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Identification of anti-flaviviral drugs with mosquitocidal and anti-Zika virus activity in <i>Aedes aegypti</i>

PLoS Neglected Tropical Diseases News - 20 August 2019 - 9:00pm

by Shengzhang Dong, Seokyoung Kang, George Dimopoulos

Zika virus (ZIKV), an emerging arbovirus belonging to the genus Flavivirus, is transmitted by Aedes mosquitoes. ZIKV infection can cause microcephaly of newborn babies and Guillain–Barré syndrome in adults. Because no licensed vaccine or specific antiviral treatment is available for ZIKV infection, the most commonly used approach to control the spread of ZIKV is suppression of the mosquito vector population. A novel proposed strategy to block arthropod virus (arbovirus) transmission is based on the chemical inhibition of virus infection in mosquitoes. However, only a few drugs and compounds have been tested with such properties. Here we present a comprehensive screen of 55 FDA-approved anti-flaviviral drugs for potential anti-ZIKV and mosquitocidal activity. Four drugs (auranofin, actinomycin D (Act-D), bortezomib and gemcitabine) were toxic to C6/36 cells, and two drugs (5-fluorouracil and mycophenolic acid (MPA)) significantly reduced ZIKV production in C6/36 cells at 2 μM and 0.5 μM, respectively. Three drugs (Act-D, cyclosporin A, ivermectin) exhibited a strong adulticidal activity, and six drugs (U18666A, retinoic acid p-hydroxyanilide (4-HPR), clotrimazole, bortezomib, MPA, imatinib mesylate) significantly suppressed ZIKV infection in mosquito midguts. Some of these FDA-approved drugs may have potential for use for the development of ZIKV transmission-blocking strategies.

Development of a multiple-antigen protein fusion vaccine candidate that confers protection against <i>Bacillus anthracis</i> and <i>Yersinia pestis</i>

PLoS Neglected Tropical Diseases News - 20 August 2019 - 9:00pm

by Theresa B. Gallagher, Gabriela Mellado-Sanchez, Ana L. Jorgensen, Stephen Moore, James P. Nataro, Marcela F. Pasetti, Les W. Baillie

Bacillus anthracis and Yersinia pestis are zoonotic bacteria capable of causing severe and sometimes fatal infections in animals and humans. Although considered as diseases of antiquity in industrialized countries due to animal and public health improvements, they remain endemic in vast regions of the world disproportionally affecting the poor. These pathogens also remain a serious threat if deployed in biological warfare. A single vaccine capable of stimulating rapid protection against both pathogens would be an extremely advantageous public health tool. We produced multiple-antigen fusion proteins (MaF1 and MaF2) containing protective regions from B. anthracis protective antigen (PA) and lethal factor (LF), and from Y. pestis V antigen (LcrV) and fraction 1 (F1) capsule. The MaF2 sequence was also expressed from a plasmid construct (pDNA-MaF2). Immunogenicity and protective efficacy were investigated in mice following homologous and heterologous prime-boost immunization. Antibody responses were determined by ELISA and anthrax toxin neutralization assay. Vaccine efficacy was determined against lethal challenge with either anthrax toxin or Y. pestis. Both constructs elicited LcrV and LF-specific serum IgG, and MaF2 elicited toxin-neutralizing antibodies. Immunizations with MaF2 conferred 100% and 88% protection against Y. pestis and anthrax toxin, respectively. In contrast, pDNA-MaF2 conferred only 63% protection against Y. pestis and no protection against anthrax toxin challenge. pDNA-MaF2-prime MaF2-boost induced 75% protection against Y. pestis and 25% protection against anthrax toxin. Protection was increased by the molecular adjuvant CARDif. In conclusion, MaF2 is a promising multi-antigen vaccine candidate against anthrax and plague that warrants further investigation.

Detection of classic and cryptic <i>Strongyloides</i> genotypesby deep amplicon sequencing: A preliminary survey of dog and human specimens collected from remote Australian communities

PLoS Neglected Tropical Diseases News - 20 August 2019 - 9:00pm

by Meruyert Beknazarova, Joel L. N. Barratt, Richard S. Bradbury, Meredith Lane, Harriet Whiley, Kirstin Ross

Strongyloidiasis is caused by the human infective nematodes Strongyloides stercoralis, Strongyloides fuelleborni subsp. fuelleborni and Strongyloides fuelleborni subsp. kellyi. The zoonotic potential of S. stercoralis and the potential role of dogs in the maintenance of strongyloidiasis transmission has been a topic of interest and discussion for many years. In Australia, strongyloidiasis is prevalent in remote socioeconomically disadvantaged communities in the north of the continent. Being an isolated continent that has been separated from other regions for a long geological period, description of diversity of Australian Strongyloides genotypes adds to our understanding of the genetic diversity within the genus. Using PCR and amplicon sequencing (Illumina sequencing technology), we sequenced the Strongyloides SSU rDNA hyper-variable I and hyper-variable IV regions using Strongyloides-specific primers, and a fragment of the mtDNA cox1 gene using primers that are broadly specific for Strongyloides sp. and hookworms. These loci were amplified from DNA extracted from Australian human and dog faeces, and one human sputum sample. Using this approach, we confirm for the first time that potentially zoonotic S. stercoralis populations are present in Australia, suggesting that dogs represent a potential reservoir of human strongyloidiasis in remote Australian communities.

Assessment of the new World Health Organization's dengue classification for predicting severity of illness and level of healthcare required

PLoS Neglected Tropical Diseases News - 20 August 2019 - 9:00pm

by Balgees A. Ajlan, Maram M. Alafif, Maha M. Alawi, Naeema A. Akbar, Eman K. Aldigs, Tariq A. Madani

The objective of this study was to assess the validity of the new dengue classification proposed by the World Health Organization (WHO) in 2009 and to develop pragmatic guidelines for case triage and management. This retrospective study involved 357 laboratory-confirmed cases of dengue infection diagnosed at King Abdulaziz University Hospital, Jeddah, Saudi Arabia over a 4-year period from 2014 to 2017. The sensitivity of the new classification for identifying severe cases was limited (65%) but higher than the old one (30%). It had a higher sensitivity for identifying patients who needed advanced healthcare compared to the old one (72% versus 32%, respectively). We propose adding decompensation of chronic diseases and thrombocytopenia-related bleeding to the category of severe dengue in the new classification. This modification improves sensitivity from 72% to 98% for identifying patients who need advanced healthcare without altering specificity (97%). It also improves sensitivity in predicting severe outcomes from 32% to 88%. In conclusion, the new classification had a low sensitivity for identifying patients needing advanced care and for predicting morbidity and mortality. We propose to include decompensation of chronic diseases and thrombocytopenia-related bleeding to the category of severe dengue in the new classification to improve the sensitivity of predicting cases requiring advanced care.

Distribution of geographical scale, data aggregation unit and period in the correlation analysis between temperature and incidence of HFRS in mainland China: A systematic review of 27 ecological studies

PLoS Neglected Tropical Diseases News - 19 August 2019 - 9:00pm

by Xing-Hua Bai, Cheng Peng, Tao Jiang, Zhu-Min Hu, De-Sheng Huang, Peng Guan

Background

Changes in climate and environmental conditions could be the driving factors for the transmission of hantavirus. Thus, a thorough collection and analysis of data related to the epidemic status of hemorrhagic fever with renal syndrome (HFRS) and the association between HFRS incidence and meteorological factors, such as air temperature, is necessary for the disease control and prevention.

Methods

Journal articles and theses in both English and Chinese from Jan 2014 to Feb 2019 were identified from PubMed, Web of Science, Chinese National Knowledge Infrastructure, Wanfang Data and VIP Info. All identified studies were subject to the six criteria established to ensure the consistency with research objectives, (i) they provided the data of the incidence of HFRS in mainland China; (ii) they provided the type of air temperature indexes; (iii) they indicated the underlying geographical scale information, temporal data aggregation unit, and the data sources; (iv) they provided the statistical analysis method that had been used; (v) from peer-reviewed journals or dissertation; (vi) the time range for the inclusion of data exceeded two consecutive calendar years.

Results

A total of 27 publications were included in the systematic review, among them, the correlation between HFRS activity and air temperature was explored in 12 provinces and autonomous regions and also at national level. The study period ranged from 3 years to 54 years with a median of 10 years, 62.3% of the studies were based on the monthly HFRS incidence data, 21 studies considered the lagged effect of air temperature factors on the HFRS activity and the longest lag period considered in the included studies was 34 weeks. The correlation between HFRS activity and air temperature varied widely, and the effect of temperature on the HFRS epidemic was seasonal.

Conclusions

The present systematic review described the heterogeneity of geographical scale, data aggregation unit and study period chosen in the ecological studies that seeking the correlation between air temperature indexes and the incidence of HFRS in mainland China during the period from January 2014 to February 2019. The appropriate adoption of geographical scale, data aggregation unit, the length of lag period and the length of incidence collection period should be considered when exploring the relationship between HFRS incidence and meteorological factors such as air temperature. Further investigation is warranted to detect the thresholds of meteorological factors for the HFRS early warning purposes, to measure the duration of lagged effects and determine the timing of maximum effects for reducing the effects of meteorological factors on HFRS via continuous interventions and to identify the vulnerable populations for target protection.

Late-onset ulnar neuritis following treatment of lepromatous leprosy infection

PLoS Neglected Tropical Diseases News - 19 August 2019 - 9:00pm

by Trevor Wellington, Christina Schofield

Neuritis is a frequent complication of Myocobacteria leprae infection and treatment due to the variety of mechanisms through which it can occur. Not only can mycobacterial invasion into peripheral nerves directly cause damage and inflammation, but immune-mediated inflammatory episodes (termed leprosy reactions) can also manifest as neuritis at any point during infection. Treatment of leprosy reactions with thalidomide can also lead to neuritis due to an adverse drug effect. Neuritis can emerge years after initial diagnosis and treatment, although it is most frequently found at time of diagnosis or early into the treatment course. Treatment of neuritis is dependent on high-dose corticosteroid therapy as well as therapy for suspected underlying etiology. Here, we present a case of ulnar neuritis presenting in a patient with lepromatous leprosy four years after treatment of initial infection, with subsequent improvement after corticosteroid burst while maintained on thalidomide therapy.

Comparative and functional genomics of the protozoan parasite <i>Babesia divergens</i> highlighting the invasion and egress processes

PLoS Neglected Tropical Diseases News - 19 August 2019 - 9:00pm

by Luis Miguel González, Karel Estrada, Ricardo Grande, Verónica Jiménez-Jacinto, Leticia Vega-Alvarado, Elena Sevilla, Jorge de la Barrera, Isabel Cuesta, Ángel Zaballos, José Manuel Bautista, Cheryl A. Lobo, Alejandro Sánchez-Flores, Estrella Montero

Babesiosis is considered an emerging disease because its incidence has significantly increased in the last 30 years, providing evidence of the expanding range of this rare but potentially life-threatening zoonotic disease. Babesia divergens is a causative agent of babesiosis in humans and cattle in Europe. The recently sequenced genome of B. divergens revealed over 3,741 protein coding-genes and the 10.7-Mb high-quality draft become the first reference tool to study the genome structure of B. divergens. Now, by exploiting this sequence data and using new computational tools and assembly strategies, we have significantly improved the quality of the B. divergens genome. The new assembly shows better continuity and has a higher correspondence to B. bovis chromosomes. Moreover, we present a differential expression analysis using RNA sequencing of the two different stages of the asexual lifecycle of B. divergens: the free merozoite capable of invading erythrocytes and the intraerythrocytic parasite stage that remains within the erythrocyte until egress. Comparison of mRNA levels of both stages identified 1,441 differentially expressed genes. From these, around half were upregulated and the other half downregulated in the intraerythrocytic stage. Orthogonal validation by real-time quantitative reverse transcription PCR confirmed the differential expression. A moderately increased expression level of genes, putatively involved in the invasion and egress processes, were revealed in the intraerythrocytic stage compared with the free merozoite. On the basis of these results and in the absence of molecular models of invasion and egress for B. divergens, we have proposed the identified genes as putative molecular players in the invasion and egress processes. Our results contribute to an understanding of key parasitic strategies and pathogenesis and could be a valuable genomic resource to exploit for the design of diagnostic methods, drugs and vaccines to improve the control of babesiosis.

Ecology and seasonality of sandflies and potential reservoirs of cutaneous leishmaniasis in Ochollo, a hotspot in southern Ethiopia

PLoS Neglected Tropical Diseases News - 19 August 2019 - 9:00pm

by Myrthe Pareyn, Emma Van den Bosch, Nigatu Girma, Natalie van Houtte, Stefan Van Dongen, Gert Van der Auwera, Fekadu Massebo, Simon Shibru, Herwig Leirs

Background

Ochollo is a village in southern Ethiopia burdened with cutaneous leishmaniasis (CL), where Phlebotomus pedifer is the only vector for Leishmania aethiopica and hyraxes are confirmed reservoir hosts. A detailed description of the different players of transmission, and the ecology and seasonality of the vector needs to be established in order to accomplish efficient control programs.

Methods and findings

Between March 2017 and February 2018, a monthly sandfly collection was carried out in different habitats and records of temperature and humidity were taken. Rodents and hyraxes were trapped in the dry and wet season. All samples were screened for Leishmania kinetoplast DNA (kDNA). Positive samples were further processed for determination of the Leishmania species and the species of the sandfly/small mammal that was found infected. Additionally, the species of 400 sandfly specimens from different habitats and seasons was identified.17,190 Sergentomyia and Phlebotomus sandflies were caught and showed an overall kDNA prevalence of 2.6%, all were L. aethiopica infections only found in P. pedifer. The overall sandfly and P. pedifer abundance peaked in the dry season and was negatively correlated with the %RH. The kDNA prevalence varied over the months and was negatively correlated with the temperature. Total sandfly abundance did not differ between the sampled habitats, but P. pedifer was the distinct predominant species only in caves. Moreover, significantly more infected sandflies were found in caves. Only 1/192 rodents were kDNA positive, while 20.0% (5/25) of Heterohyrax brucei were found infected.

Conclusions

This study suggests that caves may be a source of multiplication of the infection. If an outdoor control program would be considered, it would be useful to focus on caves in the wet season, when the sandfly abundance is lowest. The captured rodent species appear not important for transmission and the contribution of hyraxes in transmission should be further investigated.

Vaccination coverage in the context of the emerging Yellow Fever threat in French Guiana

PLoS Neglected Tropical Diseases News - 19 August 2019 - 9:00pm

by Claude Flamand, Sarah Bailly, Camille Fritzell, Sandrine Fernandes Pellerin, Alhassane Toure, Naïssa Chateau, Mona Saout, Sébastien Linares, Fabien Dubois, Laurent Filleul, Mirdad Kazanji

Background

French Guiana, a French overseas department located in South America between Brazil and Surinam, is the only European territory geographically located in the Amazonian forest complex and is considered endemic for yellow fever (YF).In the context of the emergent threat of YF in Latin America, we conducted a large household cross-sectional survey from June to October 2017 to estimate vaccination coverage in the population and to determine associations with sociodemographic and geographical characteristics.

Methodology/Principal findings

In total, 1,415 households and 2,697 individuals were included from the 22 municipalities of French Guiana. YF vaccination coverage was estimated at 95.0% (95% CI: 93.4–96.2) in the entire territory but was spatially heterogeneous, with the lowest levels estimated in the western part of the territory along the Surinamese cross-border region, particularly in children under 16 years who were not enrolled in school, immigrant adults and disadvantaged populations with low socioeconomic indexes.

Conclusions/Significance

Despite the good vaccination coverage against YF in the general population of French Guiana resulting from the compulsory nature of YF vaccination for residents and travelers, there is an urgent need to improve vaccination coverage in vulnerable populations living in the northwestern part of the territory to limit the risk of transmission in the context of the emerging YF threat in South America.Despite the relative rarity of YF and the significant number of infectious and tropical diseases in French Guiana, clinicians should adopt a high index of suspicion for YF, particularly in vulnerable and at-risk populations.

The diagnosis of scabies by non-expert examiners: A study of diagnostic accuracy

PLoS Neglected Tropical Diseases News - 19 August 2019 - 9:00pm

by Millicent H. Osti, Oliver Sokana, Christina Gorae, Margot J. Whitfeld, Andrew C. Steer, Daniel Engelman

Background

Although scabies is estimated to be one of the most common skin conditions globally, prevalence data is not available in most settings. Disease mapping is required to develop and monitor successful control programs. Non-expert health workers are likely to play an important role in scabies mapping activities in endemic settings.

Methodology

Four non-expert health workers were trained in the diagnosis of scabies and impetigo. The health worker diagnosis was compared to a reference consensus diagnosis of two doctors experienced in diagnosis. The study was conducted in a primary school in Gizo, Solomon Islands, in August 2018. The six examiners consecutively assessed school students, blinded to each other’s findings. Training and diagnostic procedures followed criteria for scabies diagnosis established by the International Alliance for the Control of Scabies in 2018.

Principal findings

Amongst the 171 students who underwent clinical assessment the prevalence of scabies and impetigo according to the reference standard was 55% and 45% respectively. Sensitivity of the non-expert health workers’ diagnosis compared to the reference standard was 55.3% for scabies (95% confidence interval [CI], 50.1–60.4) with a specificity of 89.9% (95% CI 86–93.1) and 52.6% for impetigo (95% CI 46.9–58.3) with a specificity 97.8% (95% CI 95.7–99). Sensitivity for moderate to severe scabies was 93.5% (95% CI 86.3–97.6) with a specificity of 74% (95% CI 70.2–77.5).

Conclusions

Following brief training, the diagnostic accuracy of non-expert health workers for scabies and impetigo was promising, especially for moderate to severe disease. Modifications to training and processes are recommended to further improve accuracy. The diagnosis by non-expert health workers may be acceptable for scabies and impetigo mapping in endemic areas.

Characterization of <i>Entamoeba histolytica</i> adenosine 5′-phosphosulfate (APS) kinase; validation as a target and provision of leads for the development of new drugs against amoebiasis

PLoS Neglected Tropical Diseases News - 19 August 2019 - 9:00pm

by Fumika Mi-ichi, Takeshi Ishikawa, Vo Kha Tam, Sharmina Deloer, Shinjiro Hamano, Tsuyoshi Hamada, Hiroki Yoshida

Background

Amoebiasis, caused by Entamoeba histolytica infection, is a global public health problem. However, available drugs to treat amoebiasis are currently limited, and no effective vaccine exists. Therefore, development of new preventive measures against amoebiasis is urgently needed.

Methodology/Principal findings

Here, to develop new drugs against amoebiasis, we focused on E. histolytica adenosine 5′-phosphosulfate kinase (EhAPSK), an essential enzyme in Entamoeba sulfolipid metabolism. Fatty alcohol disulfates and cholesteryl sulfate, sulfolipids synthesized in Entamoeba, play important roles in trophozoite proliferation and cyst formation. These processes are closely associated with clinical manifestation and severe pathogenesis of amoebiasis and with disease transmission, respectively. We validated a combination approach of in silico molecular docking analysis and an in vitro enzyme activity assay for large scale screening. Docking simulation ranked the binding free energy between a homology modeling structure of EhAPSK and 400 compounds. The 400 compounds were also screened by a 96-well plate-based in vitro APSK activity assay. Among fifteen compounds identified as EhAPSK inhibitors by the in vitro system, six were ranked by the in silico analysis as having high affinity toward EhAPSK. Furthermore, 2-(3-fluorophenoxy)-N-[4-(2-pyridyl)thiazol-2-yl]-acetamide, 3-phenyl-N-[4-(2-pyridyl)thiazol-2-yl]-imidazole-4-carboxamide, and auranofin, which were identified as EhAPSK inhibitors by both in silico and in vitro analyses, halted not only Entamoeba trophozoite proliferation but also cyst formation. These three compounds also dose-dependently impaired the synthesis of sulfolipids in E. histolytica.

Conclusions/Significance

Hence, the combined approach of in silico and in vitro-based EhAPSK analyses identified compounds that can be evaluated for their effects on Entamoeba. This can provide leads for the development of new anti-amoebic and amoebiasis transmission-blocking drugs. This strategy can also be applied to identify specific APSK inhibitors, which will benefit research into sulfur metabolism and the ubiquitous pathway terminally synthesizing essential sulfur-containing biomolecules.

Using detergent-enhanced LAMP for African trypanosome detection in human cerebrospinal fluid and implications for disease staging

PLoS Neglected Tropical Diseases News - 19 August 2019 - 9:00pm

by Dennis J. Grab, Olga V. Nikolskaia, Bertrand Courtioux, Oriel M. M. Thekisoe, Stefan Magez, Maxim Bogorad, J. Stephen Dumler, Sylvie Bisser

Objective

Where human African trypanosomiasis (HAT) patients are seen, failure to microscopically diagnose infections by Trypanosoma brucei gambiense in blood smears and/or cerebrospinal fluid (CSF) in the critical early stages of the disease is the single most important factor in treatment failure, a result of delayed treatment onset or its absence. We hypothesized that the enhanced sensitivity of detergent-enhanced loop-mediated isothermal amplification (LAMP) will allow for point of care (POC) detection of African trypanosomes in the CSF of HAT patients where the probability for detecting a single parasite or parasite DNA molecule in 1 μL of CSF sample is negligible by current methods.

Methodology

We used LAMP targeting the multicopy pan-T. brucei repetitive insertion mobile element (RIME LAMP) and the Trypanosoma brucei gambiense 5.8S rRNA-internal transcribed spacer 2 gene (TBG1 LAMP). We tested 1 μL out of 20 μL sham or Triton X-100 treated CSFs from 73 stage-1 and 77 stage-2 HAT patients from the Central African Republic and 100 CSF negative controls.

Results

Under sham conditions, parasite DNA was detected by RIME and TBG1 LAMP in 1.4% of the stage-1 and stage-2 gambiense HAT CSF samples tested. After sample incubation with detergent, the number of LAMP parasite positive stage-2 CSF’s increased to 26%, a value which included the 2 of the 4 CSF samples where trypanosomes were identified microscopically. Unexpected was the 41% increase in parasite positive stage-1 CSF’s detected by LAMP. Cohen’s kappa coefficients for RIME versus TBG1 LAMP of 0.92 (95%CI: 0.82–1.00) for stage-1 and 0.90 (95%CI: 0.80–1.00) for stage-2 reflected a high level of agreement between the data sets indicating that the results were not due to amplicon contamination, data confirmed in χ2 tests (p<0.001) and Fisher’s exact probability test (p = 4.7e-13).

Conclusion

This study detected genomic trypanosome DNA in the CSF independent of the HAT stage and may be consistent with early CNS entry and other scenarios that identify critical knowledge gaps for future studies. Detergent-enhanced LAMP could be applicable for non-invasive African trypanosome detection in human skin and saliva or as an epidemiologic tool for the determination of human (or animal) African trypanosome prevalence in areas where chronically low parasitemias are present.

<i>Wuchereria bancrofti</i> infection is linked to systemic activation of CD4 and CD8 T cells

PLoS Neglected Tropical Diseases News - 19 August 2019 - 9:00pm

by Inge Kroidl, Mkunde Chachage, Jonathan Mnkai, Anthony Nsojo, Myrna Berninghoff, Jaco J. Verweij, Lucas Maganga, Nyanda E. Ntinginya, Leonard Maboko, Petra Clowes, Michael Hoelscher, Elmar Saathoff, Christof Geldmacher

Background

Susceptibility to HIV has been linked to systemic CD4+ T cell activation in cohorts of seronegative individuals with high HIV-exposure risk. We recently described an increased risk of HIV transmission in individuals infected with Wuchereria bancrofti, the causative agent for lymphatic filariasis, in a prospective cohort study. However, the reason for this phenomenon needs further investigation.

Methodology/Principal findings

Two-hundred and thirty-five HIV negative adults were tested using Trop Bio ELISA for detection of W. bancrofti infection and Kato Katz urine filtration and stool based RT-PCR for detection of soil transmitted helminths and schistosomiasis. FACS analysis of the fresh peripheral whole blood was used to measure T cell activation markers (HLA-DR, CD38), differentiation markers (CD45, CD27), markers for regulatory T cells (FoxP3, CD25) and the HIV entry receptor CCR5. Frequencies of activated HLA-DRpos CD4 T cells were significantly increased in subjects with W. bancrofti infection (n = 33 median: 10.71%) compared to subjects without any helminth infection (n = 42, median 6.97%, p = 0.011) or those with other helminths (Schistosoma haematobium, S. mansoni, Trichuris trichiura, Ascaris lumbricoides, hookworm) (n = 151, median 7.38%, p = 0.009). Similarly, a significant increase in HLA-DRposCD38pos CD4 T cells and effector memory cells CD4 T cells (CD45ROposCD27neg) was observed in filarial infected participants. Multivariable analyses further confirmed a link between W. bancrofti infection and systemic activation of CD4 T cells independent of age, fever, gender or other helminth infections.

Conclusions/Significance

W. bancrofti infection is linked to systemic CD4 T cell activation, which may contribute to the increased susceptibility of W. bancrofti infected individuals to HIV infection.

Antibodies to <i>Plasmodium vivax</i> reticulocyte binding protein 2b are associated with protection against <i>P</i>. <i>vivax</i> malaria in populations living in low malaria transmission regions of Brazil and Thailand

PLoS Neglected Tropical Diseases News - 19 August 2019 - 9:00pm

by Wen-Qiang He, Stephan Karl, Michael T. White, Wang Nguitragool, Wuelton Monteiro, Andrea Kuehn, Jakub Gruszczyk, Camila T. França, Jetsumon Sattabongkot, Marcus V. G. Lacerda, Wai-Hong Tham, Ivo Mueller

Background

The Plasmodium vivax Reticulocyte Binding Protein (PvRBP) family is involved in red blood cell recognition and members of this family are potential targets for antibodies that may block P. vivax invasion. To date, the acquisition of immunity against PvRBPs in low malaria transmission settings and in a broad age group of exposed individuals has not been investigated.

Methodology/Principal findings

Total IgG antibody levels to six members of the PvRBP family (PvRBP1a, PvRBP1b, PvRBP2a, PvRBP2b, a non-binding fragment of PvRBP2c (PvRBP2cNB) and PvRBP2-P2) were measured in samples collected from individuals living in two regions of low P. vivax endemicity in Brazil and Thailand. In both settings, levels of total IgG to PvRBP1a, PvRBP2b, PvRBP2cNB, and PvRBP2P-2 increased significantly with age (rho = 0.17–0.49; P<0.001). IgG responses to PvRBP1a, PvRBP2b and PvRBP2cNB were significantly higher in infected individuals by using Wilcoxon’s signed-rank test (P<0.001). Of the six PvRBPs examined, only antibodies to PvRBP2b were associated with protection against clinical malaria in both settings.

Conclusion/Significance

Our results indicate that PvRBP2b warrants further preclinical development as a blood-stage vaccine candidate against P. vivax. Total IgG responses to PvRBPs were also shown to be promising immunological markers of exposure to P. vivax infection.

Is there a gap between health education content and practice toward schistosomiasis prevention among schoolchildren along the shores of Lake Victoria in Kenya?

PLoS Neglected Tropical Diseases News - 19 August 2019 - 9:00pm

by Rie Takeuchi, Sammy M. Njenga, Yoshio Ichinose, Satoshi Kaneko, Crystal A. Estrada, Jun Kobayashi

Despite provision of preventive measures against schistosomiasis such as mass drug administration (MDA), the prevalence of Schistosoma mansoni remains high in communities living near Lake Victoria. This study aimed to analyse the status of schistosomiasis, including its prevalence, health education, knowledge, attitudes, and practices (KAP) among pupils, and water use in schools in Mbita situated along the shores of Lake Victoria. Four primary schools were selected as target schools and pupils in classes six and seven were recruited as study participants. The prevalence of S. mansoni was examined by Kato-Katz method. Simultaneously, a KAP survey toward schistosomiasis was conducted among the pupils. Health education contents were extracted from textbooks. All primary schools in the study site were surveyed regarding how each secured water used for daily school life. The prevalence of S. mansoni was 56% and 36% in 2015 and 2016, respectively. 60–70% of pupils chose a correct answer for the mode of transmission. More than 70% of pupils answered that bathing in Lake Victoria causes Schistosoma infection; however, more than 70% of pupils bathed in Lake Victoria sometimes or every day. According to the science textbook, “avoiding contact with contaminated water” is the way to prevent schistosomiasis; however, 66% of schools asked pupils to bring water from Lake Victoria. The prevalence of S. mansoni among pupils remains high. Schoolchildren are taught to avoid contact with contaminated water but are often asked to fetch water from the lake. From the school health viewpoint, health education that reflects the social and cultural context of the community in the contents and teaching methods are needed. In addition to this, provision of sanitation infrastructure is needed. A comprehensive and innovative approach which harmonises central and local governments and other stakeholders, as well as community is important to prevent schistosomiasis.

Antimicrobial activity of Mycobacteriophage D29 Lysin B during <i>Mycobacterium ulcerans</i> infection

PLoS Neglected Tropical Diseases News - 19 August 2019 - 9:00pm

by Alexandra G. Fraga, Gabriela Trigo, Ramya K. Murthy, Shamim Akhtar, Madhavi Hebbur, Ana Rita Pacheco, Juan Dominguez, Rita Silva-Gomes, Carine M. Gonçalves, Hugo Oliveira, António G. Castro, Umender Sharma, Joana Azeredo, Jorge Pedrosa

Buruli Ulcer (BU) is a cutaneous disease caused by Mycobacterium ulcerans. The pathogenesis of this disease is closely related to the secretion of the toxin mycolactone that induces extensive destruction of the skin and soft tissues. Currently, there are no effective measures to prevent the disease and, despite availability of antibiotherapy and surgical treatments, these therapeutic options are often associated with severe side effects. Therefore, it is important to develop alternative strategies for the treatment of BU. Endolysins (lysins) are phage encoded enzymes that degrade peptidoglycan of bacterial cell walls. Over the past years, lysins have been emerging as alternative antimicrobial agents against bacterial infections. However, mycobacteria have an unusual outer membrane composed of mycolylarabinogalactan-peptidoglycan. To overcome this complex barrier, some mycobacteriophages encode a lipolytic enzyme, Lysin B (LysB). In this study, we demonstrate for the first time that recombinant LysB displays lytic activity against M. ulcerans isolates. Moreover, using a mouse model of M. ulcerans footpad infection, we show that subcutaneous treatment with LysB prevented further bacterial proliferation, associated with IFN-γ and TNF production in the draining lymph node. These findings highlight the potential use of lysins as a novel therapeutic approach against this neglected tropical disease.

Transcriptional blood signatures for active and amphotericin B treated visceral leishmaniasis in India

PLoS Neglected Tropical Diseases News - 16 August 2019 - 9:00pm

by Michaela Fakiola, Om Prakash Singh, Genevieve Syn, Toolika Singh, Bhawana Singh, Jaya Chakravarty, Shyam Sundar, Jenefer M. Blackwell

Amphotericin B provides improved therapy for visceral leishmaniasis (VL) caused by Leishmania donovani, with single dose liposomal-encapsulated Ambisome providing the best cure rates. The VL elimination program aims to reduce the incidence rate in the Indian subcontinent to <1/10,000 population/year. Ability to predict which asymptomatic individuals (e.g. anti-leishmanial IgG and/or Leishmania-specific modified Quantiferon positive) will progress to clinical VL would help in monitoring disease outbreaks. Here we examined whole blood transcriptional profiles associated with asymptomatic infection, active disease, and in treated cases. Two independent microarray experiments were performed, with analysis focussed primarily on differentially expressed genes (DEGs) concordant across both experiments. No DEGs were identified for IgG or Quantiferon positive asymptomatic groups compared to negative healthy endemic controls. We therefore concentrated on comparing concordant DEGs from active cases with all healthy controls, and in examining differences in the transcriptome following different regimens of drug treatment. In these comparisons 6 major themes emerged: (i) expression of genes and enrichment of gene sets associated with erythrocyte function in active cases; (ii) strong evidence for enrichment of gene sets involved in cell cycle in comparing active cases with healthy controls; (iii) identification of IFNG encoding interferon-γ as the major hub gene in concordant gene expression patterns across experiments comparing active cases with healthy controls or with treated cases; (iv) enrichment for interleukin signalling (IL-1/3/4/6/7/8) and a prominent role for CXCL10/9/11 and chemokine signalling pathways in comparing active cases with treated cases; (v) the novel identification of Aryl Hydrocarbon Receptor signalling as a significant canonical pathway when comparing active cases with healthy controls or with treated cases; and (vi) global expression profiling support for more effective cure at day 30 post-treatment with a single dose of liposomal encapsulated amphotericin B compared to multi-dose non-liposomal amphotericin B treatment over 30 days. (296 words; 300 words allowed).

Incidence dynamics and investigation of key interventions in a dengue outbreak in Ningbo City, China

PLoS Neglected Tropical Diseases News - 15 August 2019 - 9:00pm

by Bo Yi, Yi Chen, Xiao Ma, Jia Rui, Jing-An Cui, Haibin Wang, Jia Li, Soi-Fan Chan, Rong Wang, Keqin Ding, Lei Xie, Dongliang Zhang, Shuli Jiao, Xuying Lao, Yi-Chen Chiang, Yanhua Su, Benhua Zhao, Guozhang Xu, Tianmu Chen

Background

The reported incidence of dengue fever increased dramatically in recent years in China. This study aimed to investigate and to assess the effectiveness of intervention implemented in a dengue outbreak in Ningbo City, Zhejiang Province, China.

Methods

Data of a dengue outbreak were collected in Ningbo City in China by a field epidemiological survey according to a strict protocol and case definition. Serum specimens of all cases were collected for diagnosis and the virological characteristics were detected by using polymerase chain reaction (PCR) and gene sequencing. Vector surveillance was implemented during the outbreak to collect the larva and adult mosquito densities to calculate the Breteau Index (BI) and human biting rate (HBR), respectively. Data of monthly BI and light-trap density in 2018 were built to calculate the seasonality of the vector. A transmission mathematical model was developed to dynamic the incidence of the disease. The parameters of the model were estimated by the data of the outbreak and vector surveillance data in 2018. The effectiveness of the interventions implemented during the outbreak was assessed by the data and the modelling.

Results

From 11 August to 8 September, 2018, a dengue outbreak was reported with 27 confirmed cases in a population of 5536-people community (community A) of Ningbo City. Whole E gene sequences were obtained from 24 cases and were confirmed as dengue virus type 1 (DENV-1). The transmission source of the outbreak was origin from community B where a dengue case having the same E gene sequence was onset on 30 July. Aedes albopictus was the only vector species in the area. The value of BI and HBR was 57.5 and 12 per person per hour respectively on 18 August, 2018 and decreased dramatically after interventions. The transmission model fitted well (χ2 = 6.324, P = 0.388) with the reported cases data. With no intervention, the total simulated number of the cases would be 1728 with a total attack rate (TAR) of 31.21% (95%CI: 29.99%– 32.43%). Case isolation and larva control (LC) have almost the same TAR and duration of outbreak (DO) as no intervention. Different levels of reducing HBR (rHBR) had different effectiveness with TARs ranging from 1.05% to 31.21% and DOs ranging from 27 days to 102 days. Adult vector control (AVC) had a very low TAR and DO. “LC+AVC” had a similar TAR and DO as that of AVC. “rHBR100%+LC”, “rHBR100%+AVC”, “rHBR100%+LC+AVC” and “rHBR100%+LC+AVC+Iso” had the same effectiveness.

Conclusions

Without intervention, DENV-1 could be transmitted rapidly within a short period of time and leads to high attack rate in community in China. AVC or rHBR should be recommended as primary interventions to control rapid transmission of the dengue virus at the early stage of an outbreak.

Systematic review on antigens for serodiagnosis of visceral leishmaniasis, with a focus on East Africa

PLoS Neglected Tropical Diseases News - 15 August 2019 - 9:00pm

by Vera Kühne, Zahra Rezaei, Paul Pitzinger, Philippe Büscher

Background

Accurate and accessible diagnosis is key for the control of visceral leishmaniasis (VL). Yet, current diagnostic tests for VL have severe limitations: they are invasive or not suitable as point of care (POC) test or their performance is suboptimal in East Africa. We analysed the antigens in the VL serodiagnostics development pipeline to identify shortcomings and to propose strategies in the development of an alternative POC test for VL in East Africa.

Objectives

The objective of this study was to identify and to analyse all antigens for VL serodiagnosis that have been published before 2018 in order to identify candidates and gaps in the pipeline for a new POC test in East Africa.

Methods

A systematic literature search was performed on PubMed for original research articles on Leishmania-specific antigens for antibody detection of VL in humans. From each article, the following information was extracted: the antigen name, test format and characteristics, its reported sensitivity and specificity and study cohort specifications.

Results

One hundred and seven articles containing information about 96 tests based on 89 different antigens were included in this study. Eighty six of these tests, comprising 80 antigens, were evaluated in phase I and II studies only. Only 20 antigens, all of which are native, contain a carbohydrate and/or lipid moiety. Twenty-four antigens, of which 7 are non-native, are composed of antigen mixtures. Nineteen tests, comprising 18 antigens, have been evaluated on East African specimens, of which only 2 (rK28 based immunochromatographic test and intact promastigote based indirect fluorescent antibody technique) consistently showed sensitivities above 94 and specificities above 97% in a phase III study and one in a phase II study (dot blot with SLA). Only rK28 is a non-native mixture of antigens which we consider suitable for further evaluation and implementation.

Conclusions

The development pipeline for an alternative serodiagnostic test for VL is almost empty. Most antigens are not sufficiently evaluated. Non-protein antigens and antigen mixtures are being neglected. We propose to expand the evaluation of existing antigen candidates and to investigate the diagnostic potential of defined non-native carbohydrate and lipid antigens for VL serodiagnosis in East Africa.

Relationship between treatment regimens for visceral leishmaniasis and development of post-kala-azar dermal leishmaniasis and visceral leishmaniasis relapse: A cohort study from Bangladesh

PLoS Neglected Tropical Diseases News - 15 August 2019 - 9:00pm

by Dinesh Mondal, Amresh Kumar, Abhijit Sharma, Moshtaq Mural Ahmed, Md. Golam Hasnain, Abdul Alim, M. Mamun Huda, Ridwanur Rahman, Jorge Alvar, Be-Nazir Ahmed, Rashidul Haque

Background

We investigated the relationship of treatment regimens for visceral leishmaniasis (VL) with post-kala-azar dermal leishmaniasis (PKDL) and visceral leishmaniasis relapse (VLR) development.

Methods

Study subjects included cohorts of patients cured of VL since treatment with monotherapy by sodium stibogluconate (SSG), miltefosine (MF), paromomycin intramuscular injection (PMIM), liposomal amphotericin B [AmBisome (AMB)] in a single dose (SDAMB) and in multidose (MDAMB), and combination therapies by AMB+PMIM, AMB+MF, and PMIM+MF. Follow up period was 4 years after treatment. Cohorts were prospective except SSG (retrospective) and MF (partially retrospective). We compared incidence proportion and rate in 100-person-4year of PKDL and VLR by treatment regimens using univariate and multivariate analysis.

Findings

974 of 984 enrolled participants completed the study. Overall incidence proportion for PKDL and VLR was 12.3% (95% CI, 10.4%–14.5%) and 7.0% (95% CI, 5.6%–8.8%) respectively. The incidence rate (95% CI) of PKDL and VLR was 14.0 (8.6–22.7) and 7.6 (4.1–14.7) accordingly. SSG cohort had the lowest incidence rate of PKDL at 3.0 (1.3–7.3) and VLR at 1.8 (0.6–5.6), followed by MDAMB at 8.2 (4.3–15.7) for PKDL and at 2.7 (0.9–8.4) for VLR.

Interpretation

Development of PKDL and VLR is related with treatment regimens for VL. SSG and MDAMB resulted in less incidence of PKDL and VLR compared to other treatment regimens. MDAMB should be considered for VL as a first step for prevention of PKDL and VLR since SSG is highly toxic and not recommended for VL.

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