow-up in chronic Chagas disease patients´ cohort and its correlation with disease progression and heart commitment was evaluated. Strong inverse correlation (ρ = -0.6375, p = 0.0005) between anti-T. cruzi IgG1 titers and left ventricular ejection fraction (LVEF) in chronic Chagas cardiomyopathy (CCC) patients were observed after disease progression. Elevated levels of anti-T. cruzi IgG3 titers were detected in all T. cruzi-infected patients, indicating a lack of correlation of this IgG isotype with disease progression. Furthermore, low levels of anti-T. cruzi IgG2, IgG4, and IgA were detected in all patients through the follow-up. Although without statistical significance anti-T. cruzi IgE tends to be more reactive in patients with the indeterminate form (IND) of the disease (p = 0.0637). As this study was conducted in patients with many years of chronic disease no anti-T. cruzi IgM was detected. Taken together, these results indicate that the levels of anti-T. cruzi IgG1 could be considered to seek for promising biomarkers to predict the severity of chronic Chagas disease cardiomyopathy.

Impact of mass drug administration for elimination of lymphatic filariasis in Nepal

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

by Chet Raj Ojha, Basant Joshi, Khagendra Prakash KC, Shyam Prakash Dumre, Keshav Kumar Yogi, Bandana Bhatta, Tulasi Adhikari, Kathryn Crowley, Babu Ram Marasaini

Background

Lymphatic filariasis (LF) is a neglected tropical disease transmitted by mosquitoes. Nepal has implemented a national effort to eliminate LF by 2020 through mass drug administration (MDA) using diethylcarbamazine (DEC) and albendazole (ALB). We assessed the impact of MDAs on LF in selected districts of Nepal after the recommended six MDA rounds had been completed.

Methodology and principal findings

Baseline surveys were conducted in seven districts and mapping data were used as baseline in the other three districts before starting MDA in 2009. LF antigen (Ag) prevalence ranged from 1.06% to 20% among districts included in the baseline and mapping study. The number of people who received DEC and ALB were recorded during each MDA round and population-based cluster surveys were conducted at least once in each district during the life of the program. The reported MDA coverage in five districts was consistently at least 65%. Two districts achieved the targeted coverage in four out of five rounds and the rest three districts achieved the target only in the first round. A pre-transmission assessment survey (pre-TAS) was conducted in one sentinel site and at least one spot check site in each of the districts after five MDA rounds. In pre-TAS, all the sites of five districts (Pyuthan, Arghakhanchi, Kaski, Bhaktapur, and Kathmandu) and all but one spot check site of Lalitpur district had LF Ag < 2% (ranging from 0.0% to 1.99%). Transmission assessment survey (TAS) was conducted in six evaluation units (EUs) consisting of six districts qualified on pre-TAS. Though MDA coverage of 65% was not achieved in three districts (Kathmandu, Lalitpur and Bhaktapur), Nepal government in consultation with World Health Organization (WHO) decided to conduct TAS. All six EUs achieved the LF Ag threshold required to stop MDA in TAS, despite the low reported MDA coverage in those three districts.

Conclusions

Although Nepal has achieved significant progress towards LF elimination, five rounds of MDA were not sufficient to disrupt the transmission cycle in all districts, probably because of high baseline prevalence.

CD8<sup>+</sup> T cells provide immune protection against murine disseminated endotheliotropic <i>Orientia tsutsugamushi</i> infection

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

by Guang Xu, Nicole L. Mendell, Yuejin Liang, Thomas R. Shelite, Yenny Goez-Rivillas, Lynn Soong, Donald H. Bouyer, David H. Walker

Scrub typhus, caused by a Gram-negative obligately intracellular coccobacillus, Orientia tsutsugamushi, is a long neglected but important tropical disease. Orientia tsutsugamushi causes illness in one million people each year, and 1 billion people are at risk. Without appropriate diagnosis and treatment, the disease can cause severe multiorgan failure with a case fatality rate of 7–15%. The current gaps in knowledge of immunity include the unknown mechanisms of host immunity to O. tsutsugamushi. Using an intravenous (i.v.) disseminated infection mouse model, we observed that more CD8+ T cells than CD4+ T cells were present in the spleen of infected mice at 12 dpi. We also determined that Treg cells and the proportion of T cells producing IL-10 were significantly increased from 6 dpi, which correlated with the onset of illness, body weight loss, and increased bacterial loads. We further studied CD8-/-, MHC I-/- and wild type control (WT) C57BL/6J mice to determine the importance of CD8+ T cells and MHC I molecules. After infection with an ordinarily sub-lethal dose of O. tsutsugamushi, all CD8-/- and MHC I-/- mice were moribund between 12 and 15 dpi, whereas all WT mice survived. Bacterial loads in the lung, kidney, liver and spleen of CD8-/- and MHC I-/- mice were significantly greater than those in WT mice. Interferon-γ (IFN-γ) and granzyme B mRNA levels in the liver of CD8-/- and MHC I-/- mice were significantly greater than in WT mice. In addition, more severe histopathologic lesions were observed in CD8-/- mice. Finally, adoptive transfer confirmed a major role of immune CD8+ T cells as well as a less effective contribution by immune CD8 T cell-depleted splenocytes in protection against O. tsutsugamushi infection. These studies demonstrated the critical importance of CD8+ T cells in the host immune response during O. tsutsugamushi infection.

2b-RAD genotyping for population genomic studies of Chagas disease vectors: <i>Rhodnius ecuadoriensis</i> in Ecuador

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

by Luis E. Hernandez-Castro, Marta Paterno, Anita G. Villacís, Björn Andersson, Jaime A. Costales, Michele De Noia, Sofía Ocaña-Mayorga, Cesar A. Yumiseva, Mario J. Grijalva, Martin S. Llewellyn

Background

Rhodnius ecuadoriensis is the main triatomine vector of Chagas disease, American trypanosomiasis, in Southern Ecuador and Northern Peru. Genomic approaches and next generation sequencing technologies have become powerful tools for investigating population diversity and structure which is a key consideration for vector control. Here we assess the effectiveness of three different 2b restriction site-associated DNA (2b-RAD) genotyping strategies in R. ecuadoriensis to provide sufficient genomic resolution to tease apart microevolutionary processes and undertake some pilot population genomic analyses.

Methodology/Principal findings

The 2b-RAD protocol was carried out in-house at a non-specialized laboratory using 20 R. ecuadoriensis adults collected from the central coast and southern Andean region of Ecuador, from June 2006 to July 2013. 2b-RAD sequencing data was performed on an Illumina MiSeq instrument and analyzed with the STACKS de novo pipeline for loci assembly and Single Nucleotide Polymorphism (SNP) discovery. Preliminary population genomic analyses (global AMOVA and Bayesian clustering) were implemented. Our results showed that the 2b-RAD genotyping protocol is effective for R. ecuadoriensis and likely for other triatomine species. However, only BcgI and CspCI restriction enzymes provided a number of markers suitable for population genomic analysis at the read depth we generated. Our preliminary genomic analyses detected a signal of genetic structuring across the study area.

Conclusions/Significance

Our findings suggest that 2b-RAD genotyping is both a cost effective and methodologically simple approach for generating high resolution genomic data for Chagas disease vectors with the power to distinguish between different vector populations at epidemiologically relevant scales. As such, 2b-RAD represents a powerful tool in the hands of medical entomologists with limited access to specialized molecular biological equipment.

The natural history of acute Ebola virus disease among patients managed in five Ebola treatment units in West Africa: A retrospective cohort study

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

by Kelly Skrable, Reshma Roshania, Michaela Mallow, Vanessa Wolfman, Matthew Siakor, Adam C. Levine

Introduction

Previous studies of Ebola Virus Disease (EVD) have focused on clinical symptoms and Ebola virus (EBOV) cycle threshold (CT) values recorded at patient triage. Our study explores EVD symptoms and EBOV CT values from onset of illness to recovery or death in a diverse population of patients.

Methodology/Principal findings

We analyzed clinical care data from EBOV positive patients admitted to five Ebola treatment units in West Africa from 2014–2015. Prevalence of clinical signs/symptoms and CT values were explored using descriptive statistics. Logistic regression was used to examine their association with mortality. Survival was analyzed using Kaplan-Meier estimators from symptom onset date to death. During the first week of illness, dyspnea (OR = 2.44, 95% CI: 1.07–5.85) and tachycardia (OR = 10.22, 95% CI: 2.20–56.71) were associated with higher odds of mortality. Dyspnea (OR = 2.33, 95% CI: 1.210–4.581), bleeding (OR = 2.51, 95% CI: 1.219–5.337), and diarrhoea (OR = 2.79, 95% CI: 1.171–6.970) at any point during the illness course were associated with higher odds of mortality. Higher initial (OR = 0.85, 95% CI: 0.81–0.89) and mean (OR = 0.60, 95% CI: 0.53–0.66) CT values were associated with lower odds of mortality. CT values reached their nadir after 3–5 days of illness and then rose in both survivors and non-survivors until recovery or death.

Conclusions/Significance

Our study demonstrates the population prevalence of clinical signs/symptoms and EBOV CT values over time in a large, diverse cohort of patients with EVD, as well as associations between symptoms/EBOV CT values and mortality. These findings have implications on surveillance, operational planning, and clinical care for future EVD outbreaks.

Dengue prediction by the web: Tweets are a useful tool for estimating and forecasting Dengue at country and city level

PLoS Neglected Tropical Diseases News - 18 July 2017 - 9:00pm

by Cecilia de Almeida Marques-Toledo, Carolin Marlen Degener, Livia Vinhal, Giovanini Coelho, Wagner Meira, Claudia Torres Codeço, Mauro Martins Teixeira

Background

Infectious diseases are a leading threat to public health. Accurate and timely monitoring of disease risk and progress can reduce their impact. Mentioning a disease in social networks is correlated with physician visits by patients, and can be used to estimate disease activity. Dengue is the fastest growing mosquito-borne viral disease, with an estimated annual incidence of 390 million infections, of which 96 million manifest clinically. Dengue burden is likely to increase in the future owing to trends toward increased urbanization, scarce water supplies and, possibly, environmental change. The epidemiological dynamic of Dengue is complex and difficult to predict, partly due to costly and slow surveillance systems.

Methodology / Principal findings

In this study, we aimed to quantitatively assess the usefulness of data acquired by Twitter for the early detection and monitoring of Dengue epidemics, both at country and city level at a weekly basis. Here, we evaluated and demonstrated the potential of tweets modeling for Dengue estimation and forecast, in comparison with other available web-based data, Google Trends and Wikipedia access logs. Also, we studied the factors that might influence the goodness-of-fit of the model. We built a simple model based on tweets that was able to ‘nowcast’, i.e. estimate disease numbers in the same week, but also ‘forecast’ disease in future weeks. At the country level, tweets are strongly associated with Dengue cases, and can estimate present and future Dengue cases until 8 weeks in advance. At city level, tweets are also useful for estimating Dengue activity. Our model can be applied successfully to small and less developed cities, suggesting a robust construction, even though it may be influenced by the incidence of the disease, the activity of Twitter locally, and social factors, including human development index and internet access.

Conclusions

Tweets association with Dengue cases is valuable to assist traditional Dengue surveillance at real-time and low-cost. Tweets are able to successfully nowcast, i.e. estimate Dengue in the present week, but also forecast, i.e. predict Dengue at until 8 weeks in the future, both at country and city level with high estimation capacity.

Potential risk factors associated with human alveolar echinococcosis: Systematic review and meta-analysis

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

by Franz J. Conraths, Carolina Probst, Alessia Possenti, Belgees Boufana, Rosella Saulle, Giuseppe La Torre, Luca Busani, Adriano Casulli

Background

Human alveolar echinococcosis (AE) is a severe zoonotic disease caused by the metacestode stage of Echinococcus multilocularis. AE is commonly associated with a long incubation period that may last for more than ten years. The objective of this systematic literature review was to identify and summarize the current knowledge on statistically relevant potential risk factors (PRFs) associated with AE in humans.

Methodology/Principal findings

Six bibliographic databases were searched, generating a total of 1,009 publications. Following the removal of duplicate records and the exclusion of papers that failed to meet the criteria of a previously agreed a priori protocol, 23 publications were retained; however, 6 of these did not contain data in a format that allowed their inclusion in the meta-analysis. The remaining 17 publications (6 case-control and 11 cross-sectional studies) were meta-analysed to investigate associations between AE and PRFs. Pooled odds ratio (OR) were used as a measure of effect and separately analysed for case-control and cross-sectional studies. In the case-control studies, the following PRFs for human AE showed higher odds of outcome: “dog ownership”, “cat ownership”, “have a kitchen garden”, “occupation: farmer”, “haymaking in meadows not adjacent to water”, “went to forests for vocational reasons”, “chewed grass” and “hunting / handling foxes”. In the cross-sectional studies, the following PRFs showed higher odds of outcome: “dog ownership”, “play with dogs”, “gender: female”, “age over 20 years”, “ethnic group: Tibetan”, “low income”, “source of drinking water other than well or tap”, “occupation: herding” and “low education”. Our meta-analysis confirmed that the chance of AE transmission through ingestion of food and water contaminated with E. multilocularis eggs exists, but showed also that food- and water-borne PRFs do not significantly increase the risk of infection.

Conclusions/significance

This systematic review analysed international peer-reviewed articles that have over the years contributed to our current understanding of the epidemiology of human AE. The identification of potential risk factors may help researchers and decision makers improve surveillance and/or preventive measures that aim at decreasing human infection with E. multilocularis. More primary studies are needed to confirm potential risk factors and their role in the epidemiology of human AE.

Characterizing the malaria rural-to-urban transmission interface: The importance of reactive case detection

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

by Karen Molina Gómez, M. Alejandra Caicedo, Alexandra Gaitán, Manuela Herrera-Varela, María Isabel Arce, Andrés F. Vallejo, Julio Padilla, Pablo Chaparro, M. Andreína Pacheco, Ananias A. Escalante, Myriam Arevalo-Herrera, Sócrates Herrera Valencia

Background

Reported urban malaria cases are increasing in Latin America, however, evidence of such trend remains insufficient. Here, we propose an integrated approach that allows characterizing malaria transmission at the rural-to-urban interface by combining epidemiological, entomological, and parasite genotyping methods.

Methods/Principal findings

A descriptive study that combines active (ACD), passive (PCD), and reactive (RCD) case detection was performed in urban and peri-urban neighborhoods of Quibdó, Colombia. Heads of households were interviewed and epidemiological surveys were conducted to assess malaria prevalence and identify potential risk factors. Sixteen primary cases, eight by ACD and eight by PCD were recruited for RCD. Using the RCD strategy, prevalence of 1% by microscopy (6/604) and 9% by quantitative polymerase chain reaction (qPCR) (52/604) were found. A total of 73 houses and 289 volunteers were screened leading to 41 secondary cases, all of them in peri-urban settings (14% prevalence). Most secondary cases were genetically distinct from primary cases indicating that there were independent occurrences. Plasmodium vivax was the predominant species (76.3%, 71/93), most of them being asymptomatic (46/71). Urban and peri-urban neighborhoods had significant sociodemographic differences. Twenty-four potential breeding sites were identified, all in peri-urban areas. The predominant vectors for 1,305 adults were Anopheles nuneztovari (56,2%) and An. Darlingi (42,5%). One An. nuneztovari specimen was confirmed naturally infected with P. falciparum by ELISA.

Conclusions

This study found no evidence supporting the existence of urban malaria transmission in Quibdó. RCD strategy was more efficient for identifying malaria cases than ACD alone in areas where malaria transmission is variable and unstable. Incorporating parasite genotyping allows discovering hidden patterns of malaria transmission that cannot be detected otherwise. We propose to use the term “focal case” for those primary cases that lead to discovery of secondary but genetically unrelated malaria cases indicating undetected malaria transmission.

Zika virus inhibits eIF2α-dependent stress granule assembly

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

by Raquel Amorim, Abdelkrim Temzi, Bryan D. Griffin, Andrew J. Mouland

Zika virus (ZIKV), a member of the Flaviviridae family, is the most recent emerging arbovirus with pandemic potential. During infection, viruses trigger the host cell stress response, leading to changes in RNA translation and the assembly of large aggregates of stalled translation preinitiation complexes, termed stress granules (SGs). Several reports demonstrate that flaviviruses modulate the assembly of stress granules (SG). As an emerging pathogen, little is known however about how ZIKV modulates the host cell stress response. In this work, we investigate how ZIKV modulates SG assembly. We demonstrate that ZIKV negatively impacts SG assembly under oxidative stress conditions induced by sodium arsenite (Ars), a treatment that leads to the phosphorylation of eIF2α. By contrast, no measurable difference in SG assembly was observed between mock and ZIKV-infected cells treated with sodium selenite (Se) or Pateamine A (PatA), compounds that trigger eIF2α-independent SG assembly. Interestingly, ZIKV infection markedly impaired the phosphorylation of eIF2α triggered in Ars-treated infected cells, and the abrogation of SG assembly in ZIKV-infected cells is, at least in part, dependent on eIF2α dephosphorylation. These data demonstrate that ZIKV elicits mechanisms to counteract host anti-viral stress responses to promote a cellular environment propitious for viral replication.

Antibody trapping: A novel mechanism of parasite immune evasion by the trematode <i>Echinostoma caproni</i>

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

by Alba Cortés, Javier Sotillo, Carla Muñoz-Antolí, Javier Molina-Durán, J. Guillermo Esteban, Rafael Toledo

Background

Helminth infections are among the most prevalent neglected tropical diseases, causing an enormous impact in global health and the socioeconomic growth of developing countries. In this context, the study of helminth biology, with emphasis on host-parasite interactions, appears as a promising approach for developing new tools to prevent and control these infections.

Methods/Principal findings

The role that antibody responses have on helminth infections is still not well understood. To go in depth into this issue, work on the intestinal helminth Echinostoma caproni (Trematoda: Echinostomatidae) has been undertaken. Adult parasites were recovered from infected mice and cultured in vitro. Double indirect immunofluorescence at increasing culture times was done to show that in vivo-bound surface antibodies become trapped within a layer of excretory/secretory products that covers the parasite. Entrapped antibodies are then degraded by parasite-derived proteases, since protease inhibitors prevent for antibody loss in culture. Electron microscopy and immunogold-labelling of secreted proteins provide evidence that this mechanism is consistent with tegument dynamics and ultrastructure, hence it is feasible to occur in vivo. Secretory vesicles discharge their content to the outside and released products are deposited over the parasite surface enabling antibody trapping.

Conclusion/Significance

At the site of infection, both parasite secretion and antibody binding occur simultaneously and constantly. The continuous entrapment of bound antibodies with newly secreted products may serve to minimize the deleterious effects of the antibody-mediated attack. This mechanism of immune evasion may aid to understand the limited effect that antibody responses have in helminth infections, and may contribute to the basis for vaccine development against these highly prevalent diseases.

Unraveling the genetic diversity and phylogeny of <i>Leishmania</i> RNA virus 1 strains of infected <i>Leishmania</i> isolates circulating in French Guiana

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

by Sourakhata Tirera, Marine Ginouves, Damien Donato, Ignacio S. Caballero, Christiane Bouchier, Anne Lavergne, Eliane Bourreau, Emilie Mosnier, Vincent Vantilcke, Pierre Couppié, Ghislaine Prevot, Vincent Lacoste

Introduction

Leishmania RNA virus type 1 (LRV1) is an endosymbiont of some Leishmania (Vianna) species in South America. Presence of LRV1 in parasites exacerbates disease severity in animal models and humans, related to a disproportioned innate immune response, and is correlated with drug treatment failures in humans. Although the virus was identified decades ago, its genomic diversity has been overlooked until now.

Methodology/Principles findings

We subjected LRV1 strains from 19 L. (V.) guyanensis and one L. (V.) braziliensis isolates obtained from cutaneous leishmaniasis samples identified throughout French Guiana with next-generation sequencing and de novo sequence assembly. We generated and analyzed 24 unique LRV1 sequences over their full-length coding regions. Multiple alignment of these new sequences revealed variability (0.5%–23.5%) across the entire sequence except for highly conserved motifs within the 5’ untranslated region. Phylogenetic analyses showed that viral genomes of L. (V.) guyanensis grouped into five distinct clusters. They further showed a species-dependent clustering between viral genomes of L. (V.) guyanensis and L. (V.) braziliensis, confirming a long-term co-evolutionary history. Noteworthy, we identified cases of multiple LRV1 infections in three of the 20 Leishmania isolates.

Conclusions/Significance

Here, we present the first-ever estimate of LRV1 genomic diversity that exists in Leishmania (V.) guyanensis parasites. Genetic characterization and phylogenetic analyses of these viruses has shed light on their evolutionary relationships. To our knowledge, this study is also the first to report cases of multiple LRV1 infections in some parasites. Finally, this work has made it possible to develop molecular tools for adequate identification and genotyping of LRV1 strains for diagnostic purposes. Given the suspected worsening role of LRV1 infection in the pathogenesis of human leishmaniasis, these data have a major impact from a clinical viewpoint and for the management of Leishmania-infected patients.

Zika virus alters the microRNA expression profile and elicits an RNAi response in <i>Aedes aegypti</i> mosquitoes

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

by Miguel A. Saldaña, Kayvan Etebari, Charles E. Hart, Steven G. Widen, Thomas G. Wood, Saravanan Thangamani, Sassan Asgari, Grant L. Hughes

Zika virus (ZIKV), a flavivirus transmitted primarily by Aedes aegypti, has recently spread globally in an unprecedented fashion, yet we have a poor understanding of host-microbe interactions in this system. To gain insights into the interplay between ZIKV and the mosquito, we sequenced the small RNA profiles in ZIKV-infected and non-infected Ae. aegypti mosquitoes at 2, 7 and 14 days post-infection. ZIKA induced an RNAi response in the mosquito with virus-derived short interfering RNAs and PIWI-interacting RNAs dramatically increased in abundance post-infection. Further, we found 17 host miRNAs that were modulated by ZIKV infection at all time points. Strikingly, many of these regulated miRNAs have been reported to have their expression altered by dengue and West Nile viruses, while the response was divergent from that induced by the alphavirus Chikungunya virus in mosquitoes. This suggests that conserved miRNA responses occur within mosquitoes in response to flavivirus infection. This study expands our understanding of ZIKV-vector interactions and provides potential avenues to be further investigated to target ZIKV in the mosquito host.

Genetic polymorphisms of the <i>IL6</i> and <i>NOD2</i> genes are risk factors for inflammatory reactions in leprosy

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

by Carolinne Sales-Marques, Cynthia Chester Cardoso, Lucia Elena Alvarado-Arnez, Ximena Illaramendi, Anna Maria Sales, Mariana de Andréa Hacker, Mayara Garcia de Mattos Barbosa, José Augusto da Costa Nery, Roberta Olmo Pinheiro, Euzenir Nunes Sarno, Antonio Guilherme Pacheco, Milton Ozório Moraes

The pathways that trigger exacerbated immune reactions in leprosy could be determined by genetic variations. Here, in a prospective approach, both genetic and non-genetic variables influencing the amount of time before the development of reactional episodes were studied using Kaplan–Meier survival curves, and the genetic effect was estimated by the Cox proportional-hazards regression model. In a sample including 447 leprosy patients, we confirmed that gender (male), and high bacillary clinical forms are risk factors for leprosy reactions. From the 15 single nucleotide polymorphisms (SNPs) at the 8 candidate genes genotyped (TNF/LTA, IFNG, IL10, TLR1, NOD2, SOD2, and IL6) we observed statistically different survival curves for rs751271 at the NOD2 and rs2069845 at the IL6 genes (log-rank p-values = 0.002 and 0.023, respectively), suggesting an influence on the amount of time before developing leprosy reactions. Cox models showed associations between the SNPs rs751271 at NOD2 and rs2069845 at IL6 with leprosy reactions (HRGT = 0.45, p = 0.002; HRAG = 1.88, p = 0.0008, respectively). Finally, IL-6 and IFN-γ levels were confirmed as high, while IL-10 titers were low in the sera of reactional patients. Rs751271-GT genotype-bearing individuals correlated (p = 0.05) with lower levels of IL-6 in sera samples, corroborating the genetic results. Although the experimental size may be considered a limitation of the study, the findings confirm the association of classical variables such as sex and clinical forms with leprosy, demonstrating the consistency of the results. From the results, we conclude that SNPs at the NOD2 and IL6 genes are associated with leprosy reactions as an outcome. NOD2 also has a clear functional pro-inflammatory link that is coherent with the exacerbated responses observed in these patients.

Community effectiveness of pyriproxyfen as a dengue vector control method: A systematic review

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

by Dorit Maoz, Tara Ward, Moody Samuel, Pie Müller, Silvia Runge-Ranzinger, Joao Toledo, Ross Boyce, Raman Velayudhan, Olaf Horstick

Background

Vector control is the only widely utilised method for primary prevention and control of dengue. The use of pyriproxyfen may be promising, and autodissemination approach may reach hard to reach breeding places. It offers a unique mode of action (juvenile hormone mimic) and as an additional tool for the management of insecticide resistance among Aedes vectors. However, evidence of efficacy and community effectiveness (CE) remains limited.

Objective

The aim of this systematic review is to compile and analyse the existing literature for evidence on the CE of pyriproxyfen as a vector control method for reducing Ae. aegypti and Ae. albopictus populations and thereby human dengue transmission.

Methods

Systematic search of PubMed, Embase, Lilacs, Cochrane library, WHOLIS, Web of Science, Google Scholar as well as reference lists of all identified studies. Removal of duplicates, screening of abstracts and assessment for eligibility of the remaining studies followed. Relevant data were extracted, and a quality assessment conducted. Results were classified into four main categories of how pyriproxyfen was applied: - 1) container treatment, 2) fumigation, 3) auto-dissemination or 4) combination treatments,–and analysed with a view to their public health implication.

Results

Out of 745 studies 17 studies were identified that fulfilled all eligibility criteria. The results show that pyriproxyfen can be effective in reducing the numbers of Aedes spp. immatures with different methods of application when targeting their main breeding sites. However, the combination of pyriproxyfen with a second product increases efficacy and/or persistence of the intervention and may also slow down the development of insecticide resistance. Open questions concern concentration and frequency of application in the various treatments. Area-wide ultra-low volume treatment with pyriproxyfen currently lacks evidence and cannot be recommended. Community participation and acceptance has not consistently been successful and needs to be further assessed. While all studies measured entomological endpoints, only two studies measured the reduction in human dengue cases, with inconclusive results.

Conclusions

Although pyriproxyfen is highly effective in controlling the immature stages of dengue transmitting mosquitoes, and–to a smaller degree–adult mosquitoes, there is weak evidence for a reduction of human dengue cases. More well designed larger studies with appropriate standardised outcome measures are needed before pyriproxyfen is incorporated in routine vector control programmes. Additionally, resistance to pyriproxyfen has been reported and needs investigation.

Magnetic resonance imaging and spectroscopy for differential assessment of liver abnormalities induced by <i>Opisthorchis felineus</i> in an animal model

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

by Alexandra G. Pershina, Vladimir V. Ivanov, Lina V. Efimova, Oleg B. Shevelev, Sergey V. Vtorushin, Tatjana V. Perevozchikova, Alexey E. Sazonov, Ludmila M. Ogorodova

Background

European liver fluke Opisthorchis felineus, causing opisthorchiasis disease, is widespread in Russia, Ukraine, Kazakhstan and sporadically detected in the EU countries. O. felineus infection leads to hepatobiliary pathological changes, cholangitis, fibrosis and, in severe cases, malignant transformation of bile ducts. Due to absence of specific symptoms, the infection is frequently neglected for a long period. The association of opisthorchiasis with almost incurable bile duct cancer and rising international migration of people that increases the risk of the parasitic etiology of liver fibrosis in non-endemic regions determine high demand for development of approaches to opisthorchiasis detection.

Methodology/Principal findings

In vivo magnetic resonance imaging and spectroscopy (MRI and MRS) were applied for differential assessment of hepatic abnormalities induced by O. felineus in an experimental animal model. Correlations of the MR-findings with the histological data as well as the data of the biochemical analysis of liver tissue were found. MRI provides valuable information about the severity of liver impairments induced by opisthorchiasis. An MR image of O. felineus infected liver has a characteristic pattern that differs from that of closely related liver fluke infections. 1H and 31P MRS in combination with biochemical analysis data showed that O. felineus infection disturbed hepatic metabolism of the host, which was accompanied by cholesterol accumulation in the liver.

Conclusions

A non-invasive approach based on the magnetic resonance technique is very advantageous and may be successfully used not only for diagnosing and evaluating liver damage induced by O. felineus, but also for investigating metabolic changes arising in the infected organ. Since damages induced by the liver fluke take place in different liver lobes, MRI has the potential to overcome liver biopsy sampling variability that limits predictive validity of biopsy analysis for staging liver fluke-induced fibrosis.

Arginase activity in pathogenic and non-pathogenic species of <i>Leishmania</i> parasites

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

by Alireza Badirzadeh, Tahereh Taheri, Yasaman Taslimi, Zahra Abdossamadi, Maryam Heidari-Kharaji, Elham Gholami, Baharehsadat Sedaghat, Maryam Niyyati, Sima Rafati

Proliferation of Leishmania (L.) parasites depends on polyamine availability, which can be generated by the L-arginine catabolism and the enzymatic activity of arginase (ARG) of the parasites and of the mammalian hosts. In the present study, we characterized and compared the arginase (arg) genes from pathogenic L. major and L. tropica and from non-pathogenic L. tarentolae. We quantified the level of the ARG activity in promastigotes and macrophages infected with pathogenic L. major and L. tropica and non-pathogenic L. tarentolae amastigotes. The ARG's amino acid sequences of the pathogenic and non-pathogenic Leishmania demonstrated virtually 98.6% and 88% identities with the reference L. major Friedlin ARG. Higher ARG activity was observed in all pathogenic promastigotes as compared to non-pathogenic L. tarentolae. In vitro infection of human macrophage cell line (THP1) with pathogenic and non-pathogenic Leishmania spp. resulted in increased ARG activities in the infected macrophages. The ARG activities present in vivo were assessed in susceptible BALB/c and resistant C57BL/6 mice infected with L. major, L. tropica and L. tarentolae. We demonstrated that during the development of the infection, ARG is induced in both strains of mice infected with pathogenic Leishmania. However, in L. major infected BALB/c mice, the induction of ARG and parasite load increased simultaneously according to the time course of infection, whereas in C57BL/6 mice, the enzyme is upregulated solely during the period of footpad swelling. In L. tropica infected mice, the footpads' swellings were slow to develop and demonstrated minimal cutaneous pathology and ARG activity. In contrast, ARG activity was undetectable in mice inoculated with the non-pathogenic L. tarentolae. Our data suggest that infection by Leishmania parasites can increase ARG activity of the host and provides essential polyamines for parasite salvage and its replication. Moreover, the ARG of Leishmania is vital for parasite proliferation and required for infection in mice. ARG activity can be used as one of the main marker of the disease severity.

Yeast-expressed recombinant As16 protects mice against <i>Ascaris suum</i> infection through induction of a Th2-skewed immune response

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

by Junfei Wei, Leroy Versteeg, Zhuyun Liu, Brian Keegan, Ana Clara Gazzinelli-Guimarães, Ricardo T. Fujiwara, Neima Briggs, Kathryn M. Jones, Ulrich Strych, Coreen M. Beaumier, Maria Elena Bottazzi, Peter J. Hotez, Bin Zhan

Background

Ascariasis remains the most common helminth infection in humans. As an alternative or complementary approach to global deworming, a pan-anthelminthic vaccine is under development targeting Ascaris, hookworm, and Trichuris infections. As16 and As14 have previously been described as two genetically related proteins from Ascaris suum that induced protective immunity in mice when formulated with cholera toxin B subunit (CTB) as an adjuvant, but the exact protective mechanism was not well understood.

Methodology/Principal findings

As16 and As14 were highly expressed as soluble recombinant proteins (rAs16 and rAs14) in Pichia pastoris. The yeast-expressed rAs16 was highly recognized by immune sera from mice infected with A. suum eggs and elicited 99.6% protection against A. suum re-infection. Mice immunized with rAs16 formulated with ISA720 displayed significant larva reduction (36.7%) and stunted larval development against A. suum eggs challenge. The protective immunity was associated with a predominant Th2-type response characterized by high titers of serological IgG1 (IgG1/IgG2a > 2000) and high levels of IL-4 and IL-5 produced by restimulated splenocytes. A similar level of protection was observed in mice immunized with rAs16 formulated with alum (Alhydrogel), known to induce mainly a Th2-type immune response, whereas mice immunized with rAs16 formulated with MPLA or AddaVax, both known to induce a Th1-type biased response, were not significantly protected against A. suum infection. The rAs14 protein was not recognized by A. suum infected mouse sera and mice immunized with rAs14 formulated with ISA720 did not show significant protection against challenge infection, possibly due to the protein’s inaccessibility to the host immune system or a Th1-type response was induced which would counter a protective Th2-type response.

Conclusions/Significance

Yeast-expressed rAs16 formulated with ISA720 or alum induced significant protection in mice against A. suum egg challenge that associates with a Th2-skewed immune response, suggesting that rAS16 could be a feasible vaccine candidate against ascariasis.

Cross-recognition of a pit viper (Crotalinae) polyspecific antivenom explored through high-density peptide microarray epitope mapping

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

by Mikael Engmark, Bruno Lomonte, José María Gutiérrez, Andreas H. Laustsen, Federico De Masi, Mikael R. Andersen, Ole Lund

Snakebite antivenom is a 120 years old invention based on polyclonal mixtures of antibodies purified from the blood of hyper-immunized animals. Knowledge on antibody recognition sites (epitopes) on snake venom proteins is limited, but may be used to provide molecular level explanations for antivenom cross-reactivity. In turn, this may help guide antivenom development by elucidating immunological biases in existing antivenoms. In this study, we have identified and characterized linear elements of B-cell epitopes from 870 pit viper venom protein sequences by employing a high-throughput methodology based on custom designed high-density peptide microarrays. By combining data on antibody-peptide interactions with multiple sequence alignments of homologous toxin sequences and protein modelling, we have determined linear elements of antibody binding sites for snake venom metalloproteases (SVMPs), phospholipases A2s (PLA2s), and snake venom serine proteases (SVSPs). The studied antivenom antibodies were found to recognize linear elements in each of the three enzymatic toxin families. In contrast to a similar study of elapid (non-enzymatic) neurotoxins, these enzymatic toxins were generally not recognized at the catalytic active site responsible for toxicity, but instead at other sites, of which some are known for allosteric inhibition or for interaction with the tissue target. Antibody recognition was found to be preserved for several minor variations in the protein sequences, although the antibody-toxin interactions could often be eliminated completely by substitution of a single residue. This finding is likely to have large implications for the cross-reactivity of the antivenom and indicate that multiple different antibodies are likely to be needed for targeting an entire group of toxins in these recognized sites.

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