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MyD88 activation in cardiomyocytes contributes to the heart immune response to acute <i>Trypanosoma cruzi</i> infection with no effect on local parasite control

PLoS Neglected Tropical Diseases News - 1 August 2018 - 9:00pm

by Danni Yohani Santana, Rafael Moysés Salgado, Marina Fevereiro, Rogério Silva do Nascimento, Raissa Fonseca, Niels Olsen Saraiva Câmara, Sabrina Epiphanio, Cláudio Romero Farias Marinho, Maria Luiza Barreto-Chaves, Maria Regina D’ Império-Lima, José M. Álvarez

Cardiomyopathy is the most serious consequence of Chagas disease, a neglected human disorder caused by Trypanosoma cruzi infection. Because T. cruzi parasites invade cardiomyocytes, we sought to investigate whether these cells recognize the parasite in vivo by receptors signaling through the MyD88 adaptor, which mediates the activation pathway of most Toll-like receptors (TLRs) and IL-1/IL-18 receptors, and influence the development of acute cardiac pathology. First, we showed that HL-1 cardiac muscle cell line expresses MyD88 gene and protein at resting state and after T. cruzi infection. To evaluate the role in vivo of MyD88 expression in cardiomyocytes, we generated Mer+MyD88flox+/+ mice in which tamoxifen treatment is expected to eliminate the MyD88 gene exclusively in cardiomyocytes. This Cre-loxP model was validated by both PCR and western blot analysis; tamoxifen treatment of Mer+MyD88flox+/+ mice resulted in decreased MyD88 gene and protein expression in the heart, but not in the spleen, while had no effect on littermates. The elimination of MyD88 in cardiomyocytes determined a lower increase in CCL5, IFNγ and TNFα gene transcription during acute infection by T. cruzi parasites of the Y strain, but it did not significantly modify heart leukocyte infiltration and parasitism. Together, our results show that cardiomyocytes can sense T. cruzi infection through MyD88-mediated molecular pathways and contribute to the local immune response to the parasite. The strong pro-inflammatory response of heart-recruited leukocytes may overshadow the effects of MyD88 deficiency in cardiomyocytes on the local leukocyte recruitment and T. cruzi control during acute infection.

An attenuated replication-competent chikungunya virus with a fluorescently tagged envelope

PLoS Neglected Tropical Diseases News - 31 July 2018 - 9:00pm

by Jing Jin, Michael B. Sherman, Daniel Chafets, Nuntana Dinglasan, Kai Lu, Tzong-Hae Lee, Lars-Anders Carlson, Marcus O. Muench, Graham Simmons

Background

Chikungunya virus (CHIKV) is the most common alphavirus infecting humans worldwide, causing acute and chronically debilitating arthralgia at a great economic expense.

Methodology/Principal findings

To facilitate our study of CHIKV, we generated a mCherry tagged replication-competent chimeric virus, CHIKV 37997-mCherry. Single particle cryoEM demonstrated icosahedral organization of the chimeric virus and the display of mCherry proteins on virus surface. CHIKV 37997-mCherry is attenuated in both IFNαR knockout and wild-type mice. Strong anti-CHIKV and anti-mCherry antibody responses were induced in CHIKV 37997-mCherry infected mice.

Conclusions/Significance

Our work suggests that chimeric alphaviruses displaying foreign antigen can serve as vaccines against both aphaviruses and other pathogens and diseases.

Understanding perceptions on 'Buruli' in northwestern Uganda: A biosocial investigation

PLoS Neglected Tropical Diseases News - 30 July 2018 - 9:00pm

by Georgina Pearson

Background

An understudied disease, little research thus far has explored responses to Buruli ulcer and quests for therapy from biosocial perspective, despite reports that people seek biomedical treatment too late.

Methods and findings

Taking an inductive approach and drawing on long-term ethnographic fieldwork in 2013–14, this article presents perspectives on this affliction of people living and working along the River Nile in northwest Uganda. Little is known biomedically about its presence, yet ‘Buruli’, as it is known locally, was and is a significant affliction in this region. Establishing a biosocial history of ‘Buruli’, largely obscured from biomedical perspectives, offers explanations for contemporary understandings, perceptions and practices.

Conclusions/Significance

We must move beyond over-simplifying and problematising ‘late presentation for treatment’ in public health, rather, develop biosocial approaches to understanding quests for therapy that take into account historical and contemporary contexts of health, healing and illness. Seeking to understand the context in which healthcare decisions are made, a biosocial approach enables greater depth and breadth of insight into the complexities of global and local public health priorities such as Buruli ulcer.

Ecological niche modelling and predicted geographic distribution of <i>Lutzomyia cruzi</i>, vector of <i>Leishmania infantum</i> in South America

PLoS Neglected Tropical Diseases News - 30 July 2018 - 9:00pm

by Everton Falcão de Oliveira, Eunice Aparecida Bianchi Galati, Alessandra Gutierrez de Oliveira, Elizabeth Ferreira Rangel, Bruno Moreira de Carvalho

In some transmission foci of Leishmania infantum in Brazil, Lutzomyia cruzi could be considered the main vector of this pathogen. In addition, L. cruzi is a permissive vector of L. amazonensis. Its geographical distribution seems to be restricted and limited to Cerrado and Pantanal biomes, which includes some areas in Brazil and Bolivia. Considering that predicting the distribution of the species involved in transmission cycles is an effective approach for assessing human disease risk, this study aims to predict the spatial distribution of L. cruzi using a multiscale ecological niche model based in both climate and habitat variables. Ecological niche modelling was used to identify areas in South America that are environmentally suitable for this particular vector species, but its presence is not recorded. Vector occurrence records were compiled from the literature, museum collections and Brazilian Health Departments. Bioclimatic variables, altitude, and land use and cover were used as predictors in five ecological niche model algorithms: BIOCLIM, generalised linear model (logistic regression), maximum entropy, random forests, and support vector machines. The vector occurs in areas where annual mean temperature values range from 21.76°C to 26.58°C, and annual total precipitation varies from 1005 mm and 2048 mm. Urban areas were most present around capture locations. The potential distribution area of L. cruzi according to the final ecological niche model spans Brazil and Bolivia in patches of suitable habitats inside a larger climatically favourable area. The bigger portion of this suitable area is located at Brazilian States of Mato Grosso do Sul and Mato Grosso. Our findings identified environmentally suitable areas for L. cruzi in regions without its known occurrence, so further field sampling of sand flies is recommended, especially in southern Goiás State, Mato Grosso do Sul (borders with Mato Grosso, São Paulo and Minas Gerais); and in Bolivian departments Santa Cruz and El Beni.

Differing epidemiological dynamics of Chikungunya virus in the Americas during the 2014-2015 epidemic

PLoS Neglected Tropical Diseases News - 30 July 2018 - 9:00pm

by Yi Tan, Brett E. Pickett, Susmita Shrivastava, Lionel Gresh, Angel Balmaseda, Paolo Amedeo, Lihui Hu, Vinita Puri, Nadia B. Fedorova, Rebecca A. Halpin, Matthew P. LaPointe, Marshall R. Cone, Lea Heberlein-Larson, Laura D. Kramer, Alexander T. Ciota, Aubree Gordon, Reed S. Shabman, Suman R. Das, Eva Harris

Chikungunya virus (CHIKV) has been detected sporadically since the 1950s and includes three distinct co-circulating genotypes. In late 2013, the Asian genotype of CHIKV was responsible for the Caribbean outbreak (CO) that rapidly became an epidemic throughout the Americas. There is a limited understanding of the molecular evolution of CHIKV in the Americas during this epidemic. We sequenced 185 complete CHIKV genomes collected mainly from Nicaragua in Central America and Florida in the United States during the 2014–2015 Caribbean/Americas epidemic. Our comprehensive phylogenetic analyses estimated the epidemic history of the Asian genotype and the recent Caribbean outbreak (CO) clade, revealed considerable genetic diversity within the CO clade, and described different epidemiological dynamics of CHIKV in the Americas. Specifically, we identified multiple introductions in both Nicaragua and Florida, with rapid local spread of viruses in Nicaragua but limited autochthonous transmission in Florida in the US. Our phylogenetic analysis also showed phylogeographic clustering of the CO clade. In addition, we identified the significant amino acid substitutions that were observed across the entire Asian genotype during its evolution and examined amino acid changes that were specific to the CO clade. Deep sequencing analysis identified specific minor variants present in clinical specimens below-consensus levels. Finally, we investigated the association between viral phylogeny and geographic/clinical metadata in Nicaragua. To date, this study represents the largest single collection of CHIKV complete genomes during the Caribbean/Americas epidemic and significantly expands our understanding of the emergence and evolution of CHIKV CO clade in the Americas.

Comparing the effectiveness of different strains of <i>Wolbachia</i> for controlling chikungunya, dengue fever, and zika

PLoS Neglected Tropical Diseases News - 30 July 2018 - 9:00pm

by Ling Xue, Xin Fang, James M. Hyman

Once Aedes aegypti and Aedes albopictus mosquitoes that spread Chikungunya virus, dengue virus, and Zika virus are infected with Wolbachia, they have reduced egg laying rates, reduced transmission abilities, and shorter lifespans. Since most infected mosquitoes are only infectious in the last few days of their lives, shortening a mosquito’s lifespan by a day or two can greatly reduce their abilities to spread mosquito-borne viral diseases, such as Chikungunya, dengue fever, and Zika. We developed a mathematical model to compare the effectiveness of the wMel and wAlbB strains of Wolbachia for controlling the spread of these viruses. The differences among the diseases, mosquitoes, and Wolbachia strains are captured by the model parameters for the mosquito-human transmission cycle. Moreover, the model accounts for the behavior changes of infectious population created by differences in the malaise caused by these viruses. We derived the effective and basic reproduction numbers for the model that are used to estimate the number of secondary infections from the infectious populations. In the same density of Wolbachia-free Aedes aegypti or Aedes albopictus mosquitoes, we observed that wMel and wAlbB strains of Wolbachia can reduce the transmission rates of these diseases effectively.

A longitudinal cohort study of soil-transmitted helminth infections during the second year of life and associations with reduced long-term cognitive and verbal abilities

PLoS Neglected Tropical Diseases News - 27 July 2018 - 9:00pm

by Brittany Blouin, Martin Casapia, Lawrence Joseph, Theresa W. Gyorkos

Background

Soil-transmitted helminth (STH) infection leads to malnutrition and anemia, and has been linked to impaired child development. Previous research on this topic is limited and mostly conducted in school-age children. The goal of this study was to determine the effect of the number of detected STH infections between one and two years of age on subsequent cognitive and verbal abilities, in a cohort of preschool children.

Methodology/Principal findings

A longitudinal cohort study was conducted in 880 children in Iquitos, Peru between September 2011 and July 2016. Children were recruited at one year of age and followed up at 18 months and then annually between two and five years of age. STH infection was measured with the Kato-Katz technique or the direct smear technique. Child development was measured with the Bayley Scales of Infant and Toddler Development-III at the one to three-year visits and with the Wechsler Preschool and Primary Scale of Intelligence-III at the four and five-year visits. Hierarchical multivariable linear regression models were used to account for the repeated outcome measures for each child and Bayesian latent class analysis was used to adjust for STH misclassification. Children found infected with any STH infection between one and two years of age had lower cognitive scores between two and five years of age (between group score differences (95% credible intervals) for infected once, and infected two or three times, compared to never infected: -4.31 (-10.64, -0.14) and -3.70 (-10.11, -0.11), respectively). Similar results were found for Ascaris infection and for verbal scores.

Conclusions/Significance

An association was found between having been infected with Ascaris or any STH between one and two years of age and lower cognitive and verbal abilities later in childhood. These results suggest that targeting children for STH control as of one year of age is particularly important.

A prospective cohort study comparing household contact and water <i>Vibrio cholerae</i> isolates in households of cholera patients in rural Bangladesh

PLoS Neglected Tropical Diseases News - 27 July 2018 - 9:00pm

by Christine Marie George, Khaled Hasan, Shirajum Monira, Zillur Rahman, K. M. Saif-Ur-Rahman, Mahamud-ur Rashid, Fatema Zohura, Tahmina Parvin, Md. Sazzadul Islam Bhuyian, Md. Toslim Mahmud, Shan Li, Jamie Perin, Camille Morgan, Munshi Mustafiz, R. Bradley Sack, David A. Sack, O. Colin Stine, Munirul Alam

Background

Household contacts of cholera patients are at a 100 times higher risk of developing cholera than the general population. The objective of this study was to examine the incidence of V. cholerae infections among household contacts of cholera patients in a rural setting in Bangladesh, to identify risk factors for V. cholerae infections among this population, and to investigate transmission pathways of V. cholerae using multilocus variable-number tandem-repeat analysis (MLVA).

Methodology/Principal findings

Stool from household contacts, source water and stored water samples were collected from cholera patient households on Day 1, 3, 5, and 7 after the presentation of the index patient at a health facility. Two hundred thirty clinical and water V. cholerae isolates were analyzed by MLVA. Thirty seven percent of households had at least one household contact with a V. cholerae infection. Thirteen percent of households had V. cholerae in their water source, and 27% had V. cholerae in stored household drinking water. Household contacts with V. cholerae in their water source had a significantly higher odds of symptomatic cholera (Odds Ratio (OR): 5.49, 95% Confidence Interval (CI): 1.07, 28.08). Contacts consuming street vended food had a significantly higher odds of a V. cholerae infection (OR: 9.45, 95% CI: 2.14, 41.72). Older age was significantly associated with a lower odds of a V. cholerae infection (OR: 0.96, 95% CI: 0.93, 0.99). Households with both water and clinical V. cholerae-positive samples all had isolates that were closely related by MLVA.

Conclusions/Significance

These findings emphasize the need for interventions targeting water treatment and food hygiene to reduce V. cholerae infections.

Molecular identification and antifungal susceptibility profiles of clinical strains of <i>Fonsecaea</i> spp. isolated from patients with chromoblastomycosis in Rio de Janeiro, Brazil

PLoS Neglected Tropical Diseases News - 26 July 2018 - 9:00pm

by Rowena Alves Coelho, Fábio Brito-Santos, Maria Helena Galdino Figueiredo-Carvalho, Juliana Vitoria dos Santos Silva, Maria Clara Gutierrez-Galhardo, Antonio Carlos Francesconi do Valle, Rosely Maria Zancopé-Oliveira, Luciana Trilles, Wieland Meyer, Dayvison Francis Saraiva Freitas, Rodrigo Almeida-Paes

Background

Chromoblastomycosis (CBM) is a difficult-to-treat chronic subcutaneous mycosis. In Brazil, the main agent of this disease is Fonsecaea pedrosoi, which is phenotypically very similar to other Fonsecaea species, differing only genetically. The correct species identification is relevant since different species may differ in their epidemiologic aspects, clinical presentation, and treatment response.

Methodology/Principal findings

Partial sequencing of the internal transcribed spacer (ITS) was used to identify twenty clinical isolates of Fonsecaea spp. Their in vitro antifungal susceptibility was determined using the broth microdilution method, according to the M38-A2 protocol. Amphotericin B (AMB), flucytosine (5FC), terbinafine (TRB), fluconazole (FLC), itraconazole (ITC), ketoconazole (KTC), posaconazole (POS), voriconazole (VRC), ravuconazole (RVC), caspofungin (CAS), and micafungin (MFG) were tested. The association between ITC/TRB, AMB/5FC, and ITC/CAS was studied by the checkerboard method to check synergism. The available patients’ data were correlated with the obtained laboratory results. Fonsecaea monophora (n = 10), F. pedrosoi (n = 5), and F. nubica (n = 5) were identified as CBM’ agents in the study. TRB and VRC were the drugs with the best in vitro activity with minimal inhibitory concentrations (MIC) lower than 0.25 mg/L. On the other hand, FLC, 5FC, AMB, and MFG showed high MICs. The AMB/5FC combination was synergistic for three F. monophora strains while the others were indifferent. Patients had moderate or severe CBM, and ITC therapy was not sufficient for complete cure in most of the cases, requiring adjuvant surgical approaches.

Conclusions/Significance

F. monophora, the second most frequent Fonsecaea species in South America, predominated in patients raised and born in Rio de Janeiro, Brazil, without cerebral involvement in these cases. TRB, VRC, and the AMB/5FC combination should be further investigated as a treatment option for CBM.

Molecular xenomonitoring for <i>Wuchereria bancrofti</i> in <i>Culex quinquefasciatus</i> in two districts in Bangladesh supports transmission assessment survey findings

PLoS Neglected Tropical Diseases News - 26 July 2018 - 9:00pm

by Seth R. Irish, Hasan Mohammad Al-Amin, Heather N. Paulin, A. S. M. Sultan Mahmood, Rajaul K. Khan, A. K. M. Muraduzzaman, Caitlin M. Worrell, Meerjady S. Flora, Mohammed J. Karim, Tahmina Shirin, A. K. M. Shamsuzzaman, Sanya Tahmina, Audrey Lenhart, Christine Dubray

Background

Careful monitoring for recrudescence of Wuchereria bancrofti infection is necessary in communities where mass drug administration (MDA) for the elimination of lymphatic filariasis (LF) as a public health problem has been stopped. During the post-MDA period, transmission assessment surveys (TAS) are recommended by the World Health Organization to monitor the presence of the parasite in humans. Molecular xenomonitoring (MX), a method by which parasite infection in the mosquito population is monitored, has also been proposed as a sensitive method to determine whether the parasite is still present in the human population. The aim of this study was to conduct an MX evaluation in two areas of Bangladesh, one previously endemic district that had stopped MDA (Panchagarh), and part of a non-endemic district (Gaibandha) that borders the district where transmission was most recently recorded.

Methodology/Principal findings

Mosquitoes were systematically collected from 180 trap sites per district and mosquito pools were tested for W. bancrofti using real-time PCR. A total of 23,436 intact mosquitoes, representing 31 species, were collected from the two districts, of which 10,344 (41%) were Culex quinquefasciatus, the vector of W. bancrofti in Bangladesh. All of the 594 pools of Cx. quinquefasciatus tested by real-time PCR were negative for the presence of W. bancrofti DNA.

Conclusions/Significance

This study suggested the absence of W. bancrofti in these districts. MX could be a sensitive tool to confirm interruption of LF transmission in areas considered at higher risk of recrudescence, particularly in countries like Bangladesh where entomological and laboratory capacity to perform MX is available.

Manganese superoxide dismutase deficiency exacerbates the mitochondrial ROS production and oxidative damage in Chagas disease

PLoS Neglected Tropical Diseases News - 25 July 2018 - 9:00pm

by Jake J. Wen, Nisha Jain Garg

In this study, we have investigated the effects of manganese superoxide dismutase (SOD2 or MnSOD) deficiency on mitochondrial function and oxidative stress during Chagas disease. For this, C57BL/6 wild type (WT) and MnSOD+/- mice were infected with Trypanosoma cruzi (Tc), and evaluated at 150 days’ post-infection that corresponded to chronic disease phase. Genetic deletion of SOD2 decreased the expression and activity of MnSOD, but it had no effect on the expression of other members of the SOD family. The myocardial expression and activity of MnSOD were significantly decreased in chronically infected WT mice, and it was further worsened in MnSOD+/- mice. Chronic T. cruzi infection led to a decline in mitochondrial complex I and complex II driven, ADP-coupled respiration and ATP synthesis in the myocardium of WT mice. The baseline oxidative phosphorylation (OXPHOS) capacity in MnSOD+/- mice was decreased, and it had an additive effect on mitochondrial dysregulation of ATP synthesis capacity in chagasic myocardium. Further, MnSOD deficiency exacerbated the mitochondrial rate of reactive oxygen species (ROS) production and myocardial oxidative stress (H2O2, protein carbonyls, malondialdehyde, and 4-hydroxynonenal) in Chagas disease. Peripheral and myocardial parasite burden and inflammatory response (myeloperoxidase, IL-6, lactate dehydrogenase, inflammatory infiltrate) were increased in all chagasic WT and MnSOD+/- mice. We conclude that MnSOD deficiency exacerbates the loss in mitochondrial function and OXPHOS capacity and enhances the myocardial oxidative damage in chagasic cardiomyopathy. Mitochondria targeted, small molecule mitigators of MnSOD deficiency will offer potential benefits in averting the mitochondrial dysfunction and chronic oxidative stress in Chagas disease.

Scabies and risk of skin sores in remote Australian Aboriginal communities: A self-controlled case series study

PLoS Neglected Tropical Diseases News - 25 July 2018 - 9:00pm

by Phyo Thu Zar Aung, Will Cuningham, Kerry Hwang, Ross M. Andrews, Jonathan Carapetis, Therese Kearns, Danielle Clucas, Jodie McVernon, Julie Ann Simpson, Steven Tong, Patricia Therese Campbell

Background

Skin sores caused by Group A streptococcus (GAS) infection are a major public health problem in remote Aboriginal communities. Skin sores are often associated with scabies, which is evident in scabies intervention programs where a significant reduction of skin sores is seen after focusing solely on scabies control. Our study quantifies the strength of association between skin sores and scabies among Aboriginal children from the East Arnhem region in the Northern Territory.

Methods and results

Pre-existing datasets from three published studies, which were conducted as part of the East Arnhem Healthy Skin Project (EAHSP), were analysed. Aboriginal children were followed from birth up to 4.5 years of age. Self-controlled case series design was used to determine the risks, within individuals, of developing skin sores when infected with scabies versus when there was no scabies infection. Participants were 11.9 times more likely to develop skin sores when infected with scabies compared with times when no scabies infection was evident (Incidence Rate Ratio (IRR) 11.9; 95% CI 10.3–13.7; p<0.001), and this was similar across the five Aboriginal communities. Children had lower risk of developing skin sores at age ≤1 year compared to at age >1 year (IRR 0.8; 95% CI 0.7–0.9).

Conclusion

The association between scabies and skin sores is highly significant and indicates a causal relationship. The public health importance of scabies in northern Australia is underappreciated and a concerted approach is required to recognise and eliminate scabies as an important precursor of skin sores.

<i>Schistosoma japonicum</i> IAP and Teg20 safeguard tegumental integrity by inhibiting cellular apoptosis

PLoS Neglected Tropical Diseases News - 25 July 2018 - 9:00pm

by Juntao Liu, Bikash R. Giri, Yongjun Chen, Rong Luo, Tianqi Xia, Christoph G. Grevelding, Guofeng Cheng

Schistosomes are causative agents of human schistosomiasis, which is endemic in tropical and subtropical areas of the world. Adult schistosomes can survive in their final hosts for several decades, and they have evolved various strategies to overcome the host immune response. Consequently, understanding the mechanisms that regulate parasitic cell survival will open avenues for developing novel strategies against schistosomiasis. Our previous study suggested that an inhibitor of apoptosis protein in Schistosoma japonicum (SjIAP) may play important roles in parasitic survival and development. Here, we demonstrated that SjIAP can negatively regulate cellular apoptosis in S. japonicum by suppressing caspase activity. Immunohistochemistry analysis indicated that SjIAP ubiquitously expressed within the worm body including the tegument. Silencing of SjIAP expression via small interfering RNA led to destruction of the tegument integrity in schistosomes. We further used co-immunoprecipitation to identify interaction partners of SjIAP and revealed the tegument protein SjTeg-20 as a putative interacting partner of SjIAP. The interaction between SjIAP and SjTeg-20 was confirmed by a yeast two-hybrid (Y2H) assay. Moreover, results of a TUNEL assay, RNA interference, scanning and transmission electron microscopy, caspase assays, transcript profiling, and protein localization of both interacting molecules provided first evidence for an essential role of SjIAP and SjTeg-20 to maintain the structural integrity of the tegument by negatively regulating apoptosis. Taken together, our findings suggest that the cooperative activities of SjIAP and SjTeg-20 belong to the strategic inventory of S. japonicum ensuring survival in the hostile environment within the vasculature of the final host.

A phase II study to evaluate the safety and efficacy of topical 3% amphotericin B cream (Anfoleish) for the treatment of uncomplicated cutaneous leishmaniasis in Colombia

PLoS Neglected Tropical Diseases News - 25 July 2018 - 9:00pm

by Liliana López, Iván Vélez, Claudia Asela, Claudia Cruz, Fabiana Alves, Sara Robledo, Byron Arana

Background

Pentavalent antimonials (Sb5) are the first-line drugs for treating cutaneous leishmaniasis in Colombia; however, given problems with toxicity, compliance, availability, and cost, it is imperative to look for better therapeutic options. Intravenous amphotericin B (AmB) has been used extensively to treat visceral leishmaniasis; however, evidence on its topical use for cutaneous leishmaniasis is limited. Anfoleish is a topical formulation based on 3% AmB, which was developed following GMP standards by HUMAX and PECET. Anfoleish was shown to be safe and efficacious in animal model and in an open label study in CL patients. Hereafter we show the results of the first controlled and randomized study assessing the safety and efficacy of Anfoleish administered topically, two or three times per day for 28 days, for the treatment of non-complicated cutaneous leishmaniasis in Colombia.

Methods

An open-label, randomized, non-comparative phase Ib/II clinical trial was performed. Adult volunteers with a parasitologically confirmed diagnosis of cutaneous leishmaniasis were randomly allocated to receive Anfoleish cream either 3 (TID group) or 2 (BID group) times per day for 4 weeks.

Results

80 out of 105 subjects screened were included in the study. In intention to treat analysis, final cure was observed in 13 (32.5%) out of 40 subjects (IC 95% = 20.1–48) and in 12 (30%) out of 40 subjects (IC 95% = 18.1–45.5) in the BID and TID group respectively. In the per protocol analysis, cure rates were 39.4% (n = 13) (IC 95% = 24.7–56.3) and 35.3% (n = 12) (IC 95% = 21.5–52.1) in the BID and TID groups respectively. Anfoleish proved to be safe, and the few adverse events reported were local, around the area of application of the cream, and of mild intensity.

Conclusion

Anfoleish showed to be a safe and well-tolerated intervention. Its efficacy results however do not support at this time continuing with its clinical development or recommending it for the treatment of CL. Additional, studies to improve its current formulation are needed before thinking in conducting additional studies in patients.

Trial registration

Registered in clinicaltrials.gov NCT01845727.

Field evaluation of a 0.005% fipronil bait, orally administered to <i>Rhombomys opimus</i>, for control of fleas (Siphonaptera: Pulicidae) and phlebotomine sand flies (Diptera: Psychodidae) in the Central Asian Republic of Kazakhstan

PLoS Neglected Tropical Diseases News - 25 July 2018 - 9:00pm

by David M. Poché, Zaria Torres-Poché, Aidyn Yeszhanov, Richard M. Poché, Alexander Belyaev, Vit Dvořák, Zaure Sayakova, Larisa Polyakova, Batirbek Aimakhanov

Plague (Yersinia pestis) and zoonotic cutaneous leishmaniasis (Leishmania major) are two rodent-associated diseases which are vectored by fleas and phlebotomine sand flies, respectively. In Central Asia, the great gerbil (Rhombomys opimus) serves as the primary reservoir for both diseases in most natural foci. The systemic insecticide fipronil has been previously shown to be highly effective in controlling fleas and sand flies. However, the impact of a fipronil-based rodent bait, on flea and sand fly abundance, has never been reported in Central Asia. A field trial was conducted in southeastern Kazakhstan to evaluate the efficacy of a 0.005% fipronil bait, applied to gerbil burrows for oral uptake, in reducing Xenopsylla spp. flea and Phlebotomus spp. sand fly abundance. All active gerbil burrows within the treated area were presented with ~120 g of 0.005% fipronil grain bait twice during late spring/early summer (June 16, June 21). In total, 120 occupied and 14 visited gerbil colonies were surveyed and treated, and the resulting application rate was minimal (~0.006 mg fipronil/m2). The bait resulted in 100% reduction in Xenopsylla spp. flea abundance at 80-days post-treatment. Gravid sand flies were reduced ~72% and 100% during treatment and at week-3 post-treatment, respectively. However, noticeable sand fly reduction did not occur after week-3 and results suggest environmental factors also influenced abundance significantly. In conclusion, fipronil bait, applied in southeastern Kazakhstan, has the potential to reduce or potentially eliminate Xenopsylla spp. fleas if applied at least every 80-days, but may need to be applied at higher frequency to significantly reduce the oviposition rate of Phlebotomus spp. sand flies. Fipronil-based bait may provide a means of controlling blood-feeding vectors, subsequently reducing disease risk, in Central Asia and other affected regions globally.

Innate immune receptors over expression correlate with chronic chagasic cardiomyopathy and digestive damage in patients

PLoS Neglected Tropical Diseases News - 25 July 2018 - 9:00pm

by Nathalie de Sena Pereira, Tamyres Bernadete Dantas Queiroga, Daniela Ferreira Nunes, Cléber de Mesquita Andrade, Manuela Sales Lima Nascimento, Maria Adelaide Do-Valle-Matta, Antônia Cláudia Jácome da Câmara, Lúcia Maria da Cunha Galvão, Paulo Marcos Matta Guedes, Egler Chiari

Chronic chagasic cardiomyopathy (CCC) is observed in 30% to 50% of the individuals infected by Trypanosoma cruzi and heart failure is the important cause of death among patients in the chronic phase of Chagas disease. Although some studies have elucidated the role of adaptive immune responses involving T and B lymphocytes in cardiac pathogenesis, the role of innate immunity receptors such as Toll-like receptors (TLRs) and Nod-like receptors (NLRs) in CCC pathophysiology has not yet been determined. In this study, we evaluated the association among innate immune receptors (TLR1-9 and nucleotide-binding domain-like receptor protein 3/NLRP3), its adapter molecules (Myd88, TRIF, ASC and caspase-1) and cytokines (IL-1β, IL-6, IL-12, IL-18, IL-23, TNF-α, and IFN-β) with clinical manifestation, digestive and cardiac function in patients with different clinical forms of chronic Chagas disease. The TLR8 mRNA expression levels were enhanced in the peripheral blood mononuclear cells (PBMC) from digestive and cardiodigestive patients compared to indeterminate and cardiac patients. Furthermore, mRNA expression of IFN-β (cytokine produced after TLR8 activation) was higher in digestive and cardiodigestive patients when compared to indeterminate. Moreover, there was a positive correlation between TLR8 and IFN-β mRNA expression with sigmoid and rectum size. Cardiac and cardiodigestive patients presented higher TLR2, IL-12 and TNF-α mRNA expression than indeterminate and digestive patients. Moreover, cardiac patients also expressed higher levels of NLRP3, ASC and IL-1β mRNAs than indeterminate patients. In addition, we showed a negative correlation among TLR2, IL-1β, IL-12 and TNF-α levels with left ventricular ejection fraction, and positive correlation between NLRP3 with cardiothoracic index, and TLR2, IL-1β and IL-12 with left ventricular mass index. Together, our data suggest that high expression of innate immune receptors in cardiac and digestive patients may induce an enhancement of cytokine expression and participate of cardiac and digestive dysfunction.

Comparative proteomics of the two <i>T</i>. <i>brucei</i> PABPs suggests that PABP2 controls bulk mRNA

PLoS Neglected Tropical Diseases News - 24 July 2018 - 9:00pm

by Martin Zoltner, Nina Krienitz, Mark C. Field, Susanne Kramer

Poly(A)-binding proteins (PABPs) regulate mRNA fate by controlling stability and translation through interactions with both the poly(A) tail and eIF4F complex. Many organisms have several paralogs of PABPs and eIF4F complex components and it is likely that different eIF4F/PABP complex combinations regulate distinct sets of mRNAs. Trypanosomes have five eIF4G paralogs, six of eIF4E and two PABPs, PABP1 and PABP2. Under starvation, polysomes dissociate and the majority of mRNAs, most translation initiation factors and PABP2 reversibly localise to starvation stress granules. To understand this more broadly we identified a protein interaction cohort for both T. brucei PABPs by cryo-mill/affinity purification-mass spectrometry. PABP1 very specifically interacts with the previously identified interactors eIF4E4 and eIF4G3 and few others. In contrast PABP2 is promiscuous, with a larger set of interactors including most translation initiation factors and most prominently eIF4G1, with its two partners TbG1-IP and TbG1-IP2. Only RBP23 was specific to PABP1, whilst 14 RNA-binding proteins were exclusively immunoprecipitated with PABP2. Significantly, PABP1 and associated proteins are largely excluded from starvation stress granules, but PABP2 and most interactors translocate to granules on starvation. We suggest that PABP1 regulates a small subpopulation of mainly small-sized mRNAs, as it interacts with a small and distinct set of proteins unable to enter the dominant pathway into starvation stress granules and localises preferentially to a subfraction of small polysomes. By contrast PABP2 likely regulates bulk mRNA translation, as it interacts with a wide range of proteins, enters stress granules and distributes over the full range of polysomes.

Specific human antibody responses to <i>Aedes aegypti</i> and <i>Aedes polynesiensis</i> saliva: a new epidemiological tool to assess human exposure to disease vectors in the Pacific

PLoS Neglected Tropical Diseases News - 24 July 2018 - 9:00pm

by Françoise Mathieu-Daudé, Aurore Claverie, Catherine Plichart, Denis Boulanger, Fingani A. Mphande, Hervé C. Bossin

Background

Aedes mosquitoes severely affect the health and wellbeing of human populations by transmitting infectious diseases. In French Polynesia, Aedes aegypti is the main vector of dengue, chikungunya and Zika, and Aedes polynesiensis the primary vector of Bancroftian filariasis and a secondary vector of arboviruses. Tools for assessing the risk of disease transmission or for measuring the efficacy of vector control programmes are scarce. A promising approach to quantify the human-vector contact relies on the detection and the quantification of antibodies directed against mosquito salivary proteins.

Methodology/Principal findings

An ELISA test was developed to detect and quantify the presence of immunoglobulin G (IgG) directed against proteins from salivary gland extracts (SGE) of Ae. aegypti and Ae. polynesiensis in human populations exposed to either species, through a cross-sectional study. In Tahiti and Moorea islands where Ae. aegypti and Ae. polynesiensis are present, the test revealed that 98% and 68% of individuals have developed IgG directed against Ae. aegypti and Ae. polynesiensis SGE, respectively. By comparison, ELISA tests conducted on a cohort of people from metropolitan France, not exposed to these Aedes mosquitoes, indicated that 97% of individuals had no IgG directed against SGE of either mosquito species. The analysis of additional cohorts representing different entomological Aedes contexts showed no ELISA IgG cross-reactivity between Ae. aegypti and Ae. polynesiensis SGE.

Conclusions/Significance

The IgG response to salivary gland extracts seems to be a valid and specific biomarker of human exposure to the bites of Ae. aegypti and Ae. polynesiensis. This new immuno-epidemiological tool will enhance our understanding of people exposure to mosquito bites, facilitate the identification of areas where disease transmission risk is high and permit to evaluate the efficacy of novel vector control strategies in Pacific islands and other tropical settings.

Heme crystallization in a Chagas disease vector acts as a redox-protective mechanism to allow insect reproduction and parasite infection

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

by Caroline M. Ferreira, Renata Stiebler, Francis M. Saraiva, Guilherme C. Lechuga, Ana Beatriz Walter-Nuno, Saulo C. Bourguignon, Marcelo S. Gonzalez, Patrícia Azambuja, Ana Caroline P. Gandara, Rubem F. S. Menna-Barreto, Gabriela O. Paiva-Silva, Marcia C. Paes, Marcus F. Oliveira

Heme crystallization as hemozoin represents the dominant mechanism of heme disposal in blood feeding triatomine insect vectors of the Chagas disease. The absence of drugs or vaccine for the Chagas disease causative agent, the parasite Trypanosoma cruzi, makes the control of vector population the best available strategy to limit disease spread. Although heme and redox homeostasis regulation is critical for both triatomine insects and T. cruzi, the physiological relevance of hemozoin for these organisms remains unknown. Here, we demonstrate that selective blockage of heme crystallization in vivo by the antimalarial drug quinidine, caused systemic heme overload and redox imbalance in distinct insect tissues, assessed by spectrophotometry and fluorescence microscopy. Quinidine treatment activated compensatory defensive heme-scavenging mechanisms to cope with excessive heme, as revealed by biochemical hemolymph analyses, and fat body gene expression. Importantly, egg production, oviposition, and total T. cruzi parasite counts in R. prolixus were significantly reduced by quinidine treatment. These effects were reverted by oral supplementation with the major insect antioxidant urate. Altogether, these data underscore the importance of heme crystallization as the main redox regulator for triatomine vectors, indicating the dual role of hemozoin as a protective mechanism to allow insect fertility, and T. cruzi life-cycle. Thus, targeting heme crystallization in insect vectors represents an innovative way for Chagas disease control, by reducing simultaneously triatomine reproduction and T. cruzi transmission.

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