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A case for adoption of continuous albendazole treatment regimen for human echinococcal infections

PLoS Neglected Tropical Diseases News - 17 September 2020 - 9:00pm

by Francesca Tamarozzi, John Horton, Marin Muhtarov, Michael Ramharter, Mar Siles-Lucas, Beate Gruener, Dominique A. Vuitton, Solange Bresson-Hadni, Tommaso Manciulli, Enrico Brunetti

Cystic (CE) and alveolar (AE) echinococcosis are chronic, neglected parasitic diseases burdened by high morbidity and, for AE, by high mortality, if left untreated. CE and AE have a widespread distribution, including Europe. Albendazole (ABZ), a broad-spectrum benzimidazole drug widely used to treat parasitic infections, is the drug of choice for the management of CE and AE, and is parasitostatic on echinococcal metacestodes. In Europe, ABZ is licensed for interrupted “cyclic” treatment, for a maximum of 3 cycles. However, better efficacy with no increased side effects has been shown when the drug is administered continuously and for longer periods. Current international recommendations, on the basis of clinical, pharmacological, and biological studies, recommend continuous administration of ABZ for months to years for the treatment of CE and AE, and this schedule has been widely in use for the past 20 years. However, in Europe this internationally recommended schedule, with the exception of France, is technically “off-label”, and, as such, requires an informed consent by the patient and, in some countries, even precludes the reimbursement of the drug cost. Adding to the very high cost of the drug, frequent “out-of-stock” situation, and packaging format impractical for long therapies, these conditions put patients with CE and AE regularly at risk of treatment discontinuation and disease progression. European regulations envisage variations to marketing authorization, but postauthorization studies should be carried out by the holder of the license of the drug, in the form of randomized controlled trials. While such studies do not seem feasible and would probably not be ethically justified for CE and AE, European regulations envisage other possibilities in particular situations, which apply to CE and AE, but there is limited interest to invest in this perspective. We urge a coordination between stakeholders to find effective and feasible ways to take action to revise the benzimidazole dosage regimens for CE and AE and to ensure a fair, regular, and easy access to the appropriate treatment to those suffering from these serious diseases.

Autochthonous leprosy in Spain: Has the transmission of <i>Mycobacterium leprae</i> stopped?

PLoS Neglected Tropical Diseases News - 16 September 2020 - 9:00pm

by Inés Suárez-García, Diana Gómez-Barroso, Paul E. M. Fine


The aim of this study is to explore whether transmission of M. leprae has ceased in Spain, based upon the patterns and trends of notified cases.


Data on new cases reported to the National Leprosy Registry between the years 2003–2018 were extracted. In absence of detailed travel history, cases were considered “autochthonous” or “imported” based on whether they were born within or outside of Spain. These data were analyzed by age, sex, clinical type, country of origin, and location of residence at time of notification.

Principal findings

Data were available on 61 autochthonous and 199 imported cases since 2003. There were clear declines in incidence in both groups, and more imported than autochthonous cases every year since 2006. Autochthonous cases were more frequently multibacillary and had older age at diagnosis compared to imported cases. All the autochthonous cases had been born before 1985 and were more than 25 years old at diagnosis. Male-to-female ratio increased with time for autochthonous cases (except for the last time period). The imported cases originated from 25 countries, half of them from Brasil and Paraguay. Autochthonous cases were mainly distributed in the traditionally endemic regions, especially Andalucía and the eastern Mediterranean coast.


Autochthonous and imported cases have different epidemiologic patterns in Spain. There was a clear decline in incidence rates of autochthonous disease, and patterns consistent with those reported from other regions where transmission has ceased. Autochthonous transmission of M. leprae is likely to have now effectively stopped in Spain.

Post-exposure prophylaxis (PEP) efficacy of rifampin, rifapentine, moxifloxacin, minocycline, and clarithromycin in a susceptible-subclinical model of leprosy

PLoS Neglected Tropical Diseases News - 16 September 2020 - 9:00pm

by Shannon M. Lenz, Jaymes H. Collins, Nashone A. Ray, Deanna A. Hagge, Ramanuj Lahiri, Linda B. Adams


Subclinical infection with Mycobacterium leprae is one potential source of leprosy transmission, and post-exposure prophylaxis (PEP) regimens have been proposed to control this source. Because PEP trials require considerable investment, we applied a sensitive variation of the kinetic mouse footpad (MFP) screening assay to aid in the choice of drugs and regimens for clinical trials.

Methodology/Principal findings

Athymic nude mice were inoculated in the footpad (FP) with 6 x 103 viable M. leprae and treated by gastric gavage with a single dose of Rifampin (SDR), Rifampin + Ofloxacin + Minocycline (SD-ROM), or Rifapentine + Minocycline + Moxifloxacin (SD-PMM) or with the proposed PEP++ regimen of three once-monthly doses of Rifampin + Moxifloxacin (RM), Rifampin + Clarithromycin (RC), Rifapentine + Moxifloxacin (PM), or Rifapentine + Clarithromycin (PC). At various times post-treatment, DNA was purified from the FP, and M. leprae were enumerated by RLEP quantitative PCR. A regression analysis was calculated to determine the expected RLEP value if 99.9% of the bacilli were killed after the administration of each regimen. SDR and SD-ROM induced little growth delay in this highly susceptible murine model of subclinical infection. In contrast, SD-PMM delayed measurable M. leprae growth above the inoculum by 8 months. The four multi-dose regimens delayed bacterial growth for >9months post-treatment cessation.


The delay in discernable M. leprae growth post-treatment was an excellent indicator of drug efficacy for both early (3–4 months) and late (8–9 months) drug efficacy. Our data indicates that multi-dose PEP may be required to control infection in highly susceptible individuals with subclinical leprosy to prevent disease and decrease transmission.

A comparison of three approaches for the discovery of novel tripartite attachment complex proteins in <i>Trypanosoma brucei</i>

PLoS Neglected Tropical Diseases News - 16 September 2020 - 9:00pm

by Hélène Clémentine Margareta Baudouin, Laura Pfeiffer, Torsten Ochsenreiter

Trypanosoma brucei is a single celled eukaryotic parasite and the causative agent of human African trypanosomiasis and nagana in cattle. Aside from its medical relevance, T. brucei has also been key to the discovery of several general biological principles including GPI-anchoring, RNA-editing and trans-splicing. The parasite contains a single mitochondrion with a singular genome. Recent studies have identified several molecular components of the mitochondrial genome segregation machinery (tripartite attachment complex, TAC), which connects the basal body of the flagellum to the mitochondrial DNA of T. brucei. The TAC component in closest proximity to the mitochondrial DNA is TAC102. Here we apply and compare three different approaches (proximity labelling, immunoprecipitation and yeast two-hybrid) to identify novel interactors of TAC102 and subsequently verify their localisation. Furthermore, we establish the direct interaction of TAC102 and p166 in the unilateral filaments of the TAC.

Addressing barriers of community participation and access to mass drug administration for lymphatic filariasis elimination in Coastal Kenya using a participatory approach

PLoS Neglected Tropical Diseases News - 16 September 2020 - 9:00pm

by Doris W. Njomo, Lydiah W. Kibe, Bridget W. Kimani, Collins Okoyo, Wyckliff P. Omondi, Hadley M. Sultani

Since the prioritization of Lymphatic Filariasis (LF) elimination in 1997, progress has been made in reducing disease transmission and burden. Validation of elimination through Transmission Assessment Surveys (TAS) in implementation units (IUs) that have received at least 5 rounds of mass drug administration (MDA) and achieved minimum threshold of 65% treatment coverage is required. There are IUs that do not qualify for TAS due to achievement of low treatment coverage. This study sought to identify barriers of community participation and access to MDA, develop and test strategies to be recommended for improved uptake. Two wards in Kaloleni sub-county, Kilifi county with an average treatment coverage of 56% in 2015, 50.5% in 2016 were purposively sampled and a quasi-experimental study conducted. Through systematic random sampling, 350 (pre-intervention) and 338 (post-intervention) household heads were selected and interviewed for quantitative data. For qualitative data, 16 Focus Group Discussions (FGDs) with purposively selected community groups were conducted. Participatory meetings were held with county stakeholders to agree on strategies for improved community participation in MDA. The quantitative data were analyzed using STATA version 14.1, statistical significance assessed by chi square test and qualitative data by QSR NVIVO version 10. The identified strategies were tested in experimental sites during the 2018 MDA and the usual MDA strategies applied in control sites. The results showed an increase in community participation and access to MDA in both sites 80.6% (pre-intervention), 82.9% (post-intervention). The proportion of participants who considered the treatment as necessary significantly (p = 0.001) increased to 96.2% from 88.3% and significantly dropped for those with drug swallowing problems associated with: size (p<0.001), number (p<0.027) and taste (p = 0.001). The implemented strategies may have contributed to increased participation and access to MDA and should be applied for improved treatment uptake. Health education on disease aetiology and importance of drug uptake in all rounds is key to program’s success.

ISG15 overexpression compensates the defect of Crimean-Congo hemorrhagic fever virus polymerase bearing a protease-inactive ovarian tumor domain

PLoS Neglected Tropical Diseases News - 15 September 2020 - 9:00pm

by Stephanie Devignot, Thilo Kromer, Ali Mirazimi, Friedemann Weber

Crimean-Congo Hemorrhagic Fever virus (CCHFV; family Nairoviridae) is an extremely pathogenic member of the Bunyavirales order. Previous studies have shown that the N-terminal domain of the CCHFV polymerase (L) contains an ovarian tumor-type protease (OTU) domain with the capability to remove both ubiquitin and ISG15 molecules from proteins. The approximately 200 amino acids-long OTU domain, if ectopically expressed, can interfere with both the induction of antiviral type I interferons (IFN) as well as the IFN-stimulated signaling. A OTU protease mutant (C40A), by contrast, was inactive in that respect. However, the effect of the OTU protease activity in the context of the full-length L protein (approximately 4000 amino acids) is only poorly characterized, and recombinant CCHFV with the C40A mutation could not be rescued. Here, we employed transcriptionally active virus-like particles (tc-VLPs) to investigate the interaction between the L-embedded OTU protease and the IFN system. Our data show a cis requirement of the OTU protease for optimal CCHFV polymerase activity in human HuH-7 cells. The L-embedded OTU did not influence IFN signaling, the sensitivity to IFN, or IFN induction. Moreover, the attenuation of OTU C40A-mutated L could not be relieved by inactivating the IFN response, but after overexpression of conjugation-competent ISG15 the polymerase activity recovered to wild-type levels. Consequently, ISG15 was used to produce OTU-deficient tc-VLPs, a potential vaccine candidate. Our data thus indicate that in the context of full-length L the OTU domain is important for the regulation of CCHFV polymerase by ISG15.

Wide range of G6PD activities found among ethnic groups of the Chittagong Hill Tracts, Bangladesh

PLoS Neglected Tropical Diseases News - 14 September 2020 - 9:00pm

by Benedikt Ley, Mohammad Golam Kibria, Wasif Ali Khan, Sarah Auburn, Ching Swe Phru, Nusrat Jahan, Fatema Tuj Johora, Kamala Thriemer, Jenifar Quaiyum Ami, Mohammad Sharif Hossain, Ric N. Price, Cristian Koepfli, Mohammad Shafiul Alam

The proportion of Plasmodium vivax malaria among all malarias is increasing worldwide. Treatment with 8-aminoquinolines remain the only radical cure. However, 8-aminoquinolines can cause severe hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficient patients. The population of the multi-ethnic Chittagong Hill Tracts (CHT) carry the highest malaria burden within Bangladesh. As in many countries the national treatment guidelines recommend 8-aminoquinoline based radical cure without routine G6PD deficiency (G6PDd) testing to guide treatment. Aim of this study was to determine the need for routine testing within a multi-ethnic population by assessing the prevalence of G6PDd among the local population. Participants from 11 ethnicities were randomly selected and malaria status was assessed by microscopy, rapid diagnostic test (RDT) and polymerase chain reaction (PCR). G6PD status was determined by spectrophotometry and G6PD genotyping. The adjusted male median (AMM) was defined as 100% G6PD activity, participants were categorized as G6PD deficient (<30% activity), G6PD intermediate (30% to 70% activity) or G6PD normal (>70% activity). Median G6PD activities between ethnicities were compared and the association between G6PD activity and malaria status was assessed. 1002 participants were enrolled and tested for malaria. G6PD activity was measured by spectrophotometry in 999 participants and host G6PD genotyping undertaken in 323 participants. Seven participants (0.7%) had peripheral parasitaemia detected by microscopy or RDT and 42 by PCR (4.2%). Among 106 participants (32.8%) with confirmed genotype, 99 (93.4%) had the Mahidol variant. The AMM was 7.03U/gHb with 90 (9.0%) G6PD deficient participants and 133 (13.3%) with intermediate G6PD activity. Median G6PD activity differed significantly between ethnicities (p<0.001), proportions of G6PD deficient individuals ranged from 2% to 26% but did not differ between participants with and without malaria. The high G6PDd prevalence and significant variation between ethnicities suggest routine G6PDd testing to guide 8-aminoquinoline based radical in the CHT and comparable settings.

Practical and effective diagnosis of animal anthrax in endemic low-resource settings

PLoS Neglected Tropical Diseases News - 14 September 2020 - 9:00pm

by Olubunmi R. Aminu, Tiziana Lembo, Ruth N. Zadoks, Roman Biek, Suzanna Lewis, Ireen Kiwelu, Blandina T. Mmbaga, Deogratius Mshanga, Gabriel Shirima, Matt Denwood, Taya L. Forde

Anthrax threatens human and animal health, and people’s livelihoods in many rural communities in Africa and Asia. In these areas, anthrax surveillance is challenged by a lack of tools for on-site detection. Furthermore, cultural practices and infrastructure may affect sample availability and quality. Practical yet accurate diagnostic solutions are greatly needed to quantify anthrax impacts. We validated microscopic and molecular methods for the detection of Bacillus anthracis in field-collected blood smears and identified alternative samples suitable for anthrax confirmation in the absence of blood smears. We investigated livestock mortalities suspected to be caused by anthrax in northern Tanzania. Field-prepared blood smears (n = 152) were tested by microscopy using four staining techniques as well as polymerase chain reaction (PCR) followed by Bayesian latent class analysis. Median sensitivity (91%, CI 95% [84–96%]) and specificity (99%, CI 95% [96–100%]) of microscopy using azure B were comparable to those of the recommended standard, polychrome methylene blue, PMB (92%, CI 95% [84–97%] and 98%, CI 95% [95–100%], respectively), but azure B is more available and convenient. Other commonly-used stains performed poorly. Blood smears could be obtained for <50% of suspected anthrax cases due to local customs and conditions. However, PCR on DNA extracts from skin, which was almost always available, had high sensitivity and specificity (95%, CI 95% [90–98%] and 95%, CI 95% [87–99%], respectively), even after extended storage at ambient temperature. Azure B microscopy represents an accurate diagnostic test for animal anthrax that can be performed with basic laboratory infrastructure and in the field. When blood smears are unavailable, PCR using skin tissues provides a valuable alternative for confirmation. Our findings lead to a practical diagnostic approach for anthrax in low-resource settings that can support surveillance and control efforts for anthrax-endemic countries globally.

A systematic review of the untreated mortality of murine typhus

PLoS Neglected Tropical Diseases News - 14 September 2020 - 9:00pm

by Johannes F. Doppler, Paul N. Newton

Murine typhus is an acute febrile, flea-borne disease caused by the bacteria Rickettsia typhi. The disease occurs worldwide but is likely underrecognized due to its non-specific symptoms, causing significant morbidity. A systematic review found disease complications in one-fourth of all patients and a long fever duration in those untreated. Although mortality in treated cases is estimated to be very low, some case series have shown a notably higher mortality in untreated patients. This study aimed to describe the outcomes and estimate the mortality of untreated murine typhus through a comprehensive systematic literature review. We systematically searched the literature for articles describing untreated murine typhus patients, excluding cases with no laboratory assay confirmed diagnosis, those who received efficacious treatment, had incomplete information on primary outcome and articles describing less than 10 patients and performed a narrative synthesis of the study findings. The study protocol followed the PRISMA guidelines and was part of a more extensive protocol registered at PROSPERO (CRD42018101991). Twelve studies including a total of 239 untreated patients matched the eligibility criteria. Only a single study reported one death in 28 patients, giving a patient series mortality of 3.6% and an overall mortality of 0.4% in 239 untreated patients. Complications were reported in 10 of the 12 studies and included involvement of the central nervous system, kidney and lung, with a hospitalisation rate of 70% and ICU admission rate of 27% in one study. The mean duration of fever in untreated patients was 15 days in two and 12.7 days in one study. Although the untreated mortality in this study was low, the sample size was small. Murine typhus caused significant morbidity when untreated, leading to high hospitalisation rates and highlighting the importance of early diagnosis and treatment of this neglected disease to reduce disease burden and health-care related costs.

Identifying correlates of Guinea worm (<i>Dracunculus medinensis</i>) infection in domestic dog populations

PLoS Neglected Tropical Diseases News - 14 September 2020 - 9:00pm

by Robert L. Richards, Christopher A. Cleveland, Richard J. Hall, Philip Tchindebet Ouakou, Andrew W. Park, Ernesto Ruiz-Tiben, Adam Weiss, Michael J. Yabsley, Vanessa O. Ezenwa

Few human infectious diseases have been driven as close to eradication as dracunculiasis, caused by the Guinea worm parasite (Dracunculus medinensis). The number of human cases of Guinea worm decreased from an estimated 3.5 million in 1986 to mere hundreds by the 2010s. In Chad, domestic dogs were diagnosed with Guinea worm for the first time in 2012, and the numbers of infected dogs have increased annually. The presence of the parasite in a non-human host now challenges efforts to eradicate D. medinensis, making it critical to understand the factors that correlate with infection in dogs. In this study, we evaluated anthropogenic and environmental factors most predictive of detection of D. medinensis infection in domestic dog populations in Chad. Using boosted regression tree models to identify covariates of importance for predicting D. medinensis infection at the village and spatial hotspot levels, while controlling for surveillance intensity, we found that the presence of infection in a village was predicted by a combination of demographic (e.g. fishing village identity, dog population size), geographic (e.g. local variation in elevation), and climatic (e.g. precipitation and temperature) factors, which differed between northern and southern villages. In contrast, the presence of a village in a spatial infection hotspot, was primarily predicted by geography and climate. Our findings suggest that factors intrinsic to individual villages are highly predictive of the detection of Guinea worm parasite presence, whereas village membership in a spatial infection hotspot is largely determined by location and climate. This study provides new insight into the landscape-scale epidemiology of a debilitating parasite and can be used to more effectively target ongoing research and possibly eradication and control efforts.

Interaction of Signaling Lymphocytic Activation Molecule Family 1 (SLAMF1) receptor with <i>Trypanosoma cruzi</i> is strain-dependent and affects NADPH oxidase expression and activity

PLoS Neglected Tropical Diseases News - 14 September 2020 - 9:00pm

by Cristina Poveda, Alfonso Herreros-Cabello, Francisco Callejas-Hernández, Jesús Osuna-Pérez, María C. Maza, Carlos Chillón-Marinas, Jossela Calderón, Konstantinos Stamatakis, Manuel Fresno, Núria Gironès

The receptor Signaling Lymphocyte-Activation Molecule Family 1 (SLAMF1) controls susceptibility to Infection by the lethal Trypanosoma cruzi Y strain. To elucidate whether genetic diversity of the parasite was related with disease susceptibility, we further analyzed the role of SLAMF1 using 6 different Trypanosoma cruzi strains including Y. The interaction of SLAMF1 receptor with T. cruzi was evidenced by fluorescence microscopy, flow cytometry and quantitative PCR. All the strains, except VFRA, showed a decrease in parasite load in infected macrophages in Slamf1-/- compared to BALB/c. In macrophages gene expression NADPH oxidase (NOX2), and reactive oxygen species (ROS) production increased in Slamf1-/- compared to BALB/c in 5 out of 6 strains. However, Slamf1-/-macrophages infected with VFRA strain exhibited a divergent behavior, with higher parasite load, lower NOX2 expression and ROS production compared to BALB/c. Parasitological and immunological studies in vivo with Y strain showed that in the absence of SLAMF1 the immune response protected mice from the otherwise lethal Y infection favoring a proinflammatory response likely involving CD4, CD8, dendritic cells and classically activated macrophages. In the case of VFRA, no major changes were observed in the absence of SLAMF1. Thus, the results suggest that the T. cruzi affects SLAMF1-dependent ROS production, controlling parasite replication in macrophages and affecting survival in mice in a strain-dependent manner. Further studies will focus in the identification of parasite molecules involved in SLAMF1 interaction to explain the immunopathogenesis of the disease.

Comparison of dengue case classification schemes and evaluation of biological changes in different dengue clinical patterns in a longitudinal follow-up of hospitalized children in Cambodia

PLoS Neglected Tropical Diseases News - 14 September 2020 - 9:00pm

by Philippe Dussart, Veasna Duong, Kevin Bleakley, Camille Fortas, Patrich Lorn Try, Kim Srorn Kim, Rithy Choeung, Saraden In, Anne-Claire Andries, Tineke Cantaert, Marie Flamand, Philippe Buchy, Anavaj Sakuntabhai


The World Health Organization (WHO) proposed guidelines on dengue clinical classification in 1997 and more recently in 2009 for the clinical management of patients. The WHO 1997 classification defines three categories of dengue infection according to severity: dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). Alternative WHO 2009 guidelines provide a cross-sectional classification aiming to discriminate dengue fever from dengue with warning signs (DWWS) and severe dengue (SD). The primary objective of this study was to perform a comparison of two dengue classifications. The secondary objective was to describe the changes of hematological and biochemical parameters occurring in patients presenting with different degrees of severity during the course of the disease, since progression to more severe clinical forms is unpredictable.

Methodology/Principal findings

We performed a prospective, monocentric, cross-sectional study of hospitalized children in Cambodia, aged from 2 to 15 years old with severe and non-severe dengue. We enrolled 243 patients with acute dengue-like illness: 71.2% were dengue infections confirmed using quantitative reverse transcription PCR or NS1 antigen capture ELISA, of which 87.2% and 9.0% of DF cases were respectively classified DWWS and SD, and 35.9% of DHF were designated SD using an adapted WHO 2009 classification for SD case definition. Systematic use of ultrasound at patient admission was crucial for detecting plasma leakage. No difference was observed in the concentration of secreted NS1 protein between different dengue severity groups. Lipid profiles were different between DWWS and SD at admission, characterized by a decrease in total cholesterol, HDL cholesterol, and LDL cholesterol, in SD.


Our results show discrepancies between the two classifications, including misclassification of severe dengue cases as mild cases by the WHO 1997 classification. Using an adapted WHO 2009 classification, SD more precisely defines the group of patients requiring careful clinical care at a given time during hospitalization.

The complex health seeking pathway of a human African trypanosomiasis patient in Côte d’Ivoire underlines the need of setting up passive surveillance systems

PLoS Neglected Tropical Diseases News - 14 September 2020 - 9:00pm

by Minayégninrin Koné, Emmanuel Kouassi N’Gouan, Dramane Kaba, Mathurin Koffi, Lingué Kouakou, Louis N’Dri, Cyrille Mambo Kouamé, Valentin Kouassi Nanan, Gossé Apollinaire Tapé, Bamoro Coulibaly, Fabrice Courtin, Bernardin Ahouty, Vincent Djohan, Bruno Bucheton, Philippe Solano, Philippe Büscher, Veerle Lejon, Vincent Jamonneau


Significant efforts to control human African trypanosomiasis (HAT) over the two past decades have resulted in drastic decrease of its prevalence in Côte d’Ivoire. In this context, passive surveillance, integrated in the national health system and based on clinical suspicion, was reinforced. We describe here the health-seeking pathway of a girl who was the first HAT patient diagnosed through this strategy in August 2017.


After definitive diagnosis of this patient, epidemiological investigations were carried out into the clinical evolution and the health and therapeutic itinerary of the patient before diagnosis.


At the time of diagnosis, the patient was positive in both serological and molecular tests and trypanosomes were detected in blood and cerebrospinal fluid. She suffered from important neurological disorders. The first disease symptoms had appeared three years earlier, and the patient had visited several public and private peripheral health care centres and hospitals in different cities. The failure to diagnose HAT for such a long time caused significant health deterioration and was an important financial burden for the family.


This description illustrates the complexity of detecting the last HAT cases due to complex diagnosis and the progressive disinterest and unawareness by both health professionals and the population. It confirms the need of implementing passive surveillance in combination with continued sensitization and health staff training.

The impact of semen testing for Ebola virus RNA on sexual behavior of male Ebola survivors in Liberia

PLoS Neglected Tropical Diseases News - 14 September 2020 - 9:00pm

by Kathleen Tompkins, Jerry Brown, Sam Tozay, Edwina Reeves, Korto Pewu, Harrietta Johnson, Gerald Williams, Tonia Conneh, Joseph Diggs, Jean DeMarco, Katherine King, Darrius McMillian, Carson Merenbloom, William Fischer, David Alain Wohl

Sexual transmission of Ebola virus (EBOV) is well established and has been implicated in multiple resurgences during the West African Ebola epidemic. Given the persistence of viral RNA in semen, guidelines from the World Health Organization (WHO) recommend abstinence or condom use for at least 1 year or until two semen PCR tests are negative. To better understand the impact of semen testing on sexual behavior, male EVD survivors were surveyed regarding their sexual behavior before and after semen testing. Of the 171 men who enrolled, 148 reported being sexually active following discharge from an ETU with 59% reporting episodes of condomless sex. At least one semen sample for testing was provided by 149 men and 13 of these men had EBOV RNA detected in their semen. When comparing sexual behaviors before and after semen testing, a positive semen test result had limited impact on behavior. Of those with seminal EBOV RNA detected, 61% reported no change in behavior pre- and post-semen testing with 46% engaging in condomless sex before and after testing and only 1 adopted safer sex behaviors following receipt of a positive result. Similarly, among men with undetectable EBOV in their semen, 66% reported no change in sexual behaviors with semen testing, with 55% forgoing condoms during sex. In only 11% was a negative semen result followed by abandoning condoms. There were no known sexual transmission events of Ebola virus in this cohort despite viral presence in semen during periods of condomless sex. This highlights the need to better understand the infectious potential of viral RNA persistence and determine what constitutes effective counseling for survivors and their partners.

Population genomics of louping ill virus provide new insights into the evolution of tick-borne flaviviruses

PLoS Neglected Tropical Diseases News - 14 September 2020 - 9:00pm

by Jordan J. Clark, Janice Gilray, Richard J. Orton, Margaret Baird, Gavin Wilkie, Ana da Silva Filipe, Nicholas Johnson, Colin J. McInnes, Alain Kohl, Roman Biek

The emergence and spread of tick-borne arboviruses pose an increased challenge to human and animal health. In Europe this is demonstrated by the increasingly wide distribution of tick-borne encephalitis virus (TBEV, Flavivirus, Flaviviridae), which has recently been found in the United Kingdom (UK). However, much less is known about other tick-borne flaviviruses (TBFV), such as the closely related louping ill virus (LIV), an animal pathogen which is endemic to the UK and Ireland, but which has been detected in other parts of Europe including Scandinavia and Russia. The emergence and potential spatial overlap of these viruses necessitates improved understanding of LIV genomic diversity, geographic spread and evolutionary history. We sequenced a virus archive composed of 22 LIV isolates which had been sampled throughout the UK over a period of over 80 years. Combining this dataset with published virus sequences, we detected no sign of recombination and found low diversity and limited evidence for positive selection in the LIV genome. Phylogenetic analysis provided evidence of geographic clustering as well as long-distance movement, including movement events that appear recent. However, despite genomic data and an 80-year time span, we found that the data contained insufficient temporal signal to reliably estimate a molecular clock rate for LIV. Additional analyses revealed that this also applied to TBEV, albeit to a lesser extent, pointing to a general problem with phylogenetic dating for TBFV. The 22 LIV genomes generated during this study provide a more reliable LIV phylogeny, improving our knowledge of the evolution of tick-borne flaviviruses. Our inability to estimate a molecular clock rate for both LIV and TBEV suggests that temporal calibration of tick-borne flavivirus evolution should be interpreted with caution and highlight a unique aspect of these viruses which may be explained by their reliance on tick vectors.

Heterogeneity of dengue transmission in an endemic area of Colombia

PLoS Neglected Tropical Diseases News - 14 September 2020 - 9:00pm

by María Isabel Estupiñán Cárdenas, Víctor Mauricio Herrera, María Consuelo Miranda Montoya, Anyela Lozano Parra, Zuly Milena Zaraza Moncayo, Janeth Patricia Flórez García, Isabel Rodríguez Barraquer, Luis Ángel Villar Centeno

Population based serological surveys are the gold-standard to quantify dengue (DENV) transmission. The purpose of this study was to estimate the age-specific seroprevalence and the force of infection of DENV in an endemic area of Colombia. Between July and October 2014, we conducted a household based cross-sectional survey among 1.037 individuals aged 2 to 40 years living in 40 randomly selected locations in urban Piedecuesta, Santander, Colombia. In addition, we also enrolled 246 indviduals living in rural “veredas”. Participants were asked to answer a questionnaire that included demographic, socioeconomic and environmental questions and to provide a 5 ml blood sample. Sera were tested using the IgG indirect ELISA (Panbio) kit to determine past DENV infection. The overall DENV seroprevalence was 70% (95% CI = 67%-71%), but was significantly higher in urban (81%, 95% CI = 78%-83%) as compared to rural (21%, 95% CI = 17%-27%) locations. Age was a major predictor of seropositivity, consistent with endemic circulation of the virus. Using catalytic models we estimated that on average, 12% (95%CI = 11%-13%) of susceptible individuals living in the city are infected by DENV each year. Beyond age, the only predictor of seropositivity in urban locations was prior history of dengue diagnosed by a physician (aPR 1.15, 95% CI = 0.98–1.35). Among participants living in rural settings, those that reported traveling outside of their vereda were more likely to be seropositive (aPR 3.60, 95%CI = 1.54–8.42) as well as those who were born outside of Santander department (aPR = 2.77, 95%CI = 1.20–6.37). These results are consistent with long term endemic circulation of DENV in Piedecuesta, with large heterogeneities between urban and rural areas located just a few kilometers apart. Design of DENV control interventions, including vaccination, will need to consider this fine scale spatial heterogeneity.

Dynamics of serological responses to defined recombinant proteins during <i>Schistosoma mansoni</i> infection in mice before and after the treatment with praziquantel

PLoS Neglected Tropical Diseases News - 11 September 2020 - 9:00pm

by Eman Sayed Mohammed, Risa Nakamura, Yombo DJ Kalenda, Sharmina Deloer, Taeko Moriyasu, Mio Tanaka, Yoshito Fujii, Satoshi Kaneko, Kenji Hirayama, Ahmed I. Ibrahim, Mahmoud A. El-Seify, Asmaa M. Metwally, Shinjiro Hamano

To eliminate schistosomiasis, appropriate diagnostic tests are required to monitor its prevalence and transmission, especially in the settings with low endemicity resulting from the consecutive mass drug administration. Antibodies that react with either crude soluble schistosome egg antigens or soluble worm antigen preparations have been used to monitor infection in low-prevalence regions. However, these detection methods cannot discriminate current and past infections and are cross-reactive with other parasites because both antigens contain numerous proteins and glycans from schistosomes, and standard preparations need maintenance of the life cycle of the schistosome. To evaluate the potential utility of nine recombinant Schistosoma mansoni proteins as single defined antigens for serological diagnosis, we monitored the kinetics of antibodies to each antigen during S. mansoni infection in mice before and after the treatment with praziquantel. C57BL/6 mice were infected with 50 cercariae. The levels of immunoglobulin G (IgG) raised against five recombinant antigens (RP26, sm31, sm32, GST, and LAP1) significantly increased as early as 2–4 weeks after infection and rapidly declined by 2 weeks after the treatment, whereas those raised against crude S. mansoni egg antigens or other antigens remained elevated long after the treatment. The IgG1 raised against RP26, sm31, and serpin decreased after the treatment with praziquantel, whereas the IgE raised against serpin declined strikingly after the treatment. This study clarifies the dynamics of the serological responses to recombinant S. mansoni proteins during infection and after the treatment with praziquantel and identifies several candidate antigens with potential utility in the monitoring and surveillance of schistosomiasis toward the elimination of schistosomiasis.

Dengue infection modulates locomotion and host seeking in <i>Aedes aegypti</i>

PLoS Neglected Tropical Diseases News - 10 September 2020 - 9:00pm

by Anaïs K. Tallon, Marcelo G. Lorenzo, Luciano A. Moreira, Luis E. Martinez Villegas, Sharon Rose Hill, Rickard Ignell

Pathogens may manipulate their human and mosquito hosts to enhance disease transmission. Dengue, caused by four viral serotypes, is the fastest-growing transmissible disease globally resulting in 50–100 million infections annually. Transmission of the disease relies on the interaction between humans and the vector Aedes aegypti and is largely dependent on the odor-mediated host seeking of female mosquitoes. In this study, we use activity monitors to demonstrate that dengue virus-1 affects the locomotion and odor-mediated behavior of Ae. aegypti, reflecting the progression of infection within the mosquito. Mosquitoes 4–6 days post-infection increase locomotion, but do not alter their odor-driven host-seeking response. In contrast, females 14–16 days post-infection are less active, yet more sensitive to human odors as assessed by behavioral and electrophysiological assays. Such an increase in physiological and behavioral sensitivity is reflected by the antennal-specific increase in abundance of neural signaling transcripts in 14 days post-infection females, as determined by transcriptome analysis. This suggests that the sensitivity of the mosquito peripheral olfactory system is altered by the dengue virus by enhancing the overall neural responsiveness of the antenna, rather than the selective regulation of chemosensory-related genes. Our study reveals that dengue virus-1 enhances vector-related behaviors in the early stages post-infection that aid in avoiding predation and increasing spatial exploration. On the other hand, at the later stages of infection, the virus enhances the host-seeking capacity of the vector, thereby increasing the risk of virus transmission. A potential mechanism is discussed.

A bug’s life: Delving into the challenges of helminth microbiome studies

PLoS Neglected Tropical Diseases News - 10 September 2020 - 9:00pm

by Fabio Formenti, Alba Cortés, Paul J. Brindley, Cinzia Cantacessi, Gabriel Rinaldi

<i>Fasciola hepatica</i> Extracellular Vesicles isolated from excretory-secretory products using a gravity flow method modulate dendritic cell phenotype and activity

PLoS Neglected Tropical Diseases News - 8 September 2020 - 9:00pm

by Anna Murphy, Krystyna Cwiklinski, Richard Lalor, Barry O’Connell, Mark W. Robinson, Jared Gerlach, Lokesh Joshi, Michelle Kilcoyne, John P. Dalton, Sandra M. O’Neill

Parasite-released extracellular vesicles (EVs) deliver signals to the host immune system that are critical to maintaining the long-term relationship between parasite and host. In the present study, total EVs (FhEVs) released in vitro by adults of the helminth parasite Fasciola hepatica were isolated using a recently described gravity flow method that protects their structural integrity. The FhEVs molecular cargo was defined using proteomic analysis and their surface topology characterised by glycan microarrays. The proteomic analysis identified 618 proteins, 121 of which contained putative N-linked glycosylation sites while 132 proteins contained putative O-linked glycosylation sites. Glycan arrays revealed surface-exposed glycans with a high affinity for mannose-binding lectins indicating the predominance of oligo mannose-rich glycoproteins, as well as other glycans with a high affinity for complex-type N-glycans. When added to bone-marrow derived dendritic cells isolated FhEV induced a novel phenotype that was categorised by the secretion of low levels of TNF, enhanced expression of cell surface markers (CD80, CD86, CD40, OX40L, and SIGNR1) and elevation of intracellular markers (SOCS1 and SOCS3). When FhEV-stimulated BMDCs were introduced into OT-II mice by adoptive transfer, IL-2 secretion from skin draining lymph nodes (sdLN) and spleen cells was inhibited in response to both specific and non-specific antigen stimulation. Immunisation of mice with a suspension of FhEV did not elicit significant immune responses; however, in the presence of alum, FhEVs induced a mixed Th1/Th2 immune response with high antigen specific antibody titres. Thus, we have demonstrated that FhEVs induce a unique phentotype in DC capable of suppressing IL-2 secretion from T-cells. Our studies add to the growing immuno-proteomic database that will be an important source for the discovery of future parasite vaccines and immunotherapeutic biologicals.