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Cysteine proteases during larval migration and development of helminths in their final host

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

by Alexandra Grote, Conor R. Caffrey, Karina M. Rebello, David Smith, John P. Dalton, Sara Lustigman

Neglected tropical diseases caused by metazoan parasites are major public health concerns, and therefore, new methods for their control and elimination are needed. Research over the last 25 years has revealed the vital contribution of cysteine proteases to invasion of and migration by (larval) helminth parasites through host tissues, in addition to their roles in embryogenesis, molting, egg hatching, and yolk degradation. Their central function to maintaining parasite survival in the host has made them prime intervention targets for novel drugs and vaccines. This review focuses on those helminth cysteine proteases that have been functionally characterized during the varied early stages of development in the human host and embryogenesis.

Cysteine proteases as digestive enzymes in parasitic helminths

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

by Conor R. Caffrey, Louise Goupil, Karina M. Rebello, John P. Dalton, David Smith

We briefly review cysteine proteases (orthologs of mammalian cathepsins B, L, F, and C) that are expressed in flatworm and nematode parasites. Emphasis is placed on enzyme activities that have been functionally characterized, are associated with the parasite gut, and putatively contribute to degrading host proteins to absorbable nutrients [1–4]. Often, gut proteases are expressed as multigene families, as is the case with Fasciola [5] and Haemonchus [6], presumably expanding the range of substrates that can be degraded, not least during parasite migration through host tissues [5]. The application of the free-living planarian and Caenorhabditis elegans as investigative models for parasite cysteine proteases is discussed. Finally, because of their central nutritive contribution, targeting the component gut proteases with small-molecule chemical inhibitors and understanding their utility as vaccine candidates are active areas of research [7].

Estimating the effects of variation in viremia on mosquito susceptibility, infectiousness, and <i>R0</i> of Zika in <i>Aedes aegypti</i>

PLoS Neglected Tropical Diseases News - 22 August 2018 - 9:00pm

by Blanka Tesla, Leah R. Demakovsky, Hannah S. Packiam, Erin A. Mordecai, Américo D. Rodríguez, Matthew H. Bonds, Melinda A. Brindley, Courtney C. Murdock

Zika virus (ZIKV) is an arbovirus primarily transmitted by Aedes mosquitoes. Like most viral infections, ZIKV viremia varies over several orders of magnitude, with unknown consequences for transmission. To determine the effect of viral concentration on ZIKV transmission risk, we exposed field-derived Ae. aegypti mosquitoes to four doses (103, 104, 105, 106 PFU/mL) representative of potential variation in the field. We demonstrate that increasing ZIKV dose in the blood-meal significantly increases the probability of mosquitoes becoming infected, and consequently disseminating virus and becoming infectious. Additionally, we observed significant interactions between dose and days post-infection on dissemination and overall transmission efficiency, suggesting that variation in ZIKV dose affects the rates of midgut escape and salivary gland invasion. We did not find significant effects of dose on mosquito mortality. We also demonstrate that detecting virus using RT-qPCR approaches rather than plaque assays potentially over-estimates key transmission parameters, including the time at which mosquitoes become infectious and viral burden. Finally, using these data to parameterize an R0 model, we showed that increasing viremia from 104 to 106 PFU/mL increased relative R0 3.8-fold, demonstrating that variation in viremia substantially affects transmission risk.

Therapeutic control of leishmaniasis by inhibitors of the mammalian target of rapamycin

PLoS Neglected Tropical Diseases News - 22 August 2018 - 9:00pm

by Fatemeh Khadir, Christopher R. Shaler, Ahmad Oryan, Patrick T. Rudak, Delfina M. Mazzuca, Tahereh Taheri, Jimmy D. Dikeakos, S. M. Mansour Haeryfar, Sima Rafati

Leishmaniasis is a serious global health problem affecting many people worldwide. While patients with leishmaniasis can be treated with several agents, drug toxicicty and the emergence of resistant strains render available treatments ineffective in the long run. Inhibitors of the mammalian target of rapamycin (mTOR) have been demonstrated to exert anti-pathogen properties. In this study, we tested the therapeutic efficacy of several mTOR inhibitors in controlling infection with Leishmania major. Rapamycin, GSK-2126458 and KU-0063794 were administered to BALB/c mice, which had received an intrafootpad injection of the parasite. Footpad swelling and parasite burden were assessed, and cytokine production by mouse splenocytes and phenotypic changes in draining lymph node cells were evaluated. Treatment with a clinically relevant dose of rapamycin or with GSK-2126458, but not with KU-0063794, dramatically lowered both the footpad swelling and the parasite load in the draining lymph node. Importantly, the employed dose of rapamycin did not kill the promastigotes in vitro as judged by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and electron microscopy. Moreover, the IL-4 production capacity of splenocytes harvested from infected mice that were treated with rapamycin was significantly reduced. Consequently, the IFN-γ:IL-4 production ratio was elevated, suggesting a T helper-type 1 (Th1)-skewed cytokine profile. Finally, the expression level of CD69, an early activation marker, on splenic and lymph node CD4+ and CD8+ T cells was enhanced in rapamycin-treated mice. Taken together, our findings suggest that select mTOR inhibitors may be used in therapeutic settings for the management of leishmaniasis. We propose that the beneficial effects of such inhibitors stem from their immunomodulatory properties. Therefore, the adjuvanticity of mTOR inhibitors may also be considered in vaccination strategies against Leishmania species.

Amiodarone for arrhythmia in patients with Chagas disease: A systematic review and individual patient data meta-analysis

PLoS Neglected Tropical Diseases News - 20 August 2018 - 9:00pm

by Cinara Stein, Celina Borges Migliavaca, Verônica Colpani, Priscila Raupp da Rosa, Daniel Sganzerla, Natalia Elis Giordani, Sandro Renê Pinto de Sousa Miguel, Luciane Nascimento Cruz, Carisi Anne Polanczyk, Antonio Luiz P. Ribeiro, Maicon Falavigna

Background

Chagas disease is a neglected chronic condition caused by Trypanosoma cruzi, with high prevalence and burden in Latin America. Ventricular arrhythmias are common in patients with Chagas cardiomyopathy, and amiodarone has been widely used for this purpose. The aim of our study was to assess the effect of amiodarone in patients with Chagas cardiomyopathy.

Methodology

We searched MEDLINE, Embase and LILACS up to January 2018. Data from randomized and observational studies evaluating amiodarone use in Chagas cardiomyopathy were included. Two reviewers selected the studies, extracted data and assessed risk of bias. Overall quality of evidence was accessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE).

Principal findings

We included 9 studies (3 before-after studies, 5 case series and 1 randomized controlled trial). Two studies with a total of 38 patients had the full dataset, allowing individual patient data (IPD) analysis. In 24-hour Holter, amiodarone reduced the number of ventricular tachycardia episodes in 99.9% (95%CI 99.8%-100%), ventricular premature beats in 93.1% (95%CI 82%-97.4%) and the incidence of ventricular couplets in 79% (RR 0.21, 95%CI 0.11–0.39). Studies not included in the IPD analysis showed a reduction of ventricular premature beats (5 studies), ventricular tachycardia (6 studies) and ventricular couplets (1 study). We pooled the incidence of adverse side effects with random effects meta-analysis; amiodarone was associated with corneal microdeposits (61.1%, 95%CI 19.0–91.3, 5 studies), gastrointestinal events (16.1%, 95%CI 6.61–34.2, 3 studies), sinus bradycardia (12.7%, 95%CI 3.71–35.5, 6 studies), dermatological events (10.6%, 95%CI 4.77–21.9, 3 studies) and drug discontinuation (7.68%, 95%CI 4.17–13.7, 5 studies). Quality of evidence ranged from moderate to very low.

Conclusions

Amiodarone is effective in reducing ventricular arrhythmias, but there is no evidence for hard endpoints (sudden death, hospitalization). Although our findings support the use of amiodarone, it is important to balance the potential benefits and harms at the individual level for decision-making.

Laboratory selection of <i>Aedes aegypti</i> field populations with the organophosphate malathion: Negative impacts on resistance to deltamethrin and to the organophosphate temephos

PLoS Neglected Tropical Diseases News - 20 August 2018 - 9:00pm

by Priscila Fernandes Viana Medeiros, Diogo Fernandes Bellinato, Denise Valle

Background

Resistance to pyrethroids and to the organophosphate temephos is widespread in Brazilian populations of the dengue vector, Aedes aegypti. Thereof, since 2009 Insect Growth Regulators are employed as larvicides, and malathion is used against adults.

Methodology/Principal findings

We performed laboratory selection with malathion of two A. aegypti field populations initially susceptible to this organophosphate but resistant to temephos and deltamethrin. A fixed malathion dose inducing at least 80% mortality in the first generation, was used throughout the selection process, interrupted after five generations, when the threshold of 20% mortality was reached. For each population, three experimental and two control groups, not exposed to insecticides, were kept independently. For both populations, quantitative bioassays revealed, in the selected groups, acquisition of resistance to malathion and negative impact of malathion selection on deltamethrin and temephos resistance levels. In the control groups resistance to all evaluated insecticides decreased except, unexpectedly, to deltamethrin. Analysis of the main resistance mechanisms employed routine methodologies: biochemical and molecular assays for, respectively, metabolic resistance and quantification of the NaV pyrethroid target main kdr mutations at positions 1016 and 1534. No diagnostic alteration could be specifically correlated with malathion selection, neither with the unusual deltamethrin increase in resistance levels observed in the control groups.

Conclusions/Significance

Our results confirm the multifactorial character of insecticide resistance and point to the need of high throughput methodologies and to the study of additional field vector populations in order to unravel resistance mechanisms.

The antiparasitic drug niclosamide inhibits dengue virus infection by interfering with endosomal acidification independent of mTOR

PLoS Neglected Tropical Diseases News - 20 August 2018 - 9:00pm

by Jo-Chi Kao, Wei-Chun HuangFu, Tsung-Ting Tsai, Min-Ru Ho, Ming-Kai Jhan, Ting-Jing Shen, Po-Chun Tseng, Yung-Ting Wang, Chiou-Feng Lin

Background

The antiparasitic agent niclosamide has been demonstrated to inhibit the arthropod-borne Zika virus. Here, we investigated the antiviral capacity of niclosamide against dengue virus (DENV) serotype 2 infection in vitro and in vivo.

Principle Finding

Niclosamide effectively retarded DENV-induced infection in vitro in human adenocarcinoma cells (A549), mouse neuroblastoma cells (Neuro-2a), and baby hamster kidney fibroblasts (BHK-21). Treatment with niclosamide did not retard the endocytosis of DENV while niclosamide was unable to enhance the antiviral type I interferon response. Furthermore, niclosamide did not cause a direct effect on viral replicon-based expression. Niclosamide has been reported to competitively inhibit the mTOR (mammalian target of rapamycin), STAT3 (signal transducer and activator of transcription 3), and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling pathways; however, selective inhibitors of those pathways did not reduce DENV infection. Similar to the vacuolar-type H+-ATPase inhibitor bafilomycin A1, both niclosamide and other protonophores, such as CCCP (carbonyl cyanide m-chlorophenyl hydrazone), and FCCP (carbonyl cyanide-p-trifluoromethoxyphenylhydrazone), effectively reduced endosomal acidification and viral dsRNA replication. Co-administration of a single dose of niclosamide partially decreased viral replication, viral encephalitis, and mortality in DENV-infected ICR suckling mice.

Significance

These results demonstrate that niclosamide diminishes viral infection by hindering endosomal acidification.

<i>Echinococcus</i> in wild canids in Québec (Canada) and Maine (USA)

PLoS Neglected Tropical Diseases News - 20 August 2018 - 9:00pm

by Janna M. Schurer, Emilie Bouchard, Ann Bryant, Sarah Revell, Grace Chavis, Anne Lichtenwalner, Emily J. Jenkins

Zoonotic Echinococcus spp. cestodes (E. canadensis and E. multilocularis) infect domestic animals, wildlife, and people in regions of Canada and the USA. We recovered and quantified Echinococcus spp. cestodes from 22 of 307 intestinal tracts of wild canids (23 wolves, 100 coyotes, 184 red and arctic foxes) in the state of Maine and the province of Québec. We identified the species and genotypes of three Echinococcus spp. cestodes per infected animal by sequencing mitochondrial DNA at two loci. We further confirmed the absence of E. multilocularis by extracting DNA from pools of all cestodes from each animal and running a duplex PCR capable of distinguishing the two species. We detected E. canadensis (G8 and G10), but not E. multilocularis, which is emerging as an important human and animal health concern in adjacent regions. Prevalence and median intensity of E. canadensis was higher in wolves (35%, 460) than coyotes (14%, 358). This parasite has historically been absent in Atlantic regions of North America, where suitable intermediate hosts, but not wolves, are present. Our study suggests that coyotes are serving as sylvatic definitive hosts for E. canadensis in Atlantic regions, and this may facilitate eastward range expansion of E. canadensis in the USA and Canada. As well, compared to wolves, coyotes are more likely to contaminate urban green spaces and peri-urban environments with zoonotic parasites.

Description of the first sleeping sickness case diagnosed in Burkina Faso since two decades

PLoS Neglected Tropical Diseases News - 20 August 2018 - 9:00pm

by Emilie Dama, Aboubacar Drabo, Jacques Kaboré, Elie Ouédraogo, Bamoro Coulibaly, Hamidou Ilboudo, Justin Kaboré, Charlie Franck Compaoré, Hassane Sakandé, Micheline Ouédraogo, Jean-Baptiste Rayaissé, Fabrice Courtin, Philippe Solano, François Drabo, Vincent Jamonneau

Burkina Faso belongs to a group of countries in which human African trypanosomiasis (HAT), caused by Trypanosoma brucei gambiense, is no longer considered to be a public health problem. Although no native cases have been detected since 1993, there is still the risk of HAT re-emergence due to significant population movements between Burkina Faso and active HAT foci in Côte d’Ivoire. Since 2014, Burkina Faso receives support from the WHO to implement a passive surveillance program. This resulted in the detection in 2015 of the first putative native HAT case since two decades. However, epidemiological entomological and molecular biology investigations have not been able to identify with certainty the origin of this infection or to confirm that it was due to T. b. gambiense. This case emphasises the need to strengthen passive surveillance of the disease for sustained elimination of HAT as a public health problem in Burkina Faso.

Impact of community-based integrated mass drug administration on schistosomiasis and soil-transmitted helminth prevalence in Togo

PLoS Neglected Tropical Diseases News - 20 August 2018 - 9:00pm

by Rachel N. Bronzan, Ameyo M. Dorkenoo, Yao M. Agbo, Wemboo Halatoko, Yao Layibo, Poukpessi Adjeloh, Menssah Teko, Efoe Sossou, Kossi Yakpa, Mawèké Tchalim, Gbati Datagni, Anders Seim, Koffi S. Sognikin

Background

Togo has conducted annual, integrated, community-based mass drug administration (MDA) for soil-transmitted helminths (STH) and schistosomiasis since 2010. Treatment frequency and target populations are determined by disease prevalence, as measured by baseline surveys in 2007 and 2009, and WHO guidelines. Reported programmatic treatment coverage has averaged over 94%. Togo conducted a cross-sectional survey in 2015 to assess the impact of four to five years of MDA on these diseases.

Methodology/Principal findings

In every sub-district in the country outside the capital, the same schools were visited as at baseline and a sample of fifteen children age 6 to 9 years old was drawn. Each child submitted urine and a stool sample. Urine samples were tested by dipstick for the presence of blood as a proxy measure of Schistosoma haematobium infection. Stool samples were analyzed by the Kato-Katz method for STH and Schistosoma mansoni. At baseline, 17,100 children were enrolled at 1,129 schools in 562 sub-districts; in 2015, 16,890 children were enrolled at the same schools. The overall prevalence of both STH and schistosomiasis declined significantly, from 31.5% to 11.6% for STH and from 23.5% to 5.0% for schistosomiasis (p<0.001 in both instances). Egg counts from both years were available only for hookworm and S. mansoni; intensity of infection decreased significantly for both infections from 2009 to 2015 (p<0.001 for both infections). In areas with high baseline prevalence, rebound of hookworm infection was noted in children who had not received albendazole in the past 6 months.

Conclusions/Significance

After four to five years of MDA in Togo, the prevalence and intensity of STH and schistosomiasis infection were significantly reduced compared to baseline. Data on STH indicate that stopping MDA in areas with high baseline prevalence may result in significant rebound of infection. Togo’s findings may help refine treatment recommendations for these diseases.

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