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ZIKA Virus infection in pregnant women in French Guiana: More precarious-more at risk

PLoS Neglected Tropical Diseases News - 24 March 2020 - 9:00pm

by Edouard Hallet, Claude Flamand, Dominique Rousset, Timothée Bonifay, Camille Fritzell, Séverine Matheus, Maryvonne Dueymes, Balthazar Ntab, Mathieu Nacher

Background

A recent study in French Guiana suggested that populations living in precarious neighborhoods were more at risk for Chikungunya CHIKV than those living in more privileged areas. The objective of the present study was to test the hypothesis that Zika virus (ZIKV) infection was more frequent in precarious pregnant women than in non-precarious pregnant women, as reflected by their health insurance status.

Methods

A multicentric cross-sectional study was conducted in Cayenne hospital including ZIKV pregnant women with serological or molecular proof of ZIKV during their pregnancy between January and December 2016. Health insurance information was recorded at delivery, which allowed separating women in: undocumented foreigners, precarious but with residence permit, and non-precarious.

Results

A total of 6654 women were included. Among them 1509 (22,7%) had confirmed ZIKV infection. Most women were precarious (2275/3439) but the proportion of precarious women was significantly greater in ZIKV-confirmed 728/906 (80.4%) than the ZIKV-negatives 1747/2533 (69.0%), p<0.0001. There were 1142 women classified as non-precarious, 1671 were precarious legal residents, and 1435 were precarious and undocumented. Precariousness and undocumented status were associated with a higher prevalence of ZIKV during pregnancy (adjusted prevalence ratio = 1.59 (95%CI = 1.29–1.97), p<0.0001), (adjusted prevalence ratio = 1.5 (95%CI = 1.2–1.8), p<0.0001), respectively.

Conclusions

These results illustrate that in French Guiana ZIKV transmission disproportionately affected the socially vulnerable pregnant women, presumably because of poorer housing conditions, and lack of vector control measures in poor neighborhoods.

<i>Leptospira interrogans</i>  and <i>Leptospira kirschneri</i> are the dominant <i>Leptospira</i> species causing human leptospirosis in Central Malaysia

PLoS Neglected Tropical Diseases News - 23 March 2020 - 9:00pm

by Noraini Philip, Norliza Bahtiar Affendy, Siti Nur Alia Ramli, Muhamad Arif, Pappitha Raja, Elanngovan Nagandran, Pukunan Renganathan, Niazlin Mohd Taib, Siti Norbaya Masri, Muhamad Yazli Yuhana, Leslie Thian Lung Than, Mithra Seganathirajah, Cyrille Goarant, Marga G. A. Goris, Zamberi Sekawi, Vasantha Kumari Neela

Background

Leptospirosis, commonly known as rat-urine disease, is a global but endemic zoonotic disease in the tropics. Despite the historical report of leptospirosis in Malaysia, the information on human-infecting species is limited. Determining the circulating species is important to understand its epidemiology, thereby to strategize appropriate control measures through public health interventions, diagnostics, therapeutics and vaccine development.

Methodology/Principle findings

We investigated the human-infecting Leptospira species in blood and serum samples collected from clinically suspected leptospirosis patients admitted to three tertiary care hospitals in Malaysia. From a total of 165 patients, 92 (56%) were confirmed cases of leptospirosis through Microscopic Agglutination Test (MAT) (n = 43; 47%), Polymerase Chain Reaction (PCR) (n = 63; 68%) or both MAT and PCR (n = 14; 15%). The infecting Leptospira spp., determined by partial 16S rDNA (rrs) gene sequencing revealed two pathogenic species namely Leptospira interrogans (n = 44, 70%) and Leptospira kirschneri (n = 17, 27%) and one intermediate species Leptospira wolffii (n = 2, 3%). Multilocus sequence typing (MLST) identified an isolate of L. interrogans as a novel sequence type (ST 265), suggesting that this human-infecting strain has a unique genetic profile different from similar species isolated from rodents so far.

Conclusions/Significance

Leptospira interrogans and Leptospira kirschneri were identified as the dominant Leptospira species causing human leptospirosis in Central Malaysia. The existence of novel clinically important ST 265 (infecting human), that is different from rodent L. interrogans strains cautions reservoir(s) of these Leptospira lineages are yet to be identified.

Comparison of anti-Vi IgG responses between two clinical studies of typhoid Vi conjugate vaccines (Vi-DT vs Vi-TT)

PLoS Neglected Tropical Diseases News - 23 March 2020 - 9:00pm

by Eun Young Lee, Ju Yeon Park, Deok-Ryun Kim, Manki Song, Sushant Sahastrabuddhe, Hun Kim, Yun Chon, Jae Seung Yang

Salmonella enterica serovar Typhi (S. Typhi) is a causative agent for typhoid fever and especially critical in developing countries. Although clinical studies for various typhoid conjugate vaccines (TCVs) have been performed, there are no comparative data on the immune responses of vaccines due to lack of harmonization of the serological assay. Recently, Typbar-TCV (Vi-TT) was prequalified by WHO and recommended for vaccination in endemic areas. Forty-eight serum samples were selected from a recent Vi-DT phase 1 study based on age cohort and anti-Vi IgG levels using an in-house ELISA. Anti-Vi IgG titers of 48 sera were also determined by Vacczyme ELISA, used in a Vi-TT phase 3 trial. A good correlation between the two assays was observed when the anti-Vi IgG titer was determined using Vacczyme ELISA based on the Vi-IgGR1,2011, U.S. reference reagent (Pearson correlation coefficient (r) = 0.991, P < 0.001) or Vacczyme ELISA calibrator (r = 0.991, P < 0.001). Based on the correlation, multiple linear regression model was developed to convert data of 281 sera (prior to vaccination and 28 days post first-dose) in the Vi-DT phase 1 study from in-house ELISA titers to Vacczyme ELISA values and then, compared with the Vi-TT results. Similar estimates of anti-Vi IgG GMT were observed after vaccination with the Vi-DT and Vi-TT vaccines [1626 EU/ml (95% CI: 1292–2047) vs 1293 EU/ml (95% CI: 1153–1449), respectively]. The method used here can be implemented to estimate and compare anti-Vi IgG levels between different clinical studies of TCVs. This approach enables comparison of the antibody responses among TCVs under development and may help facilitate licensing of new TCVs.

NS4/5 mutations enhance flavivirus Bamaga virus infectivity and pathogenicity <i>in vitro</i> and <i>in vivo</i>

PLoS Neglected Tropical Diseases News - 23 March 2020 - 9:00pm

by Agathe M. G. Colmant, Helle Bielefeldt-Ohmann, Laura J. Vet, Caitlin A. O’Brien, Richard A. Bowen, Airn E. Hartwig, Steven Davis, Thisun B. H. Piyasena, Gervais Habarugira, Jessica J. Harrison, Jody Hobson-Peters, Roy A. Hall

Flaviviruses such as yellow fever, dengue or Zika viruses are responsible for significant human and veterinary diseases worldwide. These viruses contain an RNA genome, prone to mutations, which enhances their potential to emerge as pathogens. Bamaga virus (BgV) is a mosquito-borne flavivirus in the yellow fever virus group that we have previously shown to be host-restricted in vertebrates and horizontally transmissible by Culex mosquitoes. Here, we aimed to characterise BgV host-restriction and to investigate the mechanisms involved. We showed that BgV could not replicate in a wide range of vertebrate cell lines and animal species. We determined that the mechanisms involved in BgV host-restriction were independent of the type-1 interferon response and RNAse L activity. Using a BgV infectious clone and two chimeric viruses generated as hybrids between BgV and West Nile virus, we demonstrated that BgV host-restriction occurred post-cell entry. Notably, BgV host-restriction was shown to be temperature-dependent, as BgV replicated in all vertebrate cell lines at 34°C but only in a subset at 37°C. Serial passaging of BgV in Vero cells resulted in adaptive mutants capable of efficient replication at 37°C. The identified mutations resulted in amino acid substitutions in NS4A-S124F, NS4B-N244K and NS5-G2C, all occurring close to a viral protease cleavage site (NS4A/2K and NS4B/NS5). These mutations were reverse engineered into infectious clones of BgV, which revealed that NS4B-N244K and NS5-G2C were sufficient to restore BgV replication in vertebrate cells at 37°C, while NS4A-S124F further increased replication efficiency. When these mutant viruses were injected into immunocompetent mice, alongside BgV and West Nile virus chimeras, infection and neurovirulence were enhanced as determined by clinical scores, seroconversion, micro-neutralisation, viremia, histopathology and immunohistochemistry, confirming the involvement of these residues in the attenuation of BgV. Our studies identify a new mechanism of host-restriction and attenuation of a mosquito-borne flavivirus.

Different populations of <i>Aedes aegypti</i> and <i>Aedes albopictus</i> (Diptera: Culicidae) from Central Africa are susceptible to Zika virus infection

PLoS Neglected Tropical Diseases News - 23 March 2020 - 9:00pm

by Basile Kamgang, Marie Vazeille, Armel Tedjou, Aurélie P. Yougang, Theodel A. Wilson-Bahun, Laurence Mousson, Charles S. Wondji, Anna-Bella Failloux

Zika virus (ZIKV) is a Flavivirus (Flaviviridae) transmitted to humans mainly by the bite of an infected Aedes mosquitoes. Aedes aegypti is the primary epidemic vector of ZIKV and Ae. albopictus, the secondary one. However, the epidemiological role of both Aedes species in Central Africa where Ae. albopictus was recently introduced is poorly characterized. Field-collected strains of Ae. aegypti and Ae. albopictus from different ecological settings in Central Africa were experimentally infected with a ZIKV strain isolated in West Africa. Mosquitoes were analysed at 14- and 21-days post-exposure. Both Ae. aegypti and Ae. albopictus were able to transmit ZIKV but with higher overall transmission efficiency for Ae. aegypti (57.9%) compared to Ae. albopictus (41.5%). In addition, disseminated infection and transmission rates for both Ae. aegypti and Ae. albopictus varied significantly according to the location where they were sampled from. We conclude that both Ae. aegypti and Ae. albopictus are able to transmit ZIKV and may intervene as active Zika vectors in Central Africa. These findings could contribute to a better understanding of the epidemiological transmission of ZIKV in Central Africa and develop suitable strategy to prevent major ZIKV outbreaks in this region.

Schistosoma species detection by environmental DNA assays in African freshwaters

PLoS Neglected Tropical Diseases News - 23 March 2020 - 9:00pm

by Hind Alzaylaee, Rupert A. Collins, Gabriel Rinaldi, Asilatu Shechonge, Benjamin Ngatunga, Eric R. Morgan, Martin J. Genner

Background

Schistosomiasis is a neglected tropical parasitic disease associated with severe pathology, mortality and economic loss worldwide. Programs for disease control may benefit from specific and sensitive diagnostic methods to detect Schistosoma trematodes in aquatic environments. Here we report the development of novel environmental DNA (eDNA) qPCR assays for the presence of the human-infecting species Schistosoma mansoni, S. haematobium and S. japonicum.

Methodology/Principal findings

We first tested the specificity of the assays across the three species using genomic DNA preparations which showed successful amplification of target sequences with no cross amplification between the three focal species. In addition, we evaluated the specificity of the assays using synthetic DNA of multiple Schistosoma species, and demonstrated a high overall specificity; however, S. japonicum and S. haematobium assays showed cross-species amplification with very closely-related species. We next tested the effectiveness of the S. mansoni assay using eDNA samples from aquaria containing infected host gastropods, with the target species revealed as present in all infected aquaria. Finally, we evaluated the effectiveness of the S. mansoni and S. haematobium assays using eDNA samples from eight discrete natural freshwater sites in Tanzania, and demonstrated strong correspondence between infection status established using eDNA and conventional assays of parasite prevalence in host snails.

Conclusions/Significance

Collectively, our results suggest that eDNA monitoring is able to detect schistosomes in freshwater bodies, but refinement of the field sampling, storage and assay methods are likely to optimise its performance. We anticipate that environmental DNA-based approaches will help to inform epidemiological studies and contribute to efforts to control and eliminate schistosomiasis in endemic areas.

Prevalence of <i>Mycobacterium leprae</i> in armadillos in Brazil: A systematic review and meta-analysis

PLoS Neglected Tropical Diseases News - 23 March 2020 - 9:00pm

by Patrícia D. Deps, João Marcelo Antunes, Adalberto Rezende Santos, Simon M. Collin

Understanding the prevalence of M. leprae infection in armadillos is important because of evidence from Brazil and other countries of an association between contact with armadillos and the development of Hansen’s Disease (leprosy). Our aim was to characterize studies which have investigated natural M. leprae infection in wild armadillos in Brazil, and to quantify and explore variability in the reported prevalence of infection. We conducted a systematic review (PROSPERO CRD42019155277) of publications in MEDLINE, EMBASE, Global Health, Scopus, LILACS, Biblioteca Digital Brasileira de Teses e Dissertações, Catálogo de Teses e Dissertações de CAPES, and Biblioteca Virtual em Saúde up to 10/2019 using Mesh and text search terms (in English, Portuguese, Spanish, and French). The 10 included studies represented a total sample of 302 armadillos comprising 207 (69%) Dasypus novemcinctus, 67 (22%) Euphractus sexcinctus, 16 (5%) Priodontes maximus, 10 (3%) Cabassous unicinctus, and 2 (1%) Cabassous tatouay from 7 different states. Methods used included histopathology (4 studies), PGL-1 and LID-1 antigen detection (4 studies) and examination for clinical signs of disease (4 studies). Eight studies used PCR of which 7 targeted the RLEP repetitive element and 3 tested for inhibitory substances. M. leprae prevalence by PCR ranged from 0% (in 3 studies) to 100% in one study, with a summary estimate of 9.4% (95% CI 0.4% to 73.1%) and a predictive interval of 0–100%. The average prevalence is equivalent to 1 in 10 armadillos in Brazil being infected with M. leprae, but wide variation in sample estimates means that the prevalence in any similar study would be entirely unpredictable. We propose instead that future studies aim to investigate transmission and persistence of M. leprae within and between armadillo populations, meanwhile adopting the precautionary principle to protect human health and an endangered species in Brazil.

Deep phosphoproteome analysis of <i>Schistosoma mansoni</i> leads development of a kinomic array that highlights sex-biased differences in adult worm protein phosphorylation

PLoS Neglected Tropical Diseases News - 23 March 2020 - 9:00pm

by Natasha L. Hirst, Jean-Christophe Nebel, Scott P. Lawton, Anthony J. Walker

Although helminth parasites cause enormous suffering worldwide we know little of how protein phosphorylation, one of the most important post-translational modifications used for molecular signalling, regulates their homeostasis and function. This is particularly the case for schistosomes. Herein, we report a deep phosphoproteome exploration of adult Schistosoma mansoni, providing one of the richest phosphoprotein resources for any parasite so far, and employ the data to build the first parasite-specific kinomic array. Complementary phosphopeptide enrichment strategies were used to detect 15,844 unique phosphopeptides mapping to 3,176 proteins. The phosphoproteins were predicted to be involved in a wide range of biological processes and phosphoprotein interactome analysis revealed 55 highly interconnected clusters including those enriched with ribosome, proteasome, phagosome, spliceosome, glycolysis, and signalling proteins. 93 distinct phosphorylation motifs were identified, with 67 providing a ‘footprint’ of protein kinase activity; CaMKII, PKA and CK1/2 were highly represented supporting their central importance to schistosome function. Within the kinome, 808 phosphorylation sites were matched to 136 protein kinases, and 68 sites within 37 activation loops were discovered. Analysis of putative protein kinase-phosphoprotein interactions revealed canonical networks but also novel interactions between signalling partners. Kinomic array analysis of male and female adult worm extracts revealed high phosphorylation of transformation:transcription domain associated protein by both sexes, and CDK and AMPK peptides by females. Moreover, eight peptides including protein phosphatase 2C gamma, Akt, Rho2 GTPase, SmTK4, and the insulin receptor were more highly phosphorylated by female extracts, highlighting their possible importance to female worm function. We envision that these findings, tools and methodology will help drive new research into the functional biology of schistosomes and other helminth parasites, and support efforts to develop new therapeutics for their control.

Quantifying geographic accessibility to improve efficiency of entomological monitoring

PLoS Neglected Tropical Diseases News - 23 March 2020 - 9:00pm

by Joshua Longbottom, Ana Krause, Stephen J. Torr, Michelle C. Stanton

Background

Vector-borne diseases are important causes of mortality and morbidity in humans and livestock, particularly for poorer communities and countries in the tropics. Large-scale programs against these diseases, for example malaria, dengue and African trypanosomiasis, include vector control, and assessing the impact of this intervention requires frequent and extensive monitoring of disease vector abundance. Such monitoring can be expensive, especially in the later stages of a successful program where numbers of vectors and cases are low.

Methodology/Principal findings

We developed a system that allows the identification of monitoring sites where pre-intervention densities of vectors are predicted to be high, and travel cost to sites is low, highlighting the most efficient locations for longitudinal monitoring. Using remotely sensed imagery and an image classification algorithm, we mapped landscape resistance associated with on- and off-road travel for every gridded location (3m and 0.5m grid cells) within Koboko district, Uganda. We combine the accessibility surface with pre-existing estimates of tsetse abundance and propose a stratified sampling approach to determine the most efficient locations for longitudinal data collection. Our modelled predictions were validated against empirical measurements of travel-time and existing maps of road networks. We applied this approach in northern Uganda where a large-scale vector control program is being implemented to control human African trypanosomiasis, a neglected tropical disease (NTD) caused by trypanosomes transmitted by tsetse flies. Our accessibility surfaces indicate a high performance when compared to empirical data, with remote sensing identifying a further ~70% of roads than existing networks.

Conclusions/Significance

By integrating such estimates with predictions of tsetse abundance, we propose a methodology to determine the optimal placement of sentinel monitoring sites for evaluating control programme efficacy, moving from a nuanced, ad-hoc approach incorporating intuition, knowledge of vector ecology and local knowledge of geographic accessibility, to a reproducible, quantifiable one.

Comparison of clinical presentation and out-comes of Chikungunya and Dengue virus infections in patients with acute undifferentiated febrile illness from the Sindh region of Pakistan

PLoS Neglected Tropical Diseases News - 23 March 2020 - 9:00pm

by Uzma Shahid, Joveria Q. Farooqi, Kelli L. Barr, S. Faisal Mahmood, Bushra Jamil, Kehkashan Imitaz, Zahida Azizullah, Faisal R. Malik, Dhani Prakoso, Maureen T. Long, Erum Khan

Background

Arboviruses are a cause of acute febrile illness and outbreaks worldwide. Recent outbreaks of Chikungunya virus (CHIKV) in dengue endemic areas have alarmed clinicians as unique clinical features differentiating CHIKV from Dengue virus (DENV) are limited. This has complicated diagnostic efforts especially in resource limited countries where lab testing is not easily available. Therefore, it is essential to analyse and compare clinical features of laboratory confirmed cases to assist clinicians in suspecting possible CHIKV infection at time of clinical presentation.

Methodology

A prospective point prevalence study was conducted, with the hypothesis that not all patients presenting with clinical suspicion of dengue infections at local hospitals are suffering from dengue and that other arboviruses such as Chikungunya, West Nile viruses, Japanese Encephalitis virus and Zika virus are co-circulating in the Sindh region of Pakistan. Out-patients and hospitalized (in-patients) of selected district hospitals in different parts of Sindh province of Pakistan were recruited. Patients with presumptive dengue like illness (Syndromic diagnosis) by the treating physicians were enrolled between 2015 and 2017.Current study is a subset of larger study mentioned above. Here-in we compared laboratory confirmed cases of CHIKV and DENV to assess clinical features and laboratory findings that may help differentiate CHIKV from DENV infection at the time of clinical presentation.

Results

Ninety-eight (n = 98) cases tested positive for CHIKV, by IgM and PCR and these were selected for comparative analysis with DENV confirmed cases (n = 171). On multivariable analysis, presence of musculoskeletal [OR = 2.5 (95% CI:1.6–4.0)] and neurological symptoms [OR = 4.4 (95% CI:1.9–10.2)], and thrombocytosis [OR = 2.2 (95% CI:1.1–4.0)] were associated with CHIKV infection, while atypical lymphocytes [OR = 8.3 (95% CI:4.2–16.7)] and thrombocytopenia [OR = 8.1 (95% CI:1.7–38.8)] were associated with DENV cases at time of presentation. These findings may help clinicians in differentiating CHIKV from DENV infection.

Conclusion

CHIKV is an important cause of illness amongst patients presenting with acute febrile illness in Sindh region of Pakistan. Arthralgia and encephalitis at time of presentation among patients with dengue-like illness should prompt suspicion of CHIKV infection, and laboratory confirmation must be sought.

Advanced case of PKDL due to delayed treatment: A rare case report

PLoS Neglected Tropical Diseases News - 23 March 2020 - 9:00pm

by Roshan Kamal Topno, Vidya Nand Rabi Das, Maneesh Kumar, Major Madhukar, Krishna Pandey, Neena Verma, Kanhaiya Agrawal, Chandra Shekhar Lal, Niyamat Ali Siddiqui, Sanjiva Bimal, Pradeep Das

Post-kala-azar dermal leishmaniasis (PKDL) is clinical outcome of visceral leishmaniasis (VL) and is thought to be the potential reservoir of parasite. Miltefosine (MF) is the only oral drug existing for treatment of post-kala-azar dermal leishmaniasis (PKDL). Increased miltefosine tolerance in clinical isolates of Leishmania donovani has been reported and is one of the major concerns in the treatment of PKDL. Here, we report a highly ulcerated PKDL case that was successfully cured after miltefosine treatment.

Inhibition of Invasive Salmonella by Orally Administered IgA and IgG Monoclonal Antibodies

PLoS Neglected Tropical Diseases News - 23 March 2020 - 9:00pm

by Angelene F. Richards, Jennifer E. Doering, Shannon A. Lozito, John J. Varrone, Graham G. Willsey, Michael Pauly, Kevin Whaley, Larry Zeitlin, Nicholas J. Mantis

Non-typhoidal Salmonella enterica strains, including serovar Typhimurium (STm), are an emerging cause of invasive disease among children and the immunocompromised, especially in regions of sub-Saharan Africa. STm invades the intestinal mucosa through Peyer’s patch tissues before disseminating systemically. While vaccine development efforts are ongoing, the emergence of multidrug resistant strains of STm affirms the need to seek alternative strategies to protect high-risk individuals from infection. In this report, we investigated the potential of an orally administered O5 serotype-specific IgA monoclonal antibody (mAb), called Sal4, to prevent infection of invasive Salmonella enterica serovar Typhimurium (STm) in mice. Sal4 IgA was delivered to mice prior to or concurrently with STm challenge. Infectivity was measured as bacterial burden in Peyer’s patch tissues one day after challenge. Using this model, we defined the minimal amount of Sal4 IgA required to significantly reduce STm uptake into Peyer’s patches. The relative efficacy of Sal4 in dimeric and secretory IgA (SIgA) forms was compared. To assess the role of isotype in oral passive immunization, we engineered a recombinant IgG1 mAb carrying the Sal4 variable regions and evaluated its ability to block invasion of STm into epithelial cells in vitro and Peyer’s patch tissues. Our results demonstrate the potential of orally administered monoclonal IgA and SIgA, but not IgG, to passively immunize against invasive Salmonella. Nonetheless, the prophylactic window of IgA/SIgA in the mouse was on the order of minutes, underscoring the need to develop formulations to protect mAbs in the gastric environment and to permit sustained release in the small intestine.

Efficacy of single versus four repeated doses of praziquantel against <i>Schistosoma mansoni</i> infection in school-aged children from Côte d'Ivoire based on Kato-Katz and POC-CCA: An open-label, randomised controlled trial (RePST)

PLoS Neglected Tropical Diseases News - 20 March 2020 - 9:00pm

by Pytsje T. Hoekstra, Miriam Casacuberta-Partal, Lisette van Lieshout, Paul L. A. M. Corstjens, Roula Tsonaka, Rufin K. Assaré, Kigbafori D. Silué, Aboulaye Meité, Eliézer K. N’Goran, Yves K. N’Gbesso, Abena S. Amoah, Meta Roestenberg, Stefanie Knopp, Jürg Utzinger, Jean T. Coulibaly, Govert J. van Dam

Background

Preventive chemotherapy with praziquantel (PZQ) is the cornerstone of schistosomiasis control. However, a single dose of PZQ (40 mg/kg) does not cure all infections. Repeated doses of PZQ at short intervals might increase efficacy in terms of cure rate (CR) and intensity reduction rate (IRR). Here, we determined the efficacy of a single versus four repeated treatments with PZQ on Schistosoma mansoni infection in school-aged children from Côte d’Ivoire, using two different diagnostic tests.

Methods

An open-label, randomized controlled trial was conducted from October 2018 to January 2019. School-aged children with a confirmed S. mansoni infection based on Kato-Katz (KK) and point-of-care circulating cathodic antigen (POC-CCA) urine cassette test were randomly assigned to receive either a single or four repeated doses of PZQ, administered at two-week intervals. The primary outcome was the difference in CR between the two treatment arms, measured by triplicate KK thick smears 10 weeks after the first treatment. Secondary outcomes included CR estimated by POC-CCA, IRR by KK and POC-CCA, and safety of repeated PZQ administration.

Principal findings

During baseline screening, 1,022 children were assessed for eligibility of whom 153 (15%) had a detectable S. mansoni infection, and hence, were randomized to the standard treatment group (N = 70) and the intense treatment group (N = 83). Based on KK, the CR was 42% (95% confidence interval (CI) 31–52%) in the standard treatment group and 86% (95% CI 75–92%) in the intense treatment group. Observed IRR was 72% (95% CI 55–83%) in the standard treatment group and 95% (95% CI 85–98%) in the intense treatment group. The CR estimated by POC-CCA was 18% (95% CI 11–27%) and 36% (95% CI 26–46%) in the standard and intense treatment group, respectively. Repeated PZQ treatment did not result in a higher number of adverse events.

Conclusion/significance

The observed CR using KK was significantly higher after four repeated treatments compared to a single treatment, without an increase in adverse events. Using POC-CCA, the observed CR was significantly lower than measured by KK, indicating that PZQ may be considerably less efficacious as concluded by KK. Our findings highlight the need for reliable and more accurate diagnostic tools, which are essential for monitoring treatment efficacy, identifying changes in transmission, and accurately quantifying the intensity of infection in distinct populations. In addition, the higher CR in the intense treatment group suggests that more focused and intense PZQ treatment can help to advance schistosomiasis control.

Trial registration

www.clinicaltrials.gov NCT02868385.

Identification of anisomycin, prodigiosin and obatoclax as compounds with broad-spectrum anti-parasitic activity

PLoS Neglected Tropical Diseases News - 20 March 2020 - 9:00pm

by Gretchen Ehrenkaufer, Pengyang Li, Erin E. Stebbins, Monica M. Kangussu-Marcolino, Anjan Debnath, Corin V. White, Matthew S. Moser, Joseph DeRisi, Jolyn Gisselberg, Ellen Yeh, Steven C. Wang, Ana Hervella Company, Ludovica Monti, Conor R. Caffrey, Christopher D. Huston, Bo Wang, Upinder Singh

Parasitic infections are a major source of human suffering, mortality, and economic loss, but drug development for these diseases has been stymied by the significant expense involved in bringing a drug though clinical trials and to market. Identification of single compounds active against multiple parasitic pathogens could improve the economic incentives for drug development as well as simplifying treatment regimens. We recently performed a screen of repurposed compounds against the protozoan parasite Entamoeba histolytica, causative agent of amebic dysentery, and identified four compounds (anisomycin, prodigiosin, obatoclax and nithiamide) with low micromolar potency and drug-like properties. Here, we extend our investigation of these drugs. We assayed the speed of killing of E. histolytica trophozoites and found that all four have more rapid action than the current drug of choice, metronidazole. We further established a multi-institute collaboration to determine whether these compounds may have efficacy against other parasites and opportunistic pathogens. We found that anisomycin, prodigiosin and obatoclax all have broad-spectrum antiparasitic activity in vitro, including activity against schistosomes, T. brucei, and apicomplexan parasites. In several cases, the drugs were found to have significant improvements over existing drugs. For instance, both obatoclax and prodigiosin were more efficacious at inhibiting the juvenile form of Schistosoma than the current standard of care, praziquantel. Additionally, low micromolar potencies were observed against pathogenic free-living amebae (Naegleria fowleri, Balamuthia mandrillaris and Acanthamoeba castellanii), which cause CNS infection and for which there are currently no reliable treatments. These results, combined with the previous human use of three of these drugs (obatoclax, anisomycin and nithiamide), support the idea that these compounds could serve as the basis for the development of broad-spectrum anti-parasitic drugs.

IL-6 produced by prostate epithelial cells stimulated with <i>Trichomonas vaginalis</i> promotes proliferation of prostate cancer cells by inducing M2 polarization of THP-1-derived macrophages

PLoS Neglected Tropical Diseases News - 20 March 2020 - 9:00pm

by Ik-Hwan Han, Hyun-Ouk Song, Jae-Sook Ryu

Trichomonas vaginalis (Tv), a protozoan parasite causing sexually-transmitted disease, has been detected in tissue of prostatitis, benign prostatic hyperplasia (BPH) and prostate cancer (PCa). IL-6, a mediator of chronic inflammation, induces the progression of prostate cancer, and influences the polarization of M2 macrophages, which are the main tumor-associated macrophages. We investigated whether IL-6 produced by human prostate epithelial cells stimulated with Tv induces the M2 polarization of THP-1-derived macrophages, which in turn promotes the progression of PCa. Conditioned medium was prepared from Tv-infected (TCM) and uninfected (CM) prostate epithelial cells (RWPE-1). Thereafter conditioned medium was prepared from macrophages after incubation with CM (M-CM) or TCM (M-TCM). RWPE-1 cells infected with Tv produced IL-6 and chemokines such as CCL2 and CXCL8. When human macrophages were treated with conditioned medium of RWPE-1 cells co-cultured with Tv (TCM), they became polarized to M2-like macrophages as indicated by the production of IL-10 and TGF-β, and the expression of CD36 and arginase-1, which are M2 macrophage markers. Moreover, proliferation of the M2-like macrophages was also increased by TCM. Blockade of IL-6 signaling with IL-6 receptor antibody and JAK inhibitor (Ruxolitinib) inhibited M2 polarization of THP-1-derived macrophages and proliferation of the macrophages. To assess the effect of crosstalk between macrophages and prostate epithelial cells inflamed by Tv infection on the growth of prostate cancer (PCa) cells, PC3, DU145 and LNCaP cells were treated with conditioned medium from THP-1-derived macrophages stimulated with TCM (M-TCM). Proliferation and migration of the PCa cells were significantly increased by the M-TCM. Our findings suggest that IL-6 produced in response to Tv infection of the prostate has an important effect on the tumor microenvironment by promoting progression of PCa cells following induction of M2 macrophage polarization.

Using a Bayesian spatiotemporal model to identify the influencing factors and high-risk areas of hand, foot and mouth disease (HFMD) in Shenzhen

PLoS Neglected Tropical Diseases News - 20 March 2020 - 9:00pm

by Xiaoyi He, Shengjie Dong, Liping Li, Xiaojian Liu, Yongsheng Wu, Zhen Zhang, Shujiang Mei

Background

The epidemic of hand, foot, and mouth disease (HFMD) has become a severe public health problem in the world and has also brought a high economic and health burden. Furthermore, the prevalence of HFMD varies significantly among different locations. However, there have been few investigations of the effects of socioeconomic factors and air pollution factors on the incidence of HFMD.

Methods

This study collected data on HFMD in Shenzhen, China, from 2012 to 2015. We selected eleven factors as potential risk factors for HFMD. A Bayesian spatiotemporal model was used to quantify the influence of the factors on HFMD and to identify the relative risks in different districts.

Results

The risk factors of HFMD were the population, population density, concentration of SO2, and concentration of NO2. The relative risks (RRs) were 1.00473 (95% CI: 1.00059–1.00761), 1.00010 (95% CI: 1.00002–1.00016), 1.00215 (95% CI: 1.00170–1.00232) and 1.00058 (95% CI: 1.00028–1.00078), respectively. The protective factors against HFMD were the per capita GDP, the number of public kindergartens, the concentration of PM10, and the concentration of O3. The RRs were 0.98840 (95% CI: 0.98660–0.99026), 0.97686 (95% CI: 0.96946–0.98403), 0.99108 (95% CI: 0.98551–0.99840) and 0.99587 (95% CI: 0.99534–0.99610), respectively. The risk of incidence in Longgang district and Pingshan district decreased, while the risk of incidence in Baoan district increased.

Conclusions

Studies have confirmed that socioeconomic factors and air pollution factors have an impact on the incidence of HFMD in Shenzhen, China. The results will be of great practical significance to local authorities, which is conducive to accurate prevention and can be used to formulate HFMD early warning systems.

Intracellular DNA replication and differentiation of <i>Trypanosoma cruzi</i> is asynchronous within individual host cells <i>in vivo</i> at all stages of infection

PLoS Neglected Tropical Diseases News - 20 March 2020 - 9:00pm

by Martin C. Taylor, Alexander Ward, Francisco Olmo, Shiromani Jayawardhana, Amanda F. Francisco, Michael D. Lewis, John M. Kelly

Investigations into intracellular replication and differentiation of Trypanosoma cruzi within the mammalian host have been restricted by limitations in our ability to detect parasitized cells throughout the course of infection. We have overcome this problem by generating genetically modified parasites that express a bioluminescent/fluorescent fusion protein. By combining in vivo imaging and confocal microscopy, this has enabled us to routinely visualise murine infections at the level of individual host cells. These studies reveal that intracellular parasite replication is an asynchronous process, irrespective of tissue location or disease stage. Furthermore, using TUNEL assays and EdU labelling, we demonstrate that within individual infected cells, replication of both mitochondrial (kDNA) and nuclear genomes is not co-ordinated within the parasite population, and that replicating amastigotes and non-replicating trypomastigotes can co-exist in the same cell. Finally, we report the presence of distinct non-canonical morphological forms of T. cruzi in the mammalian host. These appear to represent transitional forms in the amastigote to trypomastigote differentiation process. Therefore, the intracellular life-cycle of T. cruzi in vivo is more complex than previously realised, with potential implications for our understanding of disease pathogenesis, immune evasion and drug development. Dissecting the mechanisms involved will be an important experimental challenge.

Feeding behavior and activity of <i>Phlebotomus pedifer</i> and potential reservoir hosts of <i>Leishmania aethiopica</i> in southwestern Ethiopia

PLoS Neglected Tropical Diseases News - 20 March 2020 - 9:00pm

by Myrthe Pareyn, Abena Kochora, Luca Van Rooy, Nigatu Eligo, Bram Vanden Broecke, Nigatu Girma, Behailu Merdekios, Teklu Wegayehu, Louis Maes, Guy Caljon, Bernt Lindtjørn, Herwig Leirs, Fekadu Massebo

Background

Cutaneous leishmaniasis (CL) is a major public health concern in Ethiopia. However, knowledge about the complex zoonotic transmission cycle is limited, hampering implementation of control strategies. We explored the feeding behavior and activity of the vector (Phlebotomus pedifer) and studied the role of livestock in CL transmission in southwestern Ethiopia.

Methods

Blood meal origins of engorged sand flies were determined by sequencing host DNA. A host choice experiment was performed to assess the feeding preference of P. pedifer when humans and hyraxes are equally accessible. Ear and nose biopsies from livestock were screened for the presence of Leishmania parasites. Sand flies were captured indoor and outdoor with human landing catches and CDC light traps to determine at which time and where P. pedifer is mostly active.

Principal findings

A total of 180 P. pedifer sand flies were found to bite hosts of 12 genera. Humans were the predominant blood meal source indoors (65.9%, p < 0.001), while no significant differences were determined outdoors and in caves. In caves, hyraxes were represented in blood meals equally as humans (45.5% and 42.4%, respectively), but the host choice experiment revealed that sand flies have a significant preference for feeding on hyraxes (p = 0.009). Only a single goat nose biopsy from 412 animal samples was found with Leishmania RNA. We found that P. pedifer is predominantly endophagic (p = 0.003), but occurs both indoors and outdoors. A substantial number of sand flies was active in the early evening, which increased over time reaching its maximum around midnight.

Conclusion

In contrast to earlier suggestions of exclusive zoonotic Leishmania transmission, we propose that there is also human-to-human transmission of CL in southwestern Ethiopia. Livestock does not play a role in CL transmission and combined indoor and outdoor vector control measures at night are required for efficient vector control.

Vaccination with single plasmid DNA encoding IL-12 and antigens of severe fever with thrombocytopenia syndrome virus elicits complete protection in IFNAR knockout mice

PLoS Neglected Tropical Diseases News - 20 March 2020 - 9:00pm

by Jun-Gu Kang, Kyeongseok Jeon, Hooncheol Choi, Yuri Kim, Hong-Il Kim, Hyo-Jin Ro, Yong Bok Seo, Jua Shin, Junho Chung, Yoon Kyung Jeon, Yang Soo Kim, Keun Hwa Lee, Nam-Hyuk Cho

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease caused by SFTS virus (SFTSV) infection. Despite a gradual increase of SFTS cases and high mortality in endemic regions, no specific viral therapy nor vaccine is available. Here, we developed a single recombinant plasmid DNA encoding SFTSV genes, Gn and Gc together with NP-NS fusion antigen, as a vaccine candidate. The viral antigens were fused with Fms-like tyrosine kinase-3 ligand (Flt3L) and IL-12 gene was incorporated into the plasmid to enhance cell-mediated immunity. Vaccination with the DNA provides complete protection of IFNAR KO mice upon lethal SFTSV challenge, whereas immunization with a plasmid without IL-12 gene resulted in partial protection. Since we failed to detect antibodies against surface glycoproteins, Gn and Gc, in the immunized mice, antigen-specific cellular immunity, as confirmed by enhanced antigen-specific T cell responses, might play major role in protection. Finally, we evaluated the degree of protective immunity provided by protein immunization of the individual glycoprotein, Gn or Gc. Although both protein antigens induced a significant level of neutralizing activity against SFTSV, Gn vaccination resulted in relatively higher neutralizing activity and better protection than Gc vaccination. However, both antigens failed to provide complete protection. Given that DNA vaccines have failed to induce sufficient immunogenicity in human trials when compared to protein vaccines, optimal combinations of DNA and protein elements, proper selection of target antigens, and incorporation of efficient adjuvant, need to be further investigated for SFTSV vaccine development.

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