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Conservation and global distribution of non-canonical antigens in Enterotoxigenic <i>Escherichia coli</i>

PLoS Neglected Tropical Diseases News - 22 November 2019 - 10:00pm

by F. Matthew Kuhlmann, John Martin, Tracy H. Hazen, Tim J. Vickers, Madeline Pashos, Pablo C. Okhuysen, Oscar G. Gómez-Duarte, Elizabeth Cebelinski, Dave Boxrud, Felipe del Canto, Roberto Vidal, Firdausi Qadri, Makedonka Mitreva, David A. Rasko, James M. Fleckenstein

Background

Enterotoxigenic Escherichia coli (ETEC) cause significant diarrheal morbidity and mortality in children of resource-limited regions, warranting development of effective vaccine strategies. Genetic diversity of the ETEC pathovar has impeded development of broadly protective vaccines centered on the classical canonical antigens, the colonization factors and heat-labile toxin. Two non-canonical ETEC antigens, the EtpA adhesin, and the EatA mucinase are immunogenic in humans and protective in animal models. To foster rational vaccine design that complements existing strategies, we examined the distribution and molecular conservation of these antigens in a diverse population of ETEC isolates.

Methods

Geographically diverse ETEC isolates (n = 1159) were interrogated by PCR, immunoblotting, and/or whole genome sequencing (n = 46) to examine antigen conservation. The most divergent proteins were purified and their core functions assessed in vitro.

Results

EatA and EtpA or their coding sequences were present in 57.0% and 51.5% of the ETEC isolates overall, respectively; and were globally dispersed without significant regional differences in antigen distribution. These antigens also exhibited >93% amino acid sequence identity with even the most divergent proteins retaining the core adhesin and mucinase activity assigned to the prototype molecules.

Conclusions

EtpA and EatA are well-conserved molecules in the ETEC pathovar, suggesting that they serve important roles in virulence and that they could be exploited for rational vaccine design.

Efficacy of a mixture of neem seed oil (<i>Azadirachta indica</i>) and coconut oil (<i>Cocos nucifera</i>) for topical treatment of tungiasis. A randomized controlled, proof-of-principle study

PLoS Neglected Tropical Diseases News - 22 November 2019 - 10:00pm

by Lynne Elson, Kithi Randu, Hermann Feldmeier, Ulrike Fillinger

Background

Tungiasis is a neglected tropical skin disease caused by the female sand flea (Tunga penetrans), which burrows into the skin causing intense pain, itching and debilitation. People in endemic countries do not have access to an effective and safe home treatment. The aim of this study was to determine the efficacy of a traditionally used and readily available mixture of neem and coconut oil for treatment of tungiasis in coastal Kenya.

Methodology

Ninety-six children aged 6–14 years with at least one embedded viable flea were randomized to be treated with either a mixture of 20% neem (Azadirachta indica) seed oil in coconut oil (NC), or with a 0.05% potassium permanganate (KMnO4) foot bath. Up to two viable fleas were selected for each participant and monitored for 6 days after first treatment using a digital microscope for signs of viability and abnormal development. Acute pathology was assessed on all areas of the feet using a previously established score. Children reported pain levels and itching on a visual scale.

Results

The NC was not more effective in killing embedded sand fleas within 7 days than the current standard with KMnO4, killing on average 40% of the embedded sand fleas six days after the initial treatment. However, the NC was superior with respect to the secondary outcomes of abnormal development and reduced pathology. There was a higher odds that fleas rapidly aged in response to NC compared to KMnO4 (OR 3.4, 95% CI: 1.22–9.49, p = 0.019). NC also reduced acute pathology (p<0.005), and there was a higher odds of children being pain free (OR 3.5, p = 0.001) when treated with NC.

Conclusions

Whilst NC did not kill more fleas than KMnO4 within 7 days, secondary outcomes were better and suggest that a higher impact might have been observed at a longer observation period. Further trials are warranted to assess optimal mixtures and dosages.

Trial registration

The study was approved by the Kenya Medical Research Institute (KEMRI) Scientific and Ethical Review Unit (SERU), Nairobi (Non-SSC Protocol No. 514, 1st April 2016) and approved by and registered with the Pharmacy and Poisons Board’s Expert Committee on Clinical Trials PPB/ECCT/16/05/03/2016(94), the authority mandated, by Cap 244 Laws of Kenya, to regulate clinical trials in the country. The trial was also registered with the Pan African Clinical Trial Registry (PACTR201901905832601).

Rescue of infectious Arumowot virus from cloned cDNA: Posttranslational degradation of Arumowot virus NSs protein in human cells

PLoS Neglected Tropical Diseases News - 21 November 2019 - 10:00pm

by Hoai J. Hallam, Nandadeva Lokugamage, Tetsuro Ikegami

Rift Valley fever (RVF) is a mosquito-borne zoonotic disease endemic to Africa and the Middle East, affecting both humans and ruminants. There are no licensed vaccines or antivirals available for humans, whereas research using RVF virus (RVFV) is strictly regulated in many countries with safety concerns. Nonpathogenic Arumowot virus (AMTV), a mosquito-borne phlebovirus in Africa, is likely useful for the screening of broad-acting antiviral candidates for phleboviruses including RVFV, as well as a potential vaccine vector for RVF. In this study, we aimed to generate T7 RNA polymerase-driven reverse genetics system for AMTV. We hypothesized that recombinant AMTV (rAMTV) is viable, and AMTV NSs protein is dispensable for efficient replication of rAMTV in type-I IFN-incompetent cells, whereas AMTV NSs proteins support robust viral replication in type-I IFN-competent cells. The study demonstrated the rescue of rAMTV and that lacking the NSs gene (rAMTVΔNSs), that expressing green fluorescent protein (GFP) (rAMTV-GFP) or that expressing Renilla luciferase (rAMTV-rLuc) from cloned cDNA. The rAMTV-rLuc and the RVFV rMP12-rLuc showed a similar susceptibility to favipiravir or ribavirin. Interestingly, neither of rAMTV nor rAMTVΔNSs replicated efficiently in human MRC-5 or A549 cells, regardless of the presence of NSs gene. Little accumulation of AMTV NSs protein occurred in those cells, which was restored via treatment with proteasomal inhibitor MG132. In murine MEF or Hepa1-6 cells, rAMTV, but not rAMTVΔNSs, replicated efficiently, with an inhibition of IFN-β gene upregulation. This study showed an establishment of the first reverse genetics for AMTV, a lack of stability of AMTV NSs proteins in human cells, and an IFN-β gene antagonist function of AMTV NSs proteins in murine cells. The AMTV can be a nonpathogenic surrogate model for studying phleboviruses including RVFV.

Repurposing the antimalarial pyronaridine tetraphosphate to protect against Ebola virus infection

PLoS Neglected Tropical Diseases News - 21 November 2019 - 10:00pm

by Thomas R. Lane, Christopher Massey, Jason E. Comer, Manu Anantpadma, Joel S. Freundlich, Robert A. Davey, Peter B. Madrid, Sean Ekins

Recent outbreaks of the Ebola virus (EBOV) have focused attention on the dire need for antivirals to treat these patients. We identified pyronaridine tetraphosphate as a potential candidate as it is an approved drug in the European Union which is currently used in combination with artesunate as a treatment for malaria (EC50 between 420 nM—1.14 μM against EBOV in HeLa cells). Range-finding studies in mice directed us to a single 75 mg/kg i.p. dose 1 hr after infection which resulted in 100% survival and statistically significantly reduced viremia at 21 days from a lethal challenge with mouse-adapted EBOV (maEBOV). Further, an EBOV window study suggested we could dose pyronaridine 2 or 24 hrs post-exposure to result in similar efficacy. Analysis of cytokine and chemokine panels suggests that pyronaridine may act as an immunomodulator during an EBOV infection. Our studies with pyronaridine clearly demonstrate potential utility for its repurposing as an antiviral against EBOV and merits further study in larger animal models with the added benefit of already being used as a treatment against malaria.

Association of <i>IL18</i> genetic polymorphisms with Chagas disease in Latin American populations

PLoS Neglected Tropical Diseases News - 21 November 2019 - 10:00pm

by Mariana Strauss, Marialbert Acosta-Herrera, Alexia Alcaraz, Desiré Casares-Marfil, Pau Bosch-Nicolau, María Silvina Lo Presti, Israel Molina, Clara Isabel González, Chagas Genetics CYTED Network , Javier Martín

Host genetic factors have been suggested to play an important role in the susceptibility to Chagas disease. Given the influence of interleukin 18 (IL-18) in the development of the disease, in the present study, we analyzed three IL18 genetic variants (rs2043055, rs1946518, rs360719) regarding the predisposition to Trypanosoma cruzi infection and the development of chronic Chagas cardiomyopathy (CCC), in different Latin America populations. Genetic data of 3,608 patients from Colombia, Bolivia, Argentina, and Brazil were meta-analyzed to validate previous findings with increased statistical power. Seropositive and seronegative individuals were compared for T. cruzi infection susceptibility. In the Colombian cohort, the allelic frequencies of the three variants showed a significant association, with adjustment for sex and age, and also after applying multiple testing adjustments. Among the Colombian and Argentinean cohorts, rs360719 showed a significant genetic effect in a fixed-effects meta-analysis after a Bonferroni correction (OR: 0.76, CI: 0.66–0.89, P = 0.001). For CCC, the rs2043055 showed an association with protection from cardiomyopathy in the Colombian cohort (OR: 0.79, CI: 0.64–0.99, P = 0.037), with adjustment for sex and age, and after applying multiple testing adjustments. The meta-analysis of the CCC vs. asymptomatic patients from the four cohorts showed no evidence of association. In conclusion, our results validated the association found previously in the Colombian cohort suggesting that IL18 rs360719 plays an important role in the susceptibility to T. cruzi infection and no evidence of association was found between the IL18 genetic variants and CCC in the Latin American population studied.

Chikungunya virus populations experience diversity- dependent attenuation and purifying intra-vector selection in Californian <i>Aedes aegypti</i> mosquitoes

PLoS Neglected Tropical Diseases News - 21 November 2019 - 10:00pm

by Kasen K. Riemersma, Lark L. Coffey

Chikungunya virus (Togaviridae, Alphavirus; CHIKV) is a mosquito-borne global health threat that has been transmitted transiently in the southeastern United States. A primary CHIKV mosquito vector, Aedes aegypti, was recently established in the populous state of California, but the vector competence of Californian mosquitoes is unknown. Explosive CHIKV epidemics since 2004 have been associated with the acquisition of mosquito-adaptive mutations that enhance transmission by Ae. aegypti or Ae. albopictus. As a highly mutable RNA virus, CHIKV has the potential for extensive and rapid genetic diversification in vertebrate hosts and mosquito vectors. We previously demonstrated that expansion of CHIKV diversity in cell culture allows for greater adaptability to novel selection pressures, and that CHIKV fidelity variants are able to diversify more than wildtype (WT) CHIKV in mice. The evolution of intra-vector CHIKV populations and the correlation between CHIKV population diversity and infectivity and transmissibility in mosquitoes has not yet been studied. Here, we address these gaps in knowledge via experimental infection of Ae. aegypti from California with WT and fidelity variant CHIKV. We show that Ae. aegypti from California are highly competent vectors for CHIKV. We also report that CHIKV fidelity variants diversify more than WT in mosquitoes and exhibit attenuated infectivity at the level of the midgut. Furthermore, we demonstrate that intra-vector populations of CHIKV are subjected to purifying selection in mosquito bodies, and sequences of non-coding CHIKV regions are highly conserved. These findings will inform public health risk assessment for CHIKV in California and improve our understanding of constraints to CHIKV evolution in mosquitoes.

Neglected Tropical Diseases as a ‘litmus test’ for Universal Health Coverage? Understanding who is left behind and why in Mass Drug Administration: Lessons from four country contexts

PLoS Neglected Tropical Diseases News - 21 November 2019 - 10:00pm

by Laura Dean, Kim Ozano, Oluwatosin Adekeye, Ruth Dixon, Ebua Gallus Fung, Margaret Gyapong, Sunday Isiyaku, Karsor Kollie, Vida Kukula, Luret Lar, Eleanor MacPherson, Christine Makia, Estelle Kouokam Magne, Dum-Buo Nnamdi, Theobald Mue Nji, Uduak Ntuen, Akinola Oluwole, Helen Piotrowski, Marlene Siping, Marlene Ntsinda Tchoffo, Louis-Albert Tchuem Tchuenté, Rachael Thomson, Irene Tsey, Samuel Wanji, James Yashiyi, Georgina Zawolo, Sally Theobald

Introduction

Individuals and communities affected by NTDs are often the poorest and most marginalised; ensuring a gender and equity lens is centre stage will be critical for the NTD community to reach elimination goals and inform Universal Health Coverage (UHC). NTDs amenable to preventive chemotherapy have been described as a ‘litmus test’ for UHC due to the high mass drug administration (MDA) coverage rates needed to be effective and their model of community engagement. However, until now highly aggregated coverage data may have masked inequities in availability, accessibility and acceptability of medicines, slowing down the equitable achievement of elimination goals.

Methods

We conducted qualitative programmatic analysis across different country contexts through the novel application of the Tanahashi Coverage Framework enhanced by gendered intersectional theory to interrogate different components of programme coverage: availability, accessibility, acceptability, contact and effective. Drawing on communities and health implementers perspectives (using focus groups, interviews, and participatory methods) from varying levels of the health system, across four African country contexts (Cameroon, Ghana, Liberia and Nigeria), we show who is left behind and provide recommendations for programmes to respond.

Findings

We have unmasked inequities in programme delivery that repeatedly leave vulnerable populations underserved in relation to the prevention and treatment of PC NTDs across all components of coverage explored within the Tanahashi framework. Inequities are influenced by health systems challenges and limitations, due to lack of consideration of gender, power and equity issues. Effective treatment for individuals and communities is shaped by individual identities and the intersecting axes of inequity that converge to shape these positions including gender, age, disability, and geography. Health systems are inherently social and gendered thus they become mediators in managing the impact that social and structural processes have on individual health outcomes.

Significance

To our knowledge this is the only paper which has combined a comprehensive equity framework with intersectional feminist theory, to establish a fuller understanding of who is left behind and why in MDA across countries and contexts. Ensuring the most vulnerable have continued access to future treatment options will contribute to the progressive realisation of UHC, allowing the NTD community to continue to support their vision of being a true ‘litmus test’.

The genetic basis of adaptive evolution in parasitic environment from the <i>Angiostrongylus cantonensis</i> genome

PLoS Neglected Tropical Diseases News - 21 November 2019 - 10:00pm

by Lian Xu, Meng Xu, Xi Sun, Junyang Xu, Xin Zeng, Dai Shan, Dongjuan Yuan, Ping He, Weiming He, Yulan Yang, Shiqi Luo, Jie Wei, Xiaoying Wu, Zhen Liu, Xiaomin Xu, Zhensheng Dong, Langui Song, Beibei Zhang, Zilong Yu, Lifu Wang, Chi Zhang, Xiaodong Fang, Qiang Gao, Zhiyue Lv, Zhongdao Wu

Angiostrongylus cantonensis (rat lungworm) is the etiological agent of angiostrongyliasis, mainly causing eosinophilic meningitis or meningoencephalitis in human. Although the biology of A. cantonensis is relatively well known, little is understood about the mechanisms of the parasite’s development and survival in definitive hosts, or its adaptation to a broad range of snail intermediate hosts. Here, we generate a high-quality assembly of a well-defined laboratory strain of A. cantonensis from Guangzhou, China, by using Illumina and PacBio sequencing technologies. We undertake comparative analyses with representative helminth genomes and explore transcriptomic data throughout key developmental life-cycles of the parasite. We find that part of retrotransposons and gene families undergo multiple waves of expansions. These include extracellular superoxide dismutase (EC-SOD) and astacin-like proteases which are considered to be associated with invasion and survival of the parasite. Furthermore, these paralogs from different sub-clades based on phylogeny, have different expression patterns in the molluscan and rodent stages, suggesting divergent functions under the different parasitic environment. We also find five candidate convergent signatures in the EC-SOD proteins from flukes and one sub-clade of A. cantonensis. Additionally, genes encoding proteolytic enzymes, involved in host hemoglobin digestion, exhibit expansion in A. cantonensis as well as two other blood-feeding nematodes. Overall, we find several potential adaptive evolutionary signatures in A. cantonensis, and also in some other helminths with similar traits. The genome and transcriptomes provide a useful resource for detailed studies of A. cantonensis-host adaptation and an in-depth understanding of the global-spread of angiostrongyliasis.

Insufficiency of annual praziquantel treatment to control <i>Schistosoma mansoni</i> infections in adult women: A longitudinal cohort study in rural Tanzania

PLoS Neglected Tropical Diseases News - 21 November 2019 - 10:00pm

by Pallavi Mishra, Soledad Colombe, Ndalloh Paul, Jane Mlingi, Inobena Tosiri, Christine Aristide, Joanna Gao, Philibert Kashangaki, Honest Nagai, Samuel E. Kalluvya, Claudia J. de Dood, Paul L. Corstjens, Julius Mngara, Govert J. van Dam, Jennifer A. Downs

Background

Current World Health Organization (WHO) guidelines recommend annual mass drug administration using praziquantel in areas with high schistosome endemicity. Yet little is known about incidence and reinfection rates after treatment in women with frequent exposure to schistosomes. We sought to quantify response to anti-schistosome treatment and incident S. mansoni infections in a cohort of rural women living in a schistosome-endemic area of northwest Tanzania.

Methods and principal findings

We enrolled women with and without S. mansoni infection into a 12-month longitudinal cohort. Every 3 months, women were tested for schistosome infection using microscopic examinations for ova on filtered urine, Kato Katz slides, and serum Circulating Anodic Antigen (CAA). Those with schistosome infection received treatment with praziquantel 40 mg/kg according to the standard of care.We studied 35 women who were S. mansoni positive by stool microscopy and 46 women without schistosome infection who returned for at least one follow-up. Of the women who were initially infected, 14 (40%) were schistosome-positive at a follow-up visit. Four women developed incident infections, for a cumulative incidence of 8.7% and incidence rate of 0.99 per 100 person-months throughout the year among initially uninfected women. Only 3 women were egg-positive at any follow-up.Women with persistent, recurrent, or incident infection during the study period were significantly younger (p = 0.032) and had fewer children than women who remained uninfected or those who cleared the infection and did not experience recurrence (p = 0.003). Having fewer children remained significant after controlling for age (p = 0.023). There was no difference in initial intensity of infection by CAA or stool egg count, HIV status, or socioeconomic status. Although most water contact behaviors were comparable between the two groups, women with recurrent or incident schistosome infections were significantly more likely to have recently swum in the lake (p = 0.023).

Conclusions

Our data suggests that annual praziquantel treatment reduces intensity of schistosome infections but is insufficient in providing stable parasite eradication in over a third of women in endemic communities. Furthermore, microscopy lacks adequate sensitivity to evaluate efficacy of treatment in this population. Our work demonstrates that further investigation into treatment efficacy and reinfection rates is warranted and suggests that increased frequency of praziquantel treatment is needed to improve cure rates in high-risk populations.

Field study of the improved rapid sand fly exposure test in areas endemic for canine leishmaniasis

PLoS Neglected Tropical Diseases News - 21 November 2019 - 10:00pm

by Laura Willen, Tereza Lestinova, Barbora Kalousková, Petra Sumova, Tatiana Spitzova, Rita Velez, Ester Domenech, Ondřej Vaněk, Montserrat Gállego, Pascal Mertens, Petr Volf

Background

Canine leishmaniasis (CanL) is a severe chronic disease caused by Leishmania infantum and transmitted by sand flies of which the main vector in the Western part of the Mediterranean basin is Phlebotomus perniciosus. Previously, an immunochromatographic test (ICT) was proposed to allow rapid evaluation of dog exposure to P. perniciosus. In the present study, we optimized the prototype and evaluated the detection accuracy of the ICT in field conditions. Possible cross-reactions with other hematophagous arthropods were also assessed.

Methodology/Principal findings

The ICT was optimized by expressing the rSP03B protein in a HEK293 cell line, which delivered an increased specificity (94.92%). The ICT showed an excellent reproducibility and inter-person reliability, and was optimized for use with whole canine blood which rendered an excellent degree of agreement with the use of serum. Field detectability of the ICT was assessed by screening 186 dogs from different CanL endemic areas with both the SGH-ELISA and the ICT, and 154 longitudinally sampled dogs only with the ICT. The ICT results corresponded to the SGH-ELISA for most areas, depending on the statistical measure used. Furthermore, the ICT was able to show a clear seasonal fluctuation in the proportion of bitten dogs. Finally, we excluded cross-reactions between non-vector species and confirmed favorable cross-reactions with other L. infantum vectors belonging to the subgenus Larroussius.

Conclusions/Significance

We have successfully optimized the ICT, now also suitable to be used with whole canine blood. The test is able to reflect the seasonal fluctuation in dog exposure and showed a good detectability in a field population of naturally exposed dogs, particularly in areas with a high seroprevalence of bitten dogs. Furthermore, our study showed the existence of favorable cross-reactions with other sand fly vectors thereby expanding its use in the field.

Vaccination strategies to control Ebola epidemics in the context of variable household inaccessibility levels

PLoS Neglected Tropical Diseases News - 21 November 2019 - 10:00pm

by Gerardo Chowell, Amna Tariq, Maria Kiskowski

Despite a very effective vaccine, active conflict and community distrust during the ongoing DRC Ebola epidemic are undermining control efforts, including a ring vaccination strategy that requires the prompt immunization of close contacts of infected individuals. However, in April 2019, it was reported 20% or more of close contacts cannot be reached or refuse vaccination, and it is predicted that the ring vaccination strategy would not be effective with such a high level of inaccessibility. The vaccination strategy is now incorporating a “third ring” community-level vaccination that targets members of communities even if they are not known contacts of Ebola cases. To assess the impact of vaccination strategies for controlling Ebola epidemics in the context of variable levels of community accessibility, we employed an individual-level stochastic transmission model that incorporates four sources of heterogeneity: a proportion of the population is inaccessible for contact tracing and vaccination due to lack of confidence in interventions or geographic inaccessibility, two levels of population mixing resembling household and community transmission, two types of vaccine doses with different time periods until immunity, and transmission rates that depend on spatial distance. Our results indicate that a ring vaccination strategy alone would not be effective for containing the epidemic in the context of significant delays to vaccinating contacts even for low levels of household inaccessibility and affirm the positive impact of a supplemental community vaccination strategy. Our key results are that as levels of inaccessibility increase, there is a qualitative change in the effectiveness of the vaccination strategy. For higher levels of vaccine access, the probability that the epidemic will end steadily increases over time, even if probabilities are lower than they would be otherwise with full community participation. For levels of vaccine access that are too low, however, the vaccination strategies are not expected to be successful in ending the epidemic even though they help lower incidence levels, which saves lives, and makes the epidemic easier to contain and reduces spread to other communities. This qualitative change occurs for both types of vaccination strategies: ring vaccination is effective for containing an outbreak until the levels of inaccessibility exceeds approximately 10% in the context of significant delays to vaccinating contacts, a combined ring and community vaccination strategy is effective until the levels of inaccessibility exceeds approximately 50%. More broadly, our results underscore the need to enhance community engagement to public health interventions in order to enhance the effectiveness of control interventions to ensure outbreak containment.

Plague in Zimbabwe from 1974 to 2018: A review article

PLoS Neglected Tropical Diseases News - 21 November 2019 - 10:00pm

by Amon Munyenyiwa, Moses Zimba, Tamuka Nhiwatiwa, Maxwell Barson

Plague is a zoonotic disease caused by the bacterium Yersinia pestis and is transmitted through the bites of infected rodent fleas. Plague is well known for causing 3 major human pandemics that have killed millions of people since 541 A.D. The aim of this Review is to provide an overview of the epidemiology and ecology of plague in Zimbabwe with special emphasis on its introduction, its potential reservoirs and vectors, and possible causes of its persistence and cyclic outbreaks. To achieve this, we carried out a search and document reported plague outbreaks in Zimbabwe. In the country, human plague cases have been reported in Hwange, Nkayi, and Lupane since 1974. The highest number of cases occurred in 1994 in the Nkayi district of Matabeleland North Province with a total of 329 confirmed human cases and 28 deaths. Plague is encountered in 2 different foci in the country, sylvatic and rural. Risk factors for contracting plague in the country include man-to-rodent contact, cultivation, hunting, cattle herding, handling of infected materials, camping in forests, and anthropic invasion of new areas. Plague is now enzootic in Zimbabwe, and the most recent case was reported in 2012, hence its effective control requires up-to-date information on the epidemiology and ecology of the disease. This can be achieved through continuous monitoring and awareness programs in plague-prone areas.

Schistosomiasis was not associated with higher HIV-1 plasma or genital set point viral loads among HIV seroconverters from four cohort studies

PLoS Neglected Tropical Diseases News - 20 November 2019 - 10:00pm

by Aaron F. Bochner, W. Evan Secor, Jared M. Baeten, Govert J. van Dam, Adam A. Szpiro, Sammy M. Njenga, Paul L. A. M. Corstjens, Romel D. Mackelprang, Nelly R. Mugo, Julie Overbaugh, Connie Celum, Andrew Mujugira, R. Scott McClelland, Ruanne V. Barnabas

Background

Many regions of sub-Saharan Africa experience a high prevalence of both schistosomiasis and HIV-1, leading to frequent coinfection. Higher plasma HIV-1 viral loads are associated with faster disease progression and genital HIV-1 loads are a primary determinant of HIV-1 transmission risk. We hypothesized that schistosome infection would be associated with higher HIV-1 viral loads in plasma and genital samples.

Methods/Principal findings

We utilized data from individuals who HIV-1 seroconverted while enrolled in one of four prospective cohort studies. Plasma and genital viral loads collected 4–24 months after the estimated date of HIV-1 acquisition, but prior to antiretroviral therapy initiation, were included. Detection of circulating anodic antigen in archived blood samples, collected prior to HIV-1 seroconversion, identified participants with active schistosomiasis; immunoblots determined the schistosome species causing infection. Our analysis included 370 HIV-1 seroconverters with plasma viral load results, of whom 82 (22%) had schistosomiasis. We did not find a statistically significant association between schistosomiasis and higher HIV-1 set point plasma viral loads (-0.17 log10 copies/ml, 95% CI -0.38 to 0.03); S. mansoni infection was associated with a lower set point (-0.34 log10 copies/ml, 95% CI -0.58 to -0.09). We found no association between schistosomiasis and cervical (+0.07 log10 copies/swab, 95% CI -0.20 to 0.34) or vaginal (+0.11 log10 copies/swab, 95% CI -0.17 to 0.39) set point viral loads; S. haematobium infection was associated with lower cervical viral loads (-0.59 log10 copies/swab, 95% CI -1.11 to -0.06).

Conclusions/Significance

These results do not support the hypotheses that schistosome coinfection increases plasma or genital HIV-1 viral loads.

Comparative genomic analysis and molecular examination of the diversity of enterotoxigenic <i>Escherichia coli</i> isolates from Chile

PLoS Neglected Tropical Diseases News - 20 November 2019 - 10:00pm

by David A. Rasko, Felipe Del Canto, Qingwei Luo, James M. Fleckenstein, Roberto Vidal, Tracy H. Hazen

Enterotoxigenic Escherichia coli (ETEC) is one of the most common diarrheal pathogens in the low- and middle-income regions of the world, however a systematic examination of the genomic content of isolates from Chile has not yet been undertaken. Whole genome sequencing and comparative analysis of a collection of 125 ETEC isolates from three geographic locations in Chile, allowed the interrogation of phylogenomic groups, sequence types and genes specific to isolates from the different geographic locations. A total of 80.8% (101/125) of the ETEC isolates were identified in E. coli phylogroup A, 15.2% (19/125) in phylogroup B, and 4.0% (5/125) in phylogroup E. The over-representation of genomes in phylogroup A was significantly different from other global ETEC genomic studies. The Chilean ETEC isolates could be further subdivided into sub-clades similar to previously defined global ETEC reference lineages that had conserved multi-locus sequence types and toxin profiles. Comparison of the gene content of the Chilean ETEC identified genes that were unique based on geographic location within Chile, phylogenomic classifications or sequence type. Completion of a limited number of genomes provided insight into the ETEC plasmid content, which is conserved in some phylogenomic groups and not conserved in others. These findings suggest that the Chilean ETEC isolates contain unique virulence factor combinations and genomic content compared to global reference ETEC isolates.

Immune responses to O-specific polysaccharide (OSP) in North American adults infected with <i>Vibrio cholerae</i> O1 Inaba

PLoS Neglected Tropical Diseases News - 19 November 2019 - 10:00pm

by Motaher Hossain, Kamrul Islam, Meagan Kelly, Leslie M. Mayo Smith, Richelle C. Charles, Ana A. Weil, Taufiqur Rahman Bhuiyan, Pavol Kováč, Peng Xu, Stephen B. Calderwood, Jakub K. Simon, Wilbur H. Chen, Michael Lock, Caroline E. Lyon, Beth D. Kirkpatrick, Mitchell Cohen, Myron M. Levine, Marc Gurwith, Daniel T. Leung, Andrew S. Azman, Jason B. Harris, Firdausi Qadri, Edward T. Ryan

Background

Antibodies targeting O-specific polysaccharide (OSP) of Vibrio cholerae may protect against cholera; however, little is known about this immune response in infected immunologically naïve humans.

Methodology

We measured serum anti-OSP antibodies in adult North American volunteers experimentally infected with V. cholerae O1 Inaba El Tor N16961. We also measured vibriocidal and anti-cholera toxin B subunit (CtxB) antibodies and compared responses to those in matched cholera patients in Dhaka, Bangladesh, an area endemic for cholera.

Principal findings

We found prominent anti-OSP antibody responses following initial cholera infection: these responses were largely IgM and IgA, and highest to infecting serotype with significant cross-serotype reactivity. The anti-OSP responses peaked 10 days after infection and remained elevated over baseline for ≥ 6 months, correlated with vibriocidal responses, and may have been blunted in blood group O individuals (IgA anti-OSP). We found significant differences in immune responses between naïve and endemic zone cohorts, presumably reflecting previous exposure in the latter.

Conclusions

Our results define immune responses to O-specific polysaccharide in immunologically naive humans with cholera, find that they are largely IgM and IgA, may be blunted in blood group O individuals, and differ in a number of significant ways from responses in previously humans. These differences may explain in part varying degrees of protective efficacy afforded by cholera vaccination between these two populations.

Trial registration number

ClinicalTrials.gov NCT01895855.

Implementation of guppy fish <i>(Poecilia reticulata)</i>, and a novel larvicide (Pyriproxyfen) product (Sumilarv 2MR) for dengue control in Cambodia: A qualitative study of acceptability, sustainability and community engagement

PLoS Neglected Tropical Diseases News - 18 November 2019 - 10:00pm

by Muhammad Shafique, Sergio Lopes, Dyna Doum, Vanney Keo, Ly Sokha, BunLeng Sam, Chan Vibol, Neal Alexander, John Bradley, Marco Liverani, Jeffrey Hii, Leang Rithea, Siddhi Aryal, John Hustedt

Background

In Cambodia dengue vector control activities are focused on larviciding with temephos and pyrethroid based adulticide sprays to which Aedes have been shown to be increasingly resistant.A cluster randomized trial assessed the impact of using biological control tools (guppy fish, pyriproxyfen (PPF), and Communication for Behavioral Impact (COMBI) activities in combination), which would be used in a value comparison to traditional chemical control tools. Given these new intervention methods, a qualitative assessment was designed in order to represent the quality of understanding, acceptance, and implementation by participants.

Methodology/Principal findings

A total of 103 participants in 12 Focus Group Discussions (FGDs) and nine In-Depth Interviews (IDIs) were included in the study. The majority of participants in intervention villages (50 out of 80) preferred guppy fish over other vector control methods due to ease of use and rearing, quick reproduction and propensity to eat larvae. A substantial number of participants (11 out of 40) in intervention villages with PPF favored it due to long-lasting effectiveness, lack of smell and easy maintenance. Participants showed high demand for both interventions and were willing to pay between 100–500 riel (0.03–0.13 USD). Nearly all participants perceived that the interventions resulted in a reduction in Aedes mosquitos (both adults and immatures) and dengue cases. The presence of larvae in the water despite the use of PPF was a source of concern for some participants, although this was overcome in some cases with proper health education through health volunteers. Interpersonal communication through health volunteers was the most favorite method of transmitting prevention messages.

Conclusions/Significance

The community led COMBI strategy resulted in high acceptance and perceived effectiveness of the interventions in target villages. Health volunteers are an effective and accepted channel of communication to engage communities, disseminate information and promote behavioral change at the household and community level. If shown effective through corresponding entomological surveys, the interventions should be continued and further strengthened to ensure they are accessible, available and affordable.

Discovery of a small molecule inhibitor targeting dengue virus NS5 RNA-dependent RNA polymerase

PLoS Neglected Tropical Diseases News - 18 November 2019 - 10:00pm

by Hideaki Shimizu, Akatsuki Saito, Junko Mikuni, Emi E. Nakayama, Hiroo Koyama, Teruki Honma, Mikako Shirouzu, Shun-ichi Sekine, Tatsuo Shioda

Dengue is a mosquito-borne viral infection that has spread globally in recent years. Around half of the world’s population, especially in the tropics and subtropics, is at risk of infection. Every year, 50–100 million clinical cases are reported, and more than 500,000 patients develop the symptoms of severe dengue infection: dengue haemorrhagic fever and dengue shock syndrome, which threaten life in Asia and Latin America. No antiviral drug for dengue is available. The dengue virus (DENV) non-structural protein 5 (NS5), which possesses the RNA-dependent RNA polymerase (RdRp) activity and is responsible for viral replication and transcription, is an attractive target for anti-dengue drug development. In the present study, 16,240 small-molecule compounds in a fragment library were screened for their capabilities to inhibit the DENV type 2 (DENV2) RdRp activities in vitro. Based on in cellulo antiviral and cytotoxity assays, we selected the compound RK-0404678 with the EC50 value of 6.0 μM for DENV2. Crystallographic analyses revealed two unique binding sites for RK-0404678 within the RdRp, which are conserved in flavivirus NS5 proteins. No resistant viruses emerged after nine rounds of serial passage of DENV2 in the presence of RK-0404678, suggesting the high genetic barrier of this compound to the emergence of a resistant virus. Collectively, RK-0404678 and its binding sites provide a new framework for antiviral drug development.

Lymphocytes influence <i>Leishmania major</i> pathogenesis in a strain-dependent manner

PLoS Neglected Tropical Diseases News - 18 November 2019 - 10:00pm

by Md. Abu Musa, Risa Nakamura, Asma Hena, Sanjay Varikuti, Hira L. Nakhasi, Yasuyuki Goto, Abhay Satoskar, Shinjiro Hamano

Cutaneous leishmaniasis (CL) is the most common form of leishmaniasis and is caused by several species of Leishmania parasite. Clinical presentation of CL varies from a self-healing infection to a chronic form of the disease determined by the virulence of infecting Leishmania species and host immune responses to the parasite. Mouse models of CL show contradictory roles of lymphocytes in pathogenesis, while acquired immune responses are responsible for host protection from diseases. To reconcile the inconclusive roles of acquired immune responses in pathogenesis, we infected mice from various genetic backgrounds with two pathogenic strains of Leishmania major, Friedlin or 5ASKH, and assessed the outcome of the infections. Our findings showed that the genetic backgrounds of L. major determine the impact of lymphocytes for pathogenesis. In the absence of lymphocytes, L. major Friedlin induced the lowest inflammatory reaction and pathology at the site of infection, while 5ASKH infection induced a strong inflammatory reaction and severe pathology. Lymphocytes ameliorated 5ASKH mediated pathology, while it exacerbated pathology during Friedlin infection. Excess inflammatory reactions, like the recruitment of macrophages, neutrophils, eosinophils and production of pro-inflammatory cytokines, together with uncontrolled parasite growth in the absence of lymphocytes during 5ASKH infection may induce severe pathology development. Taken together our study provides insight into the impact of differences in the genetic background of Leishmania on CL pathogenesis.

Pyriproxyfen treated surface exposure exhibits reproductive disruption in dengue vector <i>Aedes aegypti</i>

PLoS Neglected Tropical Diseases News - 18 November 2019 - 10:00pm

by Kavita Yadav, Sunil Dhiman, BN Acharya, Rama Rao Ghorpade, Devanathan Sukumaran

Background

Reduced susceptibility of mosquito vectors to currently used insecticides hampers control interventions. Recently pyriproxyfen, an insect growth regulator has been demonstrated to effectively reduce the reproductive potential in vector mosquitoes.

Methods

Pyriproxyfen (PPF), in different concentrations (0.75%, 0.075%, 0.0075%, and 0.00075%) was applied on papers and Indian wild type Aedes aegypti female mosquitoes (N ≥ 20 for each treatment) were exposed onto it as per WHO guidelines, to study the reproductive disruption. PPF concentration on treated papers was quantitatively cross-determined using HPLC method. Reduction in fecundity, fertility and adult emergence in exposed female Ae. aegypti was determined. Abnormal development in ovary and eggs of exposed females was studied microscopically after different time intervals.

Results

Eggs laid, eggs hatched, pupae formed and adults emerged per female exposed in both before blood meal and after blood meal groups declined significantly from lowest to highest concentration of PPF (F ≥ 5.2; p < 0.02). Adult emergence inhibition in females exposed to PPF before and after blood meal groups ranged from 58.8% [OR = 0.18 (95% CI = 0.09–0.36)] to 79.2% [OR = 0.04 (95% CI = 0.02–0.10)] and 64.4% [OR = 0.12 (95% CI = 0.05–0.28)] to 77.2% [OR = 0.05 (95% CI = 0.02–0.14)] respectively in different concentrations. The probit model used suggested that FI50 (50% fertility inhibition) and EI50 (50% emergence inhibition) were 0.002% (p = 0.8) and 0.0001% (p = 0.99) for females exposed before blood meal, while 0.01% (p = 0.6) and <0.0001% (p = 0.98) for the females exposed after blood meal, respectively. The eggs laid by the females exposed to PPF-treated surface showed altered body organization, desegmentation and disoriented abdominal and cervical regions in the developing embryo. Quantification of PPF on impregnated papers showed that it was uniformly distributed throughout the matrix.

Conclusions

The present study has shown that tarsal contact to PPF-treated surface for a small time drastically influenced the fecundity, fertility and adult emergence in Indian wild Ae. aegypti mosquitoes. Results suggest that a certain minimum concentration of PPF through contact exposure can reduce the abundance of vector mosquitoes to a considerable level. The formulations based on combination of PPF and other compatible insecticides may be an impactful approach where susceptible mosquitoes are killed by the insecticide component while resistant mosquitoes are sterilised by PPF.

The prevalence of scabies, pyoderma and other communicable dermatoses in the Bijagos Archipelago, Guinea-Bissau

PLoS Neglected Tropical Diseases News - 18 November 2019 - 10:00pm

by Michael Marks, Thomas Sammut, Marito Gomes Cabral, Eunice Teixeira da Silva, Adriana Goncalves, Amabelia Rodrigues, Cristóvão Manjuba, Jose Nakutum, Janete Ca, Umberto D’Alessandro, Jane Achan, James Logan, Robin Bailey, David Mabey, Anna Last, Stephen L. Walker

Introduction

Skin diseases represent a significant public health problem in most low and middle income settings. Nevertheless, there is a relative paucity of high-quality epidemiological data on the prevalence of these conditions.

Materials/Methods

We conducted two cross-sectional population-based skin-surveys of children (6 months to 9 years old) in the Bijagós Archipelago of Guinea-Bissau during the dry season (February-March 2018) and the wet season (June-July 2018). Following a period of training, a nurse performed a standardised examination for communicable dermatoses for each participant. We calculated the prevalence of each skin condition and investigated demographic associations.

Results

1062 children were enrolled in the dry season survey of whom 318 (29.9%) had at least one skin diseases. The most common diagnosis was tinea capitis (154/1062, 14.5% - 95% CI 12.5–16.8%) followed by tinea corporis (84/1062, 7.9% - 95% CI 6.4–9.7%), pyoderma (82/1062, 7.7% - 95% CI 6.2–9.5%) and scabies (56/1062. 5.2% - 95%CI 4.0–6.8%). 320 children were enrolled in the wet season survey of whom 121 (37.8%) had at least one skin problem. Tinea capitis remained the most common diagnosis (79/320, 24.7% - 95% CI 20.1–29.9%), followed by pyoderma (38/320, 11.9% - 95% CI 8.6–16.1%), tinea corporis (23/320, 7.2% - 95% 4.7–10.7%) and scabies (6/320, 1.9% - 95% CI 0.8–4.2%).

Conclusions

Our study, which utilised robust population-based cluster random sampling methodology, demonstrates the substantial disease burden caused by common communicable dermatoses in this setting. Given these findings, there is a need to consider common dermatoses as part of Universal Health Coverage to deliver ‘skin-health for all’.

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