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Trajectories of hepatic and coagulation dysfunctions related to a rapidly fatal outcome among hospitalized patients with dengue fever in Tainan, 2015

PLoS Neglected Tropical Diseases News - 5 December 2019 - 10:00pm

by Chun-Yin Yeh, Bing-Ze Lu, Wei-Jie Liang, Yu-Chen Shu, Kun-Ta Chuang, Po-Lin Chen, Wen-Chien Ko, Nai-Ying Ko

Background

Hepatic dysfunction and coagulopathy are common in acute dengue illness. We analyzed the trajectories of the above parameters in the survivors and fatal patients in the outbreak in Tainan, 2015.

Methods

A retrospective study was conducted using data from a tertiary hospital between January and December 2015. Multilevel modeling (MLM) was used to identify the changes in aminotransferase (AST), alanine aminotransferase (ALT), activated partial thromboplastin time (aPTT), and platelet counts from Day 0 to Day 7 of the onset of dengue infection. The machine-learning algorithm was used by purity measure assumption to calculate the accuracy of serum transaminases and coagulation variables to discriminate between the fatal and survival groups.

Results

There were 4,069 dengue patients, of which 0.9% died in one week after illness onset (i.e., early mortality). Case fatality rate was the highest for those aged ≥70 years. Both AST and ALT values of the fatal group were significantly higher than those of the survivor group from Day 3 (AST median, 624 U/L vs. 60 U/L, p < 0.001; ALT median, 116 U/L vs. 29 U/L, p = 0.01) of illness onset and peaked on Day 6 (AST median, 9805 U/L vs. 90 U/L, p < 0.001; ALT median, 1504 U/L vs. 49 U/L, p < 0.001). AST ≥ 203 U/L, ALT ≥ 55 U/L, AST2/ALT criteria ≥337.35, or AST/platelet count ratio index (APRI) ≥ 19.18 on Day 3 of dengue infection had a high true positive rate, 90%, 78%, 100%, or 100%, respectively, of early mortality. The platelet counts of the fatal group declined significantly than those of the survivor group since Day 3 of illness onset (median, 19 x103/μl vs. 91 x103/μl, p < 0.01), and aPTT values of the fatal group significantly prolonged longer since Day 5 (median, 68.7 seconds vs. 40.1 seconds, p < 0.001).

Conclusions

AST, ALT, and platelet counts should be monitored closely from Day 0 to Day 3 of dengue infection, and aPTT be followed up on Day 5 of infection to identify the individuals at risk for early mortality.

Modelling exposure heterogeneity and density dependence in onchocerciasis using a novel individual-based transmission model, EPIONCHO-IBM: Implications for elimination and data needs

PLoS Neglected Tropical Diseases News - 5 December 2019 - 10:00pm

by Jonathan I. D. Hamley, Philip Milton, Martin Walker, Maria-Gloria Basáñez

Background

Density dependence in helminth establishment and heterogeneity in exposure to infection are known to drive resilience to interventions based on mass drug administration (MDA). However, the interaction between these processes is poorly understood. We developed a novel individual-based model for onchocerciasis transmission, EPIONCHO-IBM, which accounts for both processes. We fit the model to pre-intervention epidemiological data and explore parasite dynamics during MDA with ivermectin.

Methodology/Principal findings

Density dependence and heterogeneity in exposure to blackfly (vector) bites were estimated by fitting the model to matched pre-intervention microfilarial prevalence, microfilarial intensity and vector biting rate data from savannah areas of Cameroon and Côte d’Ivoire/Burkina Faso using Latin hypercube sampling. Transmission dynamics during 25 years of annual and biannual ivermectin MDA were investigated. Density dependence in parasite establishment within humans was estimated for different levels of (fixed) exposure heterogeneity to understand how parametric uncertainty may influence treatment dynamics. Stronger overdispersion in exposure to blackfly bites results in the estimation of stronger density-dependent parasite establishment within humans, consequently increasing resilience to MDA. For all levels of exposure heterogeneity tested, the model predicts a departure from the functional forms for density dependence assumed in the deterministic version of the model.

Conclusions/Significance

This is the first, stochastic model of onchocerciasis, that accounts for and estimates density-dependent parasite establishment in humans alongside exposure heterogeneity. Capturing the interaction between these processes is fundamental to our understanding of resilience to MDA interventions. Given that uncertainty in these processes results in very different treatment dynamics, collecting data on exposure heterogeneity would be essential for improving model predictions during MDA. We discuss possible ways in which such data may be collected as well as the importance of better understanding the effects of immunological responses on establishing parasites prior to and during ivermectin treatment.

Severe leptospirosis in tropical Australia: Optimising intensive care unit management to reduce mortality

PLoS Neglected Tropical Diseases News - 2 December 2019 - 10:00pm

by Simon Smith, Yu-Hsuan Liu, Angus Carter, Brendan J. Kennedy, Alexis Dermedgoglou, Suzanne S. Poulgrain, Matthew P. Paavola, Tarryn L. Minto, Michael Luc, Josh Hanson

Background

Severe leptospirosis can have a case-fatality rate of over 50%, even with intensive care unit (ICU) support. Multiple strategies–including protective ventilation and early renal replacement therapy (RRT)–have been recommended to improve outcomes. However, management guidelines vary widely around the world and there is no consensus on the optimal approach.

Methodology/Principal findings

All cases of leptospirosis admitted to the ICU of Cairns Hospital in tropical Australia between 1998 and 2018 were retrospectively reviewed. The patients’ demographics, presentation, management and clinical course were examined. The 55 patients’ median (interquartile range (IQR)) age was 47 (32–62) years and their median (IQR) APACHE III score was 67 (48–105). All 55 received appropriate antibiotic therapy, 45 (82%) within the first 6 hours. Acute kidney injury was present in 48/55 (87%), 18/55 (33%) required RRT, although this was usually not administered until traditional criteria for initiation were met. Moderate to severe acute respiratory distress syndrome developed in 37/55 (67%), 32/55 (58%) had pulmonary haemorrhage, and mechanical ventilation was required in 27/55 (49%). Vasopressor support was necessary in 34/55 (62%). Corticosteroids were prescribed in 20/55 (36%). The median (IQR) fluid balance in the initial three days of ICU care was +1493 (175–3567) ml. Only 2/55 (4%) died, both were elderly men with multiple comorbidities.

Conclusion

In patients with severe leptospirosis in tropical Australia, prompt ICU support that includes early antibiotics, protective ventilation strategies, conservative fluid resuscitation, traditional thresholds for RRT initiation and corticosteroid therapy is associated with a very low case-fatality rate. Prospective studies are required to establish the relative contributions of each of these interventions to optimal patient outcomes.

Mapping the global distribution of podoconiosis: Applying an evidence consensus approach

PLoS Neglected Tropical Diseases News - 2 December 2019 - 10:00pm

by Kebede Deribe, Hope Simpson, Jorge Cano, David M. Pigott, Nicole Davis Weaver, Elizabeth A. Cromwell, Oliver J. Brady, Rachel L. Pullan, Abdisalan M. Noor, Daniel Argaw, Christopher J. L. Murray, Simon J. Brooker, Simon I. Hay, Melanie J. Newport, Gail Davey

Background

Podoconiosis is a type of elephantiasis characterised by swelling of the lower legs. It is often confused with other causes of tropical lymphedema and its global distribution is uncertain. Here we synthesise the available information on the presence of podoconiosis to produce evidence consensus maps of its global geographical distribution.

Methods and findings

We systematically searched available data on podoconiosis in SCOPUS and MEDLINE from inception, updated to 10 May, 2019, and identified observational and population-based studies reporting podoconiosis. To establish existence of podoconiosis, we used the number of cases reported in studies and prevalence data with geographical locations. We then developed an index to assess evidence quality and reliability, assigning each country an evidence consensus score. Using these summary scores, we then developed a contemporary global map of national-level podoconiosis status.There is evidence of podoconiosis in 17 countries (12 in Africa, three in Latin America, and two in Asia) and consensus on presence in six countries (all in Africa). We have identified countries where surveillance is required to further define the presence or absence of podoconiosis. We have highlighted areas where evidence is currently insufficient or conflicting, and from which more evidence is needed.

Conclusion

The global distribution of podoconiosis is not clearly known; the disease extent and limits provided here inform the best contemporary map of the distribution of podoconiosis globally from available data. These results help identify surveillance needs, direct future mapping activities, and inform prevention plans and burden estimation of podoconiosis.

Polymorphism analyses and protein modelling inform on functional specialization of <i>Piwi</i> clade genes in the arboviral vector <i>Aedes albopictus</i>

PLoS Neglected Tropical Diseases News - 2 December 2019 - 10:00pm

by Michele Marconcini, Luis Hernandez, Giuseppe Iovino, Vincent Houé, Federica Valerio, Umberto Palatini, Elisa Pischedda, Jacob E. Crawford, Bradley J. White, Teresa Lin, Rebeca Carballar-Lejarazu, Lino Ometto, Federico Forneris, Anna-Bella Failloux, Mariangela Bonizzoni

Current knowledge of the piRNA pathway is based mainly on studies on Drosophila melanogaster where three proteins of the Piwi subclade of the Argonaute family interact with PIWI-interacting RNAs to silence transposable elements in gonadal tissues. In mosquito species that transmit epidemic arboviruses such as dengue and chikungunya viruses, Piwi clade genes underwent expansion, are also expressed in the soma and cross-talk with proteins of recognized antiviral function cannot be excluded for some Piwi proteins. These observations underscore the importance of expanding our knowledge of the piRNA pathway beyond the model organism D. melanogaster. Here we focus on the emerging arboviral vector Aedes albopictus and we couple traditional approaches of expression and adaptive evolution analyses with most current computational predictions of protein structure to study evolutionary divergence among Piwi clade proteins. Superposition of protein homology models indicate possible high structure similarity among all Piwi proteins, with high levels of amino acid conservation in the inner regions devoted to RNA binding. On the contrary, solvent-exposed surfaces showed low conservation, with several sites under positive selection. Analysis of the expression profiles of Piwi transcripts during mosquito development and following infection with Dengue serotype 1 or Chikungunya viruses showed a concerted elicitation of all Piwi transcripts during viral dissemination of dengue viruses while maintenance of infection relied on expression of primarily Piwi5. Opposite, establishment of persistent infection by Chikungunya virus is accompanied by increased expression of all Piwi genes, particularly Piwi4 and, again, Piwi5. Overall these results are consistent with functional specialization and a general antiviral role for Piwi5. Experimental evidences of sites under positive selection in Piwi1-3, Piwi4 and Piwi6, that have complex expression profiles, provide useful knowledge to design tailored functional experiments.

Serotype distribution and antimicrobial resistance of human <i>Salmonella enterica</i> in Bangui, Central African Republic, from 2004 to 2013

PLoS Neglected Tropical Diseases News - 2 December 2019 - 10:00pm

by Sebastien Breurec, Yann Reynaud, Thierry Frank, Alain Farra, Geoffroy Costilhes, François-Xavier Weill, Simon Le Hello

Background

Limited epidemiological and antimicrobial resistance data are available on Salmonella enterica from sub-Saharan Africa. We determine the prevalence of resistance to antibiotics in isolates in the Central African Republic (CAR) between 2004 and 2013 and the genetic basis for resistance to third-generation cephalosporin (C3G).

Methodology/Principal findings

A total of 582 non-duplicate human clinical isolates were collected. The most common serotype was Typhimurium (n = 180, 31% of the isolates). A randomly selected subset of S. Typhimurium isolates were subtyped by clustered regularly interspaced short palindromic repeat polymorphism (CRISPOL) typing. All but one invasive isolate tested (66/68, 96%) were associated with sequence type 313. Overall, the rates of resistance were high to traditional first-line drugs (18–40%) but low to many other antimicrobials, including fluoroquinolones (one resistant isolate) and C3G (only one ESBL-producing isolate). The extended-spectrum beta-lactamase (ESBL)-producing isolate and three additional ESBL isolates from West Africa were studied by whole genome sequencing. The blaCTX-M-15 gene and the majority of antimicrobial resistance genes found in the ESBL isolate were present in a large conjugative IncHI2 plasmid highly similar (> 99% nucleotide identity) to ESBL-carrying plasmids found in Kenya (S. Typhimurium ST313) and also in West Africa (serotypes Grumpensis, Havana, Telelkebir and Typhimurium).

Conclusions/Significance

Although the prevalence of ESBL-producing Salmonella isolates was low in CAR, we found that a single IncHI2 plasmid-carrying blaCTX-M-15 was widespread among Salmonella serotypes from sub-Saharan Africa, which is of concern.

Spatio-temporal patterns of scrub typhus in mainland China, 2006-2017

PLoS Neglected Tropical Diseases News - 2 December 2019 - 10:00pm

by Yujuan Yue, Dongsheng Ren, Xiaobo Liu, Yujiao Wang, Qiyong Liu, Guichang Li

Background

Scrub typhus, a serious public health problem in the Asia-Pacific area, is endemic in the “tsutsugamushi triangle” area. Scrub typhus has been widespread and has become a significant health concern in China. However, spatiotemporal patterns need to be investigated further.

Objective

This study aims to explore spatiotemporal patterns, diffusion characteristics and regional distribution differences of scrub typhus cases in mainland China from January 2006 to December 2017.

Method

Monthly cases of scrub typhus reported at the county level during 2006–2017 were obtained. Time-series analyses, spatial distribution analyses, spatial diffusion analyses, spatial autocorrelation analyses and space-time scan statistic analyses were used to explore spatiotemporal characteristics of scrub typhus.

Results

A total of 121 251 scrub typhus cases were reported in 30 provinces (or municipalities) of mainland China during 2006–2017, which rose exponentially. There were seasonal characteristics from June to November for scrub typhus. Scrub typhus had been diffused from south, southwest, southeast and eastern coasts to center, north, northeast and northwest in mainland China. Scrub typhus occurrences were from point to surrounding regions, and from south to north every year. The peak periods of scrub typhus became longer and longer from north to southwest to south in mainland China. There existed a single peak in Southwest region and North region, respectively, but existed a bimodal peak for South region. Scrub typhus cases were clustered in Yunnan, Guangdong, Guangxi, Fujian and Anhui among June to November. The scrub typhus epidemics in Guangdong and Yunnan were the most serious.

Conclusions

The results in this study can be guide targeted public health interventions against scrub typhus at the county level.

Estimating snakebite incidence from mathematical models: A test in Costa Rica

PLoS Neglected Tropical Diseases News - 2 December 2019 - 10:00pm

by Carlos A. Bravo-Vega, Juan M. Cordovez, Camila Renjifo-Ibáñez, Mauricio Santos-Vega, Mahmood Sasa

Background

Snakebite envenoming is a neglected public health challenge that affects mostly economically deprived communities who inhabit tropical regions. In these regions, snakebite incidence data is not always reliable, and access to health care is scare and heterogeneous. Thus, addressing the problem of snakebite effectively requires an understanding of how spatial heterogeneity in snakebite is associated with human demographics and snakes’ distribution. Here, we use a mathematical model to address the determinants of spatial heterogeneity in snakebite and we estimate snakebite incidence in a tropical country such as Costa Rica.

Methods and findings

We combined a mathematical model that follows the law of mass action, where the incidence is proportional to the exposed human population and the venomous snake population, with a spatiotemporal dataset of snakebite incidence (Data from year 1990 to 2007 for 193 districts) in Costa Rica. This country harbors one of the most dangerous venomous snakes, which is the Terciopelo (Bothrops asper, Garman, 1884). We estimated B. asper distribution using a maximum entropy algorithm, and its abundance was estimated based on field data. Then, the model was adjusted to the data using a lineal regression with the reported incidence. We found a significant positive correlation (R2 = 0.66, p-value < 0.01) between our estimation and the reported incidence, suggesting the model has a good performance in estimating snakebite incidence.

Conclusions

Our model underscores the importance of the synergistic effect of exposed population size and snake abundance on snakebite incidence. By combining information from venomous snakes’ natural history with census data from rural populations, we were able to estimate snakebite incidence in Costa Rica. The model was able to fit the incidence data at fine administrative scale (district level), which is fundamental for the implementation and planning of management strategies oriented to reduce snakebite burden.

A TGF-β type II receptor that associates with developmental transition in <i>Haemonchus contortus</i> in vitro

PLoS Neglected Tropical Diseases News - 2 December 2019 - 10:00pm

by Li He, Robin B. Gasser, Tingting Li, Wenda Di, Fangfang Li, Hongrun Zhang, Caixian Zhou, Rui Fang, Min Hu

Background

The TGF-β signalling pathway plays a key role in regulating dauer formation in the free-living nematode Caenorhabditis elegans, and previous work has shown that TGF-β receptors are involved in parasitic nematodes. Here, we explored the structure and function of a TGF-β type II receptor homologue in the TGF-β signalling pathway in Haemonchus contortus, a highly pathogenic, haematophagous parasitic nematode.

Methodology/Principal findings

Amino acid sequence and phylogenetic analyses revealed that the protein, called Hc-TGFBR2 (encoded by the gene Hc-tgfbr2), is a member of TGF-β II receptor family and contains conserved functional domains, both in the extracellular region containing cysteine residues that form a characteristic feature (CXCX4C) of TGF-β II receptors, and in the intracellular regions containing a serine/threonine kinase domain. The Hc-tgfbr2 gene was transcribed in all key developmental stages of H. contortus, with particularly high levels in the infective, third-stage larvae (L3s) and male adults. Immunohistochemical results revealed that Hc-TGFBR2 was expressed in the intestine, ovary and eggs within the uterus of female adults, and also in the testes of male adults of H. contortus. Double-stranded RNA interference (RNAi) in this nematode by soaking induced a marked decrease in transcription of Hc-tgfbr2 and in development from the exsheathed L3 to the fourth-stage larva (L4) in vitro.

Conclusions/Significance

These results indicate that Hc-TGFBR2 plays an important role in governing developmental processes in H. contortus via the TGF-β signalling pathway, particularly in the transition from the free-living to the parasitic stages.

Volatile metabolomic signatures of rabies immunization in two mesocarnivore species

PLoS Neglected Tropical Diseases News - 2 December 2019 - 10:00pm

by Bruce A. Kimball, Steven F. Volker, Doreen L. Griffin, Shylo R. Johnson, Amy T. Gilbert

Rabies is a zoonotic disease caused by infection with rabies virus, which circulates naturally in several wild carnivore and bat reservoirs in the United States (US). The most important reservoir in the US from an animal and public health perspective is the raccoon (Procyon lotor). To prevent the westward expansion of a significant raccoon rabies epizootic along the eastern seaboard, an operational control program implementing oral rabies vaccination (ORV) has existed in the US since the 1990s. Recently, two vaccine efficacy studies conducted with raccoons and striped skunks (Mephitis mephitis) provided the opportunity to determine if volatile fecal metabolites might be used to non-invasively monitor ORV programs and/or predict virus protection for these species. The volatile metabolome is a rich source of information that may significantly contribute to our understanding of disease and infection. Fecal samples were collected at multiple time points from raccoons and striped skunks subjected to oral treatment with rabies vaccine (or sham). Intramuscular challenge with a lethal dose of rabies virus was used to determine protection status at six (raccoons) and 11 (skunks) months post-vaccination. In addition to fecal samples, blood was collected at various time points to permit quantitative assessment of rabies antibody responses arising from immunization. Feces were analyzed by headspace gas chromatography with mass spectrometric detection and the chromatographic responses were grouped according to cluster analysis. Cluster scores were subjected to multivariate analyses of variance (MANOVA) to determine if fecal volatiles may hold a signal of immunization status. Multiple regression was then used to build models of the measured immune responses based on the metabolomic data. MANOVA results identified one cluster associated with protective status of skunks and one cluster associated with protective status of raccoons. Regression models demonstrated considerably greater success in predicting rabies antibody responses in both species. This is the first study to link volatile compounds with measures of adaptive immunity and provides further evidence that the volatile metabolome holds great promise for contributing to our understanding of disease and infections. The volatile metabolome may be an important resource for monitoring rabies immunization in raccoons and striped skunks.

In-depth comparison of cell-based methodological approaches to determine drug susceptibility of visceral <i>Leishmania</i> isolates

PLoS Neglected Tropical Diseases News - 2 December 2019 - 10:00pm

by Sarah Hendrickx, Lieselotte Van Bockstal, Guy Caljon, Louis Maes

Monitoring the drug susceptibility of Leishmania isolates still largely relies on standard in vitro cell-based susceptibility assays using (patient-isolated) promastigotes for infection. Although this assay is widely used, no fully standardized/harmonized protocol is yet available hence resulting in the application of a wide variety of host cells (primary cells and cell lines), different drug exposure times, detection methods and endpoint criteria. Advocacy for standardization to decrease inter-laboratory variation and improve interpretation of results has already repeatedly been made, unfortunately still with unsatisfactory progress. As a logical next step, it would be useful to reach at least some agreement on the type of host cell and basic experimental design for routine amastigote susceptibility determination. The present laboratory study using different L. infantum strains as a model for visceral leishmaniasis species compared primary cells (mouse peritoneal exudate (PEC), mouse bone marrow derived macrophages and human peripheral blood monocyte derived macrophages) and commercially available cell lines (THP-1, J774, RAW) for either their susceptibility to infection, their role in supporting intracellular amastigote multiplication and overall feasibility/accessibility of experimental assay protocol. The major findings were that primary cells are better than cell lines in supporting infection and intracellular parasite multiplication, with PECs to be preferred for technical reasons. Cell lines require drug exposure of >96h with THP-1 to be preferred but subject to a variable response to PMA stimulation. The fast dividing J774 and RAW cells out-compete parasite-infected cells precluding proper assay read-out. Some findings could possibly also be applicable to cutaneous Leishmania strains, but this still needs cross-checking. Besides inherent limitations in a clinical setting, susceptibility testing of clinical isolates may remain problematic because of the reliance on patient-derived promastigotes which may exhibit variable degrees of metacyclogenesis and infectivity.

CRISPR/Cas9-mediated gene deletion of the <i>ompA</i> gene in symbiotic <i>Cedecea neteri</i> impairs biofilm formation and reduces gut colonization of <i>Aedes aegypti</i> mosquitoes

PLoS Neglected Tropical Diseases News - 2 December 2019 - 10:00pm

by Shivanand Hegde, Pornjarim Nilyanimit, Elena Kozlova, Enyia R. Anderson, Hema P. Narra, Sanjeev K. Sahni, Eva Heinz, Grant L. Hughes

Background

Symbiotic bacteria are pervasive in mosquitoes and their presence can influence many host phenotypes that affect vectoral capacity. While it is evident that environmental and host genetic factors contribute in shaping the microbiome of mosquitoes, we have a poor understanding regarding how bacterial genetics affects colonization of the mosquito gut. The CRISPR/Cas9 gene editing system is a powerful tool to alter bacterial genomes facilitating investigations into host-microbe interactions but has yet to be applied to insect symbionts.

Methodology/Principal findings

To investigate the role of bacterial genetic factors in mosquito biology and in colonization of mosquitoes we used CRISPR/Cas9 gene editing system to mutate the outer membrane protein A (ompA) gene of a Cedecea neteri symbiont isolated from Aedes mosquitoes. The ompA mutant had an impaired ability to form biofilms and poorly infected Ae. aegypti when reared in a mono-association under gnotobiotic conditions. In adult mosquitoes, the mutant had a significantly reduced infection prevalence compared to the wild type or complement strains, while no differences in prevalence were seen in larvae, suggesting genetic factors are particularly important for adult gut colonization. We also used the CRISPR/Cas9 system to integrate genes (antibiotic resistance and fluorescent markers) into the symbionts genome and demonstrated that these genes were functional in vitro and in vivo.

Conclusions/Significance

Our results shed insights into the role of ompA gene in host-microbe interactions in Ae. aegypti and confirm that CRISPR/Cas9 gene editing can be employed for genetic manipulation of non-model gut microbes. The ability to use this technology for site-specific integration of genes into the symbiont will facilitate the development of paratransgenic control strategies to interfere with arboviral pathogens such Chikungunya, dengue, Zika and Yellow fever viruses transmitted by Aedes mosquitoes.

Determining the post-elimination level of vaccination needed to prevent re-establishment of dog rabies

PLoS Neglected Tropical Diseases News - 2 December 2019 - 10:00pm

by Seonghye Jeon, Julie Cleaton, Martin I. Meltzer, Emily B. Kahn, Emily G. Pieracci, Jesse D. Blanton, Ryan Wallace

Background

Once a canine rabies-free status has been achieved, there is little guidance available on vaccination standards to maintain that status. In areas with risk of reintroduction, it may be practical to continue vaccinating portions of susceptible dogs to prevent re-establishment of canine rabies.

Methods

We used a modified version of RabiesEcon, a deterministic mathematical model, to evaluate the potential impacts and cost-effectiveness of preventing the reintroduction of canine rabies through proactive dog vaccination. We analyzed four scenarios to simulate varying risk levels involving the reintroduction of canine rabies into an area where it is no longer present. In a sensitivity analysis, we examined the influences of reintroduction frequency and intensity, the density of susceptible dog population, dog birth rate, dog life expectancy, vaccine efficacy, rate of loss of vaccine immunity, and the basic reproduction number (R0).

Results

To prevent the re-establishment of canine rabies, it is necessary to vaccinate 38% to 56% of free-roaming dogs that have no immunity to rabies. These coverage levels were most sensitive to adjustments in R0 followed by the vaccine efficacy and the rate of loss of vaccine immunity. Among the various preventive vaccination strategies, it was most cost-effective to continue dog vaccination at the minimum coverage required, with the average cost per human death averted ranging from $257 to $398 USD.

Conclusions

Without strong surveillance systems, rabies-free countries are vulnerable to becoming endemic when incursions happen. To prevent this, it may be necessary to vaccinate at least 38% to 56% of the susceptible dog population depending on the risk of reintroduction and transmission dynamics.

<i>Leptospira interrogans</i> in mammals in Lviv Oblast, Ukraine, 2001-2015

PLoS Neglected Tropical Diseases News - 2 December 2019 - 10:00pm

by Olena Zubach, Oksana Semenyshyn, Lesya Hatsji, Mykhaylo Demchyshyn, Aleksander Zinchuk

This study describes changes in the prevalence of Leptospira interrogans infections among small mammals, including rats and larger domestic and wild mammals in Lviv Oblast, a region in western Ukraine from 2001–2015, using the microscopic agglutination test (MAT). A total of 439,948 domestic or wild animals were tested. We found the prevalence of Leptospira interrogans exposure varied among tested species and changed over the time. Infection was significantly less common in domestic animals, than in wild rodents. In swine the overall seroprevalence was 0.51%, while in cattle it was 0.19%. In dogs it was higher—2.75%. After 2006, evidence of infection was only observed in swine among domestic animals. The prevalence among large wild animals (0.25%) was similar to that among domestic animals. Among small mammals and rats, seroprevalence was most commonly observed among Rattus norvegicus (18.44%) and it was less common among other wild small mammals (8.74%). There were two dominant serogroups among large wild and domestic animals–L. icterohaemorrhagiae and L. hebdomadis while among wild small mammals the two most common were L. icterohaemorrhagiae and L. grippotyphosa. Wild animals with antibodies were found throughout the entire oblast.

Vaccination against the digestive enzyme Cathepsin B using a YS1646 <i>Salmonella enterica</i> Typhimurium vector provides almost complete protection against <i>Schistosoma mansoni</i> challenge in a mouse model

PLoS Neglected Tropical Diseases News - 2 December 2019 - 10:00pm

by Adam S. Hassan, Nicholas H. Zelt, Dilhan J. Perera, Momar Ndao, Brian J. Ward

Schistosoma mansoni threatens hundreds of millions of people in >50 countries. Schistosomulae migrate through the lung and adult worms reside in blood vessels adjacent to the intestinal mucosa. Current candidate vaccines aren’t designed to elicit a mucosal response. We have repurposed an attenuated Salmonella enterica Typhimurium strain (YS1646) to produce such a vaccine targeting Cathepsin B (CatB), a digestive enzyme important for parasite survival. Promoter-Type 3 secretory signal pairs were screened for protein expression in vitro and transfected into YS1646 to generate candidate vaccine strains. Two strains were selected for in vivo evaluation (nirB_SspH1 and SspH1_SspH1). Female C57BL/6 mice were immunized twice, 3 weeks apart, using six strategies: i) saline gavage (control), ii) the ‘empty’ YS1646 vector orally (PO) followed by intramuscular (IM) recombinant CatB (20μg IM rCatB), iii) two doses of IM rCatB, iv) two PO doses of YS1646-CatB, v) IM rCatB then PO YS1646-CatB and vi) PO YS1646-CatB then IM rCatB. Serum IgG responses to CatB were monitored by ELISA. Three weeks after the second dose, mice were challenged with 150 cercariae and sacrificed 7 weeks later to assess adult worm and egg burden (liver and intestine), granuloma size and egg morphology. CatB-specific IgG antibodies were low/absent in the control and PO only groups but rose substantially in other groups (5898-6766ng/mL). The highest response was in animals that received nirB_SspH1 YS1646 PO then IM rCatB. In this group, reductions in worm and intestine/liver egg burden (vs. control) were 93.1% and 79.5%/90.3% respectively (all P < .0001). Granuloma size was reduced in all vaccinated groups (range 32.86–52.83 x103μm2) and most significantly in the nirB_SspH1 + CatB IM group (34.74±3.35 x103μm2vs. 62.22±6.08 x103μm2: vs. control P < .01). Many eggs in the vaccinated animals had abnormal morphology. Targeting CatB using a multi-modality approach can provide almost complete protection against S. mansoni challenge.

How community engagement strategies shape participation in mass drug administration programmes for lymphatic filariasis: The case of Luangwa District, Zambia

PLoS Neglected Tropical Diseases News - 27 November 2019 - 10:00pm

by Adam Silumbwe, Hikabasa Halwindi, Joseph Mumba Zulu

Background

The success of the global strategy to eliminate lymphatic filariasis (LF) through mass drug administration (MDA) campaigns is dependent on meeting high coverage levels over long periods of time. Community engagement plays a critical role in driving coverage and involvement of local communities in MDA for LF. This study explored how community engagement approaches used in MDA for LF shape participation in the programme, with a view of proposing effective engagement strategies.

Methods

The study was conducted in Luangwa, a rural District of Lusaka province, Zambia. An exploratory qualitative case study approach was employed. A total of nine focus group discussions, six in-depth and seven key informant interviews were conducted with various participants that included; community members, traditional leaders and programme managers, respectively. Data were analysed using a thematic approach, aided by NVivo 10 software.

Results

Three core thematic areas emerged from the data as priority focus areas for programme planners and implementers in designing effective community engagement strategies that facilitate participation. Firstly, employing of partnership approaches through adequate and timely engagement of traditional, government and non-governmental organisation structures. Secondly, use of appropriate and innovative health education initiatives to disseminate information about the programme. Thirdly, addressing context specific programme implementation barriers affecting community engagement in MDA for LF.

Conclusion

Facilitating participation in MDA for LF will require designing and implementing effective community engagement strategies that take into account local context, but also seek to explore all avenues of maximizing participation for improved coverage levels. MDA for LF implementation teams should systematically consider the identified factors and seek to incorporate them in their implementation plans.

Comparative analysis of small RNAs released by the filarial nematode <i>Litomosoides sigmodontis in vitro</i> and <i>in vivo</i>

PLoS Neglected Tropical Diseases News - 26 November 2019 - 10:00pm

by Juan F. Quintana, Sujai Kumar, Alasdair Ivens, Franklin W. N. Chow, Anna M. Hoy, Alison Fulton, Paul Dickinson, Coralie Martin, Matthew Taylor, Simon A. Babayan, Amy H. Buck

Background

The release of small non-coding RNAs (sRNAs) has been reported in parasitic nematodes, trematodes and cestodes of medical and veterinary importance. However, little is known regarding the diversity and composition of sRNAs released by different lifecycle stages and the portion of sRNAs that persist in host tissues during filarial infection. This information is relevant to understanding potential roles of sRNAs in parasite-to-host communication, as well as to inform on the location within the host and time point at which they can be detected.

Methodology & Principal findings

We have used small RNA (sRNA) sequencing analysis to identify sRNAs in replicate samples of the excretory-secretory (ES) products of developmental stages of the filarial nematode Litomosoides sigmodontis in vitro and compare this to the parasite-derived sRNA detected in host tissues. We show that all L. sigmodontis developmental stages release RNAs in vitro, including ribosomal RNA fragments, 5’-derived tRNA fragments (5’-tRFs) and, to a lesser extent, microRNAs (miRNAs). The gravid adult females (gAF) produce the largest diversity and abundance of miRNAs in the ES compared to the adult males or microfilariae. Analysis of sRNAs detected in serum and macrophages from infected animals reveals that parasite miRNAs are preferentially detected in vivo, compared to their low levels in the ES products, and identifies miR-92-3p and miR-71-5p as L. sigmodontis miRNAs that are stably detected in host cells in vivo.

Conclusions

Our results suggest that gravid adult female worms secrete the largest diversity of extracellular sRNAs compared to adult males or microfilariae. We further show differences in the parasite sRNA biotype distribution detected in vitro versus in vivo. We identify macrophages as one reservoir for parasite sRNA during infection, and confirm the presence of parasite miRNAs and tRNAs in host serum during patent infection.

Urban livestock-keeping and dengue in urban and peri-urban Hanoi, Vietnam

PLoS Neglected Tropical Diseases News - 26 November 2019 - 10:00pm

by Frida Jakobsen, Thang Nguyen-Tien, Long Pham- Thanh, Vuong Nghia Bui, Hung Nguyen-Viet, Son Tran- Hai, Åke Lundkvist, Anh Bui- Ngoc, Johanna F. Lindahl

Urban livestock provides an important source of food and income, but it may increase the risks for disease transmission. Vectors, such as mosquitoes, might increase and thereby cause an enhanced transmission of infectious diseases, such as dengue fever; considered the most important mosquito-borne viral disease globally. This cross-sectional study evaluated the awareness of dengue fever and investigated how the presence of dengue vectors is affected by the keeping of livestock in urban households in the city of Hanoi, Vietnam. From February to March 2018, during the season of lowest occurrence of dengue in Hanoi, 140 households were interviewed, of which 69 kept livestock. A general trend was observed; respondents living in the Dan Phuong district, a peri-urban district, had better knowledge and practice regarding dengue as compared to the urban Ha Dong district. In total, 3899 mosquitoes were collected and identified, of which 52 (1.33%) were Aedes species. A significant difference between the two districts was observed, with more households in Ha Dong having Aedes spp. mosquitoes (p = 0.02) and a higher incidence of dengue fever (p = 0.001). There was no significant association between livestock-rearing and the presence of Aedes spp. mosquitoes (p = 0.955), or between livestock-rearing and the incidence of dengue fever (p = 0.08). In conclusion, this study could not find any indication that households keeping livestock were at higher risk of dengue virus infections in Hanoi during the season of lowest occurrence of dengue, but clearly indicated the need of more information provided to urban inhabitants, particularly on personal protection.

Comorbidity associated to <i>Ascaris suum</i> infection during pulmonary fibrosis exacerbates chronic lung and liver inflammation and dysfunction but not affect the parasite cycle in mice

PLoS Neglected Tropical Diseases News - 25 November 2019 - 10:00pm

by Fabrício Marcus Silva Oliveira, Pablo Hemanoel da Paixão Matias, Lucas Kraemer, Ana Clara Gazzinelli-Guimarães, Flaviane Vieira Santos, Chiara Cássia Oliveira Amorim, Denise Silva Nogueira, Camila Simões Freitas, Marcelo Vidigal Caliari, Daniella Castanheira Bartholomeu, Lilian Lacerda Bueno, Remo Castro Russo, Ricardo Toshio Fujiwara

Ascariasis is considered the most neglected tropical disease, and is a major problem for the public health system. However, idiopathic pulmonary fibrosis (IPF) is a result of chronic extracellular deposition of matrix in the pulmonary parenchyma, and thickening of the alveolar septa, which reduces alveolar gas exchange. Considering the high rates of ascariasis and pulmonary fibrosis, we believe that these two diseases may co-exist and possibly lead to comorbidities. We therefore investigated the mechanisms involved in comorbidity of Ascaris suum (A. suum) infection, which could interfere with the progression of pulmonary fibrosis. In addition, we evaluated whether a previous lung fibrosis could interfere with the pulmonary cycle of A. suum in mice. The most important findings related to comorbidity in which A. suum infection exacerbated pulmonary and liver injury, inflammation and dysfunction, but did not promote excessive fibrosis in mice during the investigated comorbidity period. Interestingly, we found that pulmonary fibrosis did not alter the parasite cycle that transmigrated preferentially through preserved but not fibrotic areas of the lungs. Collectively, our results demonstrate that A. suum infection leads to comorbidity, and contributes to the aggravation of pulmonary dysfunction during pulmonary fibrosis, which also leads to significant liver injury and inflammation, without changing the A. suum cycle in the lungs.

<i>Caenorhabditis elegans</i> muscle Cys-loop receptors as novel targets of terpenoids with potential anthelmintic activity

PLoS Neglected Tropical Diseases News - 25 November 2019 - 10:00pm

by Guillermina Hernando, Ornella Turani, Cecilia Bouzat

The anthelmintic treatment of nematode infections remains the pillar of worm control in both human and veterinary medicine. Since control is threatened by the appearance of drug resistant nematodes, there is a need to develop novel compounds, among which phytochemicals constitute potential anthelmintic agents. Caenorhabditis elegans has been pivotal in anthelmintic drug discovery and in revealing mechanisms of drug action and resistance. By using C. elegans, we here revealed the anthelmintic actions of three plant terpenoids -thymol, carvacrol and eugenol- at the behavioral level. Terpenoids produce a rapid paralysis of worms with a potency rank order carvacrol > thymol > eugenol. In addition to their paralyzing activity, they also inhibit egg hatching, which would, in turn, lead to a broader anthelmintic spectrum of activity. To identify drug targets, we performed an in vivo screening of selected strains carrying mutations in receptors involved in worm locomotion for determining resistance to the paralyzing effect of terpenoids. The assays revealed that two Cys-loop receptors with key roles in worm locomotion -Levamisole sensitive nicotinic receptor (L-AChR) and GABA(A) (UNC-49) receptor- are involved in the paralyzing effects of terpenoids. To decipher the mechanism by which terpenoids affect these receptors, we performed electrophysiological studies using a primary culture of C. elegans L1 muscle cells. Whole cell recordings from L1 cells demonstrated that terpenoids decrease macroscopic responses of L-AChR and UNC-49 receptor to their endogenous agonists, thus acting as inhibitors. Single-channel recordings from L-AChR revealed that terpenoids decrease the frequency of opening events, probably by acting as negative allosteric modulators. The fact that terpenoids act at different receptors may have important advantages regarding efficacy and development of resistance. Thus, our findings give support to the use of terpenoids as either an alternative or a complementary anthelmintic strategy to overcome the ever-increasing resistance of parasites to classical anthelmintic drugs.

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