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Characterization of a <i>Trichinella spiralis</i> putative serine protease. Study of its potential as sero-diagnostic tool

PLoS Neglected Tropical Diseases News - 14 May 2018 - 9:00pm

by Ge Ge Sun, Yan Yan Song, Peng Jiang, Hua Na Ren, Shu Wei Yan, Yue Han, Ruo Dan Liu, Xi Zhang, Zhong Quan Wang, Jing Cui

Background

Trichinellosis is a serious zoonositc parasitosis worldwide. Because its clinical manifestations aren’t specific, the diagnosis of trichinellosis is not easy to be made. Trichinella spiralis muscle larva (ML) excretory–secretory (ES) antigens are the most widely applied diagnostic antigens for human trichinellosis, but the major drawback of the ES antigens for assaying anti-Trichinella antibodies is the false negative in the early Trichinella infection period. The aim of this study was to characterize the T. spiralis putative serine protease (TsSP) and to investigate its potential use for diagnosis of trichinellosis.

Methodology/Principal findings

The full-length TsSP sequence was cloned and expressed, and recombinant TsSP (rTsSP) was purified by Ni-NTA-Sefinose Column. On Western blotting analysis the rTsSP was recognized by T. spiralis-infected mouse serum, and the natural TsSP was identified in T. spiralis ML crude and ES antigens by using anti-rTsSP serum. Expression of TsSP was detected at various T. spiralis developmental stages (newborn larvae, muscle larvae, intestinal infective larvae and adult worms). Immunolocalization identified the TsSP principally in cuticles and stichosomes of the nematode. The sensitivity of rTsSP-ELISA and ES-ELISA was 98.11% (52/53) and 88.68% (47/53) respectively (P > 0.05) when the sera from trichinellosis patients were examined. However, while twenty-one serum samples of trichinellosis patients’ sera at 19 days post-infection (dpi) were tested, the sensitivity (95.24%) of rTsSP-ELISA was distinctly higher than 71.43% of ES-ELISA (P < 0.05). The specificity (99.53%) of rTsSP-ELISA was remarkably higher than 91.98% of ES-ELISA (P < 0.01). Only one out of 20 serum samples of cysticercosis patients cross-reacted with the rTsSP. Specific anti-Trichinella IgG in infected mice was first detected by rTsSP-ELISA as soon as 7 dpi and antibody positive rate reached 100% on 10 dpi, whereas the ES-ELISA did not permit detection of 100% of infected mice before 16 dpi.

Conclusions

The rTsSP is a potential early diagnostic antigen for human trichinellosis.

Benzoxaborole treatment perturbs S-adenosyl-L-methionine metabolism in <i>Trypanosoma brucei</i>

PLoS Neglected Tropical Diseases News - 14 May 2018 - 9:00pm

by Pieter C. Steketee, Isabel M. Vincent, Fiona Achcar, Federica Giordani, Dong-Hyun Kim, Darren J. Creek, Yvonne Freund, Robert Jacobs, Kevin Rattigan, David Horn, Mark C. Field, Annette MacLeod, Michael P. Barrett

The parasitic protozoan Trypanosoma brucei causes Human African Trypanosomiasis and Nagana in other mammals. These diseases present a major socio-economic burden to large areas of sub-Saharan Africa. Current therapies involve complex and toxic regimens, which can lead to fatal side-effects. In addition, there is emerging evidence for drug resistance. AN5568 (SCYX-7158) is a novel benzoxaborole class compound that has been selected as a lead compound for the treatment of HAT, and has demonstrated effective clearance of both early and late stage trypanosomiasis in vivo. The compound is currently awaiting phase III clinical trials and could lead to a novel oral therapeutic for the treatment of HAT. However, the mode of action of AN5568 in T. brucei is unknown. This study aimed to investigate the mode of action of AN5568 against T. brucei, using a combination of molecular and metabolomics-based approaches.Treatment of blood-stage trypanosomes with AN5568 led to significant perturbations in parasite metabolism. In particular, elevated levels of metabolites involved in the metabolism of S-adenosyl-L-methionine, an essential methyl group donor, were found. Further comparative metabolomic analyses using an S-adenosyl-L-methionine-dependent methyltransferase inhibitor, sinefungin, showed the presence of several striking metabolic phenotypes common to both treatments. Furthermore, several metabolic changes in AN5568 treated parasites resemble those invoked in cells treated with a strong reducing agent, dithiothreitol, suggesting redox imbalances could be involved in the killing mechanism.

Impact of benznidazole treatment on the functional response of <i>Trypanosoma cruzi</i> antigen-specific CD4<sup>+</sup>CD8<sup>+</sup> T cells in chronic Chagas disease patients

PLoS Neglected Tropical Diseases News - 11 May 2018 - 9:00pm

by Elena Pérez-Antón, Adriana Egui, M. Carmen Thomas, Concepción J. Puerta, John Mario González, Adriana Cuéllar, Manuel Segovia, Manuel Carlos López

Background

Chagas disease is caused by Trypanosoma cruzi. The persistence of the parasite is associated with the disease chronicity and the impairment of the cellular immune response. It has been reported that the CD4+CD8+ T cell population expands in chronic Chagas disease patients. Few studies have focused on this subset of cells, and very little is known about the impact of antiparasitic treatment on this population.

Methodology

Thirty-eight chronic Chagas disease patients (20 asymptomatic and 18 symptomatic) and twelve healthy controls were enrolled in this study. Peripheral blood mononuclear cells were stimulated with soluble T. cruzi antigens to analyze the production of cytokines and cytotoxic molecules by CD4+CD8+ T cells before and after benznidazole treatment. Additionally, expression and co-expression of five inhibitory receptors in these patients after treatment were studied using a multiparameter flow cytometry technique.

Principal findings

The frequency of CD4+CD8+ T cells was higher in chronic Chagas disease patients compared with healthy donors. Furthermore, a higher ratio of CD4+CD8low/CD4+CD8high subpopulations was observed in chronic Chagas disease patients than in healthy donors. Additionally, CD4+CD8+ T cells from these patients expressed and co-expressed higher levels of inhibitory receptors in direct proportion to the severity of the pathology. Benznidazole treatment reduced the frequency of CD4+CD8+ T cells and decreased the ratio of CD4+CD8low/CD4+CD8high subpopulations. The co-expression level of the inhibitory receptor was reduced after treatment simultaneously with the enhancement of the multifunctional capacity of CD4+CD8+ T cells. After treatment, an increase in the frequency of T. cruzi antigen-specific CD4+CD8+ T cells expressing IL-2 and TNF-α was also observed.

Conclusions

CD4+CD8+ T cells could play an important role in the control of T. cruzi infection since they were able to produce effector molecules for parasite control. Benznidazole treatment partially reversed the exhaustion process caused by T. cruzi infection in these cells with an improvement in the functional response of the T. cruzi antigen-specific CD4+CD8+ T cells.

Atypical pharmacology of schistosome TRPA1-like ion channels

PLoS Neglected Tropical Diseases News - 10 May 2018 - 9:00pm

by Swarna Bais, Corbett T. Berry, Xiaohong Liu, Gordon Ruthel, Bruce D. Freedman, Robert M. Greenberg

Parasitic flatworms of the genus Schistosoma cause schistosomiasis, a neglected tropical disease estimated to affect over 200 million people worldwide. Praziquantel is the only antischistosomal currently available for treatment, and there is an urgent need for new therapeutics. Ion channels play key roles in physiology and are targets for many anthelmintics, yet only a few representatives have been characterized in any detail in schistosomes and other parasitic helminths. The transient receptor potential (TRP) channel superfamily comprises a diverse family of non-selective cation channels that play key roles in sensory transduction and a wide range of other functions. TRP channels fall into several subfamilies. Members of both the TRPA and TRPV subfamilies transduce nociceptive and inflammatory signals in mammals, and often also respond to chemical and thermal signals. We previously showed that although schistosomes contain no genes predicted to encode TRPV channels, TRPV1-selective activators such as capsaicin and resiniferatoxin elicit dramatic hyperactivity in adult worms and schistosomula. Surprisingly, this response requires expression of a S. mansoni TRPA1-like orthologue (SmTRPA). Here, we show that capsaicin induces a rise in intracellular Ca2+ in mammalian cells expressing either SmTRPA or a S. haematobium TRPA1 orthologue (ShTRPA). We also test SmTRPA and ShTRPA responses to various TRPV1 and TRPA1 modulators. Interestingly, in contrast to SmTRPA, ShTRPA is not activated by the TRPA1 activator AITC (allyl isothiocyanate), nor do S. haematobium adult worms respond to this compound, a potentially intriguing species difference. Notably, 4-hydroxynonenal (4-HNE), a host-derived, inflammatory product that directly activates mammalian TRPA1, also activates both SmTRPA and ShTRPA. Our results point to parasite TRPA1-like channels which exhibit atypical, mixed TRPA1/TRPV1-like pharmacology, and which may also function to transduce endogenous host signals.

Cost-benefit analysis of intervention policies for prevention and control of brucellosis in India

PLoS Neglected Tropical Diseases News - 10 May 2018 - 9:00pm

by Balbir B. Singh, Polychronis Kostoulas, Jatinder P. S. Gill, Navneet K. Dhand

Background

Brucellosis is endemic in the bovine population in India and causes a loss of US$ 3·4 billion to the livestock industry besides having a significant human health impact.

Methods

We developed a stochastic simulation model to estimate the impact of three alternative vaccination strategies on the prevalence of Brucella infection in the bovine populations in India for the next two decades: (a) annual mass vaccination only for the replacement calves and (b) vaccination of both the adult and young population at the beginning of the program followed by an annual vaccination of the replacement calves and, (c) annual mass vaccination of replacements for a decade followed by a decade of a test and slaughter strategy.

Findings

For all interventions, our results indicate that the prevalence of Brucella infection will drop below 2% in cattle and, below 3% in buffalo after 20 years of the implementation of a disease control program. For cattle, the Net Present Value (NPV) was found to be US $ 4·16 billion for intervention (a), US $ 8·31 billion for intervention (b) and, US $ 4·26 for intervention (c). For buffalo, the corresponding NPVs were US $ 8·77 billion, US $ 13·42 and, US $ 7·66, respectively. The benefit cost ratio (BCR) for the first, second and the third intervention for cattle were 7·98, 10·62 and, 3·16, respectively. Corresponding BCR estimates for buffalo were 17·81, 21·27 and, 3·79, respectively.

Conclusion

These results suggest that all interventions will be cost-effective with the intervention (b), i.e. the vaccination of replacements with mass vaccination at the beginning of the program, being the most cost-effective choice. Further, sensitivity analysis revealed that all interventions will be cost-effective even at the 50% of the current prevalence estimates. The results advocate for the implementation of a disease control program for brucellosis in India.

Disentangling complex parasite interactions: Protection against cerebral malaria by one helminth species is jeopardized by co-infection with another

PLoS Neglected Tropical Diseases News - 10 May 2018 - 9:00pm

by Jessica L. Abbate, Vanessa O. Ezenwa, Jean-François Guégan, Marc Choisy, Mathieu Nacher, Benjamin Roche

Multi-species interactions can often have non-intuitive consequences. However, the study of parasite interactions has rarely gone beyond the effects of pairwise combinations of species, and the outcomes of multi-parasite interactions are poorly understood. We investigated the effects of co-infection by four gastrointestinal helminth species on the development of cerebral malaria among Plasmodium falciparum-infected patients. We characterized associations among the helminth parasite infra-community, and then tested for independent (direct) and co-infection dependent (indirect) effects of helminths on cerebral malaria risk. We found that infection by Ascaris lumbricoides and Trichuris trichiura were both associated with direct reductions in cerebral malaria risk. However, the benefit of T. trichiura infection was halved in the presence of hookworm, revealing a strong indirect effect. Our study suggests that the outcome of interactions between two parasite species can be significantly modified by a third, emphasizing the critical role that parasite community interactions play in shaping infection outcomes.

Morbidity management and disability prevention for lymphatic filariasis in Sri Lanka: Current status and future prospects

PLoS Neglected Tropical Diseases News - 10 May 2018 - 9:00pm

by Nilmini Chandrasena, Ranjan Premaratna, Indeewarie. E. Gunaratna, Nilanthi R. de Silva

Background

Sri Lanka was acknowledged to have eliminated lymphatic filariasis (LF) as a public health problem in 2016, largely due to its success in Mass Drug Administration (MDA) to interrupt disease transmission. Analysis of the Strengths, Weaknesses, Opportunities and Threats (SWOT) of the national Morbidity Management and Disability Prevention (MMDP) program, the other pillar of the LF control program, was carried out with the objective of evaluating it and providing recommendations to optimize the use of available resources.

Methodology

A situation analysis of the MMDP activities provided by the state health sector was carried out using published records, in-depth interviews with key informants of the Anti Filariasis Campaign, site-visits to filariasis clinics with informal discussions with clinic workforce and personal communications to identify strengths and weaknesses; and opportunities to overcome weaknesses and perceived threats to the program were explored.The principal strength of the MMDP program was the filariasis clinics operational in most endemic districts of Sri Lanka, providing free health care and health education to clinic attendees. The weaknesses identified were the low accessibility of clinics, incomplete coverage of the endemic region and lack of facilities for rehabilitation. The perceived threats were diversion of staff and resources for control of other vector-borne infections, under-utilization of clinics and non-compliance with recommended treatment. Enhanced high level commitment for MMDP, wider publicity and referral systems, integration of MMDP with other disease management services and collaboration with welfare organizations and research groups were identified as opportunities to overcome weaknesses and challenges.

Conclusions

The recommended basic package of MMDP was functional in most of the LF-endemic region. The highlighted weaknesses and challenges, unless addressed, may threaten program sustainability. The identified opportunities for improvement of the programme could ensure better attainment of the goal of the MMDP program, namely access to basic care for all affected by lymphatic filarial disease.

Seasonal temperature variation influences climate suitability for dengue, chikungunya, and Zika transmission

PLoS Neglected Tropical Diseases News - 10 May 2018 - 9:00pm

by John H. Huber, Marissa L. Childs, Jamie M. Caldwell, Erin A. Mordecai

Dengue, chikungunya, and Zika virus epidemics transmitted by Aedes aegypti mosquitoes have recently (re)emerged and spread throughout the Americas, Southeast Asia, the Pacific Islands, and elsewhere. Understanding how environmental conditions affect epidemic dynamics is critical for predicting and responding to the geographic and seasonal spread of disease. Specifically, we lack a mechanistic understanding of how seasonal variation in temperature affects epidemic magnitude and duration. Here, we develop a dynamic disease transmission model for dengue virus and Aedes aegypti mosquitoes that integrates mechanistic, empirically parameterized, and independently validated mosquito and virus trait thermal responses under seasonally varying temperatures. We examine the influence of seasonal temperature mean, variation, and temperature at the start of the epidemic on disease dynamics. We find that at both constant and seasonally varying temperatures, warmer temperatures at the start of epidemics promote more rapid epidemics due to faster burnout of the susceptible population. By contrast, intermediate temperatures (24–25°C) at epidemic onset produced the largest epidemics in both constant and seasonally varying temperature regimes. When seasonal temperature variation was low, 25–35°C annual average temperatures produced the largest epidemics, but this range shifted to cooler temperatures as seasonal temperature variation increased (analogous to previous results for diurnal temperature variation). Tropical and sub-tropical cities such as Rio de Janeiro, Fortaleza, and Salvador, Brazil; Cali, Cartagena, and Barranquilla, Colombia; Delhi, India; Guangzhou, China; and Manila, Philippines have mean annual temperatures and seasonal temperature ranges that produced the largest epidemics. However, more temperate cities like Shanghai, China had high epidemic suitability because large seasonal variation offset moderate annual average temperatures. By accounting for seasonal variation in temperature, the model provides a baseline for mechanistically understanding environmental suitability for virus transmission by Aedes aegypti. Overlaying the impact of human activities and socioeconomic factors onto this mechanistic temperature-dependent framework is critical for understanding likelihood and magnitude of outbreaks.

A holistic approach to the mycetoma management

PLoS Neglected Tropical Diseases News - 10 May 2018 - 9:00pm

by Sahar Mubarak Bakhiet, Ahmed Hassan Fahal, Ahmed Mudawi Musa, El Samani Wadaa Mohamed, Rowa Fathelrahman Omer, Eiman Siddig Ahmed, Mustafa El Nour, El Rayah Mohamed Mustafa, Manar El Sheikh A. Rahman, Suliman Hussein Suliman, Mohamed A. Gadir El Mamoun, Hajo Mohamed El Amin

Mycetoma, one of the badly neglected tropical diseases, it is a localised chronic granulomatous inflammatory disease characterised by painless subcutaneous mass and formation of multiple sinuses that produce purulent discharge and grains. If untreated early and appropriately, it usually spread to affect the deep structures and bone resulting in massive damage, deformities and disabilities. It can also spread via the lymphatics and blood leading to distant secondary satellites associated with high morbidity and mortality. To date and despite progress in mycetoma research, a huge knowledge gap remains in mycetoma pathogenesis and epidemiology resulting in the lack of objective and effective control programmes. Currently, the available disease control method is early case detection and proper management. However, the majority of patients present late with immense disease and for many of them, heroic substantial deforming surgical excisions or amputation are the only prevailing treatment options. In this communication, the Mycetoma Research Center (MRC), Sudan shares its experience in implementing a new holistic approach to manage mycetoma patients locally at the village level. The MRC in collaboration with Sennar State Ministry of Health, Sudan had established a region mycetoma centre in one of the endemic mycetoma villages in the state. The patients were treated locally in that centre, the local medical and health personals were trained on early case detection and management, the local community was trained on mycetoma advocacy, and environmental conditions improvement. This comprehensive approach had also addressed the patients’ socioeconomic constraints that hinder early presentation and treatment. This approach has also included the active local health authorities, community and civil society participation and contributions to deliver the best management. This holistic approach for mycetoma patients’ management proved to be effective for early case detection and management, optimal treatment and treatment outcome and favourable disease prognosis. During the study period, the number of patients with massive lesions and the amputation rate had dropped and that had reduced the disease medical and socioeconomic burdens on patients and families.

New insights into leishmaniasis in the immunosuppressed

PLoS Neglected Tropical Diseases News - 10 May 2018 - 9:00pm

by Hannah Akuffo, Carlos Costa, Johan van Griensven, Sakib Burza, Javier Moreno, Mercè Herrero

Immunosuppression contributes significantly to the caseload of visceral leishmaniasis (VL). HIV coinfection, solid organ transplantation, malnutrition, and helminth infections are the most important immunosuppression-related factors. This review briefly describes the challenges of these associations. East Africa and the Indian subcontinent are the places where HIV imposes the highest burden in VL. In the highlands of Northern Ethiopia, migrant rural workers are at a greater risk of coinfection and malnutrition, while in India, HIV reduces the sustainability of a successful elimination programme. As shown from a longitudinal cohort in Madrid, VL is an additional threat to solid organ transplantation. The association with malnutrition is more complex since it can be both a cause and a consequence of VL. Different regimes for therapy and secondary prevention are discussed as well as the role of nutrients on the prophylaxis of VL in poverty-stricken endemic areas.

Attenuation and efficacy of live-attenuated Rift Valley fever virus vaccine candidates in non-human primates

by Darci R. Smith, Sara C. Johnston, Ashley Piper, Miriam Botto, Ginger Donnelly, Joshua Shamblin, César G. Albariño, Lisa E. Hensley, Connie Schmaljohn, Stuart T. Nichol, Brian H. Bird

Rift Valley fever virus (RVFV) is an important mosquito-borne veterinary and human pathogen that has caused large outbreaks of severe disease throughout Africa and the Arabian Peninsula. Currently, no licensed vaccine or therapeutics exists to treat this potentially deadly disease. The explosive nature of RVFV outbreaks and the severe consequences of its accidental or intentional introduction into RVFV-free areas provide the impetus for the development of novel vaccine candidates for use in both livestock and humans. Rationally designed vaccine candidates using reverse genetics have been used to develop deletion mutants of two known RVFV virulence factors, the NSs and NSm genes. These recombinant viruses were demonstrated to be protective and immunogenic in rats, mice, and sheep, without producing clinical illness in these animals. Here, we expand upon those findings and evaluate the single deletion mutant (ΔNSs rRVFV) and double deletion mutant (ΔNSs-ΔNSm rRVFV) vaccine candidates in the common marmoset (Callithrix jacchus), a non-human primate (NHP) model resembling severe human RVF disease. We demonstrate that both the ΔNSs and ΔNSs-ΔNSm rRVFV vaccine candidates were found to be safe and immunogenic in the current study. The vaccinated animals received a single dose of vaccine that led to the development of a robust antibody response. No vaccine-induced adverse reactions, signs of clinical illness or infectious virus were detected in the vaccinated marmosets. All vaccinated animals that were subsequently challenged with RVFV were protected against viremia and liver disease. In summary, our results provide the basis for further development of the ΔNSs and ΔNSs-ΔNSm rRVFV as safe and effective human RVFV vaccines for this significant public health threat.

Prevalence and risk factors for <i>Taenia solium</i> cysticercosis in school-aged children: A school based study in western Sichuan, People’s Republic of China

by John J. Openshaw, Alexis Medina, Stephen A. Felt, Tiaoying Li, Zhou Huan, Scott Rozelle, Stephen P. Luby

Background

Taenia solium cysticercosis affects millions of impoverished people worldwide and can cause neurocysticercosis, an infection of the central nervous system which is potentially fatal. Children may represent an especially vulnerable population to neurocysticercosis, due to the risk of cognitive impairment during formative school years. While previous epidemiologic studies have suggested high prevalence in rural China, the prevalence in children as well as risk factors and impact of disease in low-resource areas remain poorly characterized.

Methodology/Principal findings

Utilizing school based sampling, we conducted a cross-sectional study, administering a questionnaire and collecting blood for T. solium cysticercosis antibodies in 2867 fifth and sixth grade students across 27 schools in west Sichuan. We used mixed-effects logistic regression models controlling for school-level clustering to study associations between risk factors and to characterize factors influencing the administration of deworming medication. Overall prevalence of cysticercosis antibodies was 6%, but prevalence was significantly higher in three schools which all had prevalences of 15% or higher. Students from households owning pigs (adjusted odds ratio [OR] 1.81, 95% CI 1.08–3.03), from households reporting feeding their pigs human feces (adjusted OR 1.49, 95% CI 1.03–2.16), and self-reporting worms in their feces (adjusted OR 1.85, 95% CI 1.18–2.91) were more likely to have cysticercosis IgG antibodies. Students attending high prevalence schools were more likely to come from households allowing pigs to freely forage for food (OR 2.26, 95% CI 1.72–2.98) and lacking a toilet (OR 1.84, 95% CI 1.38–2.46). Children who were boarding at school were less likely to have received treatment for gastrointestinal worms (adjusted OR 0.58, 95% CI 0.42–0.80).

Conclusions/Significance

Our study indicates high prevalences of cysticercosis antibodies in young school aged children in rural China. While further studies to assess potential for school-based transmission are needed, school-based disease control may be an important intervention to ensure the health of vulnerable pediatric populations in T. solium endemic areas.

Correction: Participation of women and children in hunting activities in Sierra Leone and implications for control of zoonotic infections

by Jesse Bonwitt, Martin Kandeh, Michael Dawson, Rashid Ansumana, Foday Sahr, Ann H. Kelly, Hannah Brown

Knowledge, attitudes and practices (KAP) regarding leptospirosis among residents of riverside settlements of Santa Fe, Argentina

by Tamara Ricardo, Laura C. Bergero, Esteban P. Bulgarella, M. Andrea Previtali

Background

Leptospirosis is a global and re-emerging zoonotic disease caused by Leptospira spirochetes that are shed into the environment by infected animals. Humans can get infected via contact with animal hosts or contaminated environment. In Argentina, the highest annual incidences were reported in the province of Santa Fe, where epidemic outbreaks occurred during flooding events. This study examined the knowledge, attitudes and practices (KAP) regarding leptospirosis among residents of riverside slum settlements from Santa Fe after a major flood.

Methods and findings

A cross-sectional questionnaire was administered to 113 residents of 3 riverside settlements from Santa Fe. The influence of knowledge and attitudes regarding leptospirosis on the likelihood that an individual will use preventive practices were evaluated using linear mixed-effects models. The majority of respondents (83.2%) had previously heard about leptospirosis; however specific knowledge about leptospirosis was limited. The results of the modeling efforts, show that the likelihood of using preventive practices was associated with having greater knowledge score, but not with more positive attitudes. We also found that females were more likely to use safer practices than males.

Conclusions

Even though the majority of respondents had heard about leptospirosis, a high percentage of them had limited knowledge regarding the severity of the disease and its prevalence in the region. Our results suggest that public health interventions in these riverside communities should focus on educating the public on the multiple dimensions of leptospirosis in order to attain greater adherence to preventive practices instead of intending to change the perceptions or attitudes towards the disease, which did not have a significant influence. The key challenge lies in identifying effective strategies to reach the high risk group for leptospirosis here that is male fishermen, who spend most of the time in precarious campsites on the river islands.

Highly targeted cholera vaccination campaigns in urban setting are feasible: The experience in Kalemie, Democratic Republic of Congo

by Louis Albert Massing, Soumah Aboubakar, Alexandre Blake, Anne-Laure Page, Sandra Cohuet, Adalbert Ngandwe, Eric Mukomena Sompwe, Romain Ramazani, Marcela Allheimen, Philippe Levaillant, Pauline Lechevalier, Marie Kashimi, Axelle de la Motte, Arielle Calmejane, Malika Bouhenia, Ernest Dabire, Didier Bompangue, Benoit Kebela, Klaudia Porten, Francisco Luquero

Introduction

Oral cholera vaccines are primarily recommended by the World Health Organization for cholera control in endemic countries. However, the number of cholera vaccines currently produced is very limited and examples of OCV use in endemic countries, and especially in urban settings, are scarce. A vaccination campaign was organized by Médecins Sans Frontières and the Ministry of Health in a highly endemic area in the Democratic Republic of Congo. This study aims to describe the vaccine coverage achieved with this highly targeted vaccination campaign and the acceptability among the vaccinated communities.

Methods and findings

We performed a cross-sectional survey using random spatial sampling. The study population included individuals one year old and above, eligible for vaccination, and residing in the areas targeted for vaccination in the city of Kalemie. Data sources were household interviews with verification by vaccination card. In total 2,488 people were included in the survey. Overall, 81.9% (95%CI: 77.9–85.3) of the target population received at least one dose of vaccine. The vaccine coverage with two doses was 67.2% (95%CI: 61.9–72.0) among the target population. The vaccine coverage was higher during the first round (74.0, 95%CI: 69.3–78.3) than during the second round of vaccination (69.1%, 95%CI: 63.9–74.0). Vaccination coverage was lower in male adults. The main reason for non-vaccination was to be absent during the campaign. No severe adverse events were notified during the interviews.

Conclusions

Cholera vaccination campaigns using highly targeted strategies are feasible in urban settings. High vaccination coverage can be obtained using door to door vaccination. However, alternative strategies should be considered to reach non-vaccinated populations like male adults and also in order to improve the efficiency of the interventions.

The protein family TcTASV-C is a novel <i>Trypanosoma cruzi</i> virulence factor secreted in extracellular vesicles by trypomastigotes and highly expressed in bloodstream forms

by Lucas D. Caeiro, Catalina D. Alba-Soto, Mariana Rizzi, María Elisa Solana, Giselle Rodriguez, Agustina M. Chidichimo, Matías E. Rodriguez, Daniel O. Sánchez, Gabriela V. Levy, Valeria Tekiel

TcTASV-C is a protein family of about 15 members that is expressed only in the trypomastigote stage of Trypanosoma cruzi. We have previously shown that TcTASV-C is located at the parasite surface and secreted to the medium. Here we report that the expression of different TcTASV-C genes occurs simultaneously at the trypomastigote stage and while some secreted and parasite-associated products are found in both fractions, others are different. Secreted TcTASV-C are mainly shedded through trypomastigote extracellular vesicles, of which they are an abundant constituent, despite its scarce expression on culture-derived trypomastigotes. In contrast, TcTASV-C is highly expressed in bloodstream trypomastigotes; its upregulation in bloodstream parasites was observed in different T. cruzi strains and was specific for TcTASV-C, suggesting that some host-molecules trigger TcTASV-C expression. TcTASV-C is also strongly secreted by bloodstream parasites. A DNA prime—protein boost immunization scheme with TcTASV-C was only partially effective to control the infection in mice challenged with a highly virulent T. cruzi strain. Vaccination triggered a strong humoral response that delayed the appearance of bloodstream trypomastigotes at the early phase of the infection. Linear epitopes recognized by vaccinated mice were mapped within the TcTASV-C family motif, suggesting that blockade of secreted TcTASV-C impacts on the settlement of infection. Furthermore, although experimental and naturally T. cruzi-infected hosts did not react with antigens from extracellular vesicles, vaccinated and challenged mice recognized not only TcTASV-C but also other vesicle-antigens. We hypothesize that TcTASV-C is involved in the establishment of the initial T. cruzi infection in the mammalian host. Altogether, these results point towards TcTASV-C as a novel secreted virulence factor of T. cruzi trypomastigotes.

Antigen B from <i>Echinococcus granulosus</i> enters mammalian cells by endocytic pathways

by Edileuza Danieli da Silva, Martin Cancela, Karina Mariante Monteiro, Henrique Bunselmeyer Ferreira, Arnaldo Zaha

Background

Cystic hydatid disease is a zoonosis caused by the larval stage (hydatid) of Echinococcus granulosus (Cestoda, Taeniidae). The hydatid develops in the viscera of intermediate host as a unilocular structure filled by the hydatid fluid, which contains parasitic excretory/secretory products. The lipoprotein Antigen B (AgB) is the major component of E. granulosus metacestode hydatid fluid. Functionally, AgB has been implicated in immunomodulation and lipid transport. However, the mechanisms underlying AgB functions are not completely known.

Methodology/Principal findings

In this study, we investigated AgB interactions with different mammalian cell types and the pathways involved in its internalization. AgB uptake was observed in four different cell lines, NIH-3T3, A549, J774 and RH. Inhibition of caveolae/raft-mediated endocytosis causes about 50 and 69% decrease in AgB internalization by RH and A549 cells, respectively. Interestingly, AgB colocalized with the raft endocytic marker, but also showed a partial colocalization with the clathrin endocytic marker. Finally, AgB colocalized with an endolysosomal tracker, providing evidence for a possible AgB destination after endocytosis.

Conclusions/Significance

The results indicate that caveolae/raft-mediated endocytosis is the main route to AgB internalization, and that a clathrin-mediated entry may also occur at a lower frequency. A possible fate for AgB after endocytosis seems to be the endolysosomal system. Cellular internalization and further access to subcellular compartments could be a requirement for AgB functions as a lipid carrier and/or immunomodulatory molecule, contributing to create a more permissive microenvironment to metacestode development and survival.

Rift valley fever viral load correlates with the human inflammatory response and coagulation pathway abnormalities in humans with hemorrhagic manifestations

by Annabelle de St. Maurice, Jessica Harmon, Luke Nyakarahuka, Stephen Balinandi, Alex Tumusiime, Jackson Kyondo, Sophia Mulei, Annemarion Namutebi, Barbara Knust, Trevor Shoemaker, Stuart T. Nichol, Anita K. McElroy, Christina F. Spiropoulou

Rift Valley fever virus is an arbovirus that affects both livestock and humans throughout Africa and in the Middle East. Despite its endemicity throughout Africa, it is a rare event to identify an infected individual during the acute phase of the disease and an even rarer event to collect serial blood samples from the affected patient. Severely affected patients can present with hemorrhagic manifestations of disease. In this study we identified three Ugandan men with RVFV disease that was accompanied by hemorrhagic manifestations. Serial blood samples from these men were analyzed for a series of biomarkers specific for various aspects of human pathophysiology including inflammation, endothelial function and coagulopathy. There were significant differences between biomarker levels in controls and cases both early during the illness and after clearance of viremia. Positive correlation of viral load with markers of inflammation (IP-10, CRP, Eotaxin, MCP-2 and Granzyme B), markers of fibrinolysis (tPA and D-dimer), and markers of endothelial function (sICAM-1) were all noted. However, and perhaps most interesting given the fact that these individuals exhibited hemorrhagic manifestations of disease, was the finding of a negative correlation between viral load and P-selectin, ADAMTS13, and fibrinogen all of which are associated with coagulation pathways occurring on the endothelial surface.

A research agenda to reinforce rabies control: A qualitative and quantitative prioritization

by Anne M. G. Neevel, Tessa Hemrika, Eric Claassen, Linda H. M. van de Burgwal

Background

Despite the existence of safe and effective vaccines, rabies disease still causes an estimated 59,000 human deaths a year in the endemic areas in Asia and Africa. These numbers reflect severe drawbacks regarding the implementation of PrEP and PEP in endemic settings, such as lack of political will and low priority given to rabies. Since these contextual factors have proven to be persistent, there is an urgency to improve current strategies or develop novel approaches in order to control rabies disease in the future.

Methods/Findings

This study aimed to identify and systematically prioritize the research needs, through interviews and questionnaires with key-opinion-leaders (KOLs). A total of 46 research needs were identified and prioritized. The top research needs are considered very high priority based on both importance for rabies control and need for improvement. KOLs agree that animal rabies control remains most important for rabies control, while research on human host, agent (rabies virus) and the environment should be prioritized in terms of need for improvement. A wide variety in perceptions is observed between and within the disciplines of virology, public health and veterinary health and between KOLs with more versus those with less experience in the field.

Conclusion/Significance

The results of this study give well-defined, prioritized issues that stress the drawbacks that are experienced by KOLs in daily practice. The most important research domains are: 1) cheap and scalable production system for RIG 2) efficacy of dog mass vaccination programs and 3) cheap human vaccines. Addressing these research needs should exist next to and may reinforce current awareness and mass vaccination campaigns. The differences in perspectives between actors revealed in this study are informative for effective execution of the One Health research agenda.

Interruption of onchocerciasis transmission in Bioko Island: Accelerating the movement from control to elimination in Equatorial Guinea

by Zaida Herrador, Belén Garcia, Policarpo Ncogo, Maria Jesus Perteguer, Jose Miguel Rubio, Eva Rivas, Marta Cimas, Guillermo Ordoñez, Silvia de Pablos, Ana Hernández-González, Rufino Nguema, Laura Moya, María Romay-Barja, Teresa Garate, Kira Barbre, Agustín Benito

Background

Onchocerciasis, also known as river blindness, is a parasitic disease. More than 99 percent of all cases occur in Africa. Bioko Island (Equatorial Guinea) is the only island endemic for onchocerciasis in the world. Since 2005, when vector Simulium yahense was eliminated, there have not been any reported cases of infection. This study aimed to demonstrate that updated WHO criteria for stopping mass drug administration (MDA) have been met.

Methodology/Principal findings

A cross-sectional study was conducted from September 2016 to January 2017. Participants were 5- to 9-year-old school children. Onchocerciasis/lymphatic Filariasis (LF, only in endemic districts) rapid diagnostic tests (RDTs) were performed. Blood spots were collected from RDT positive children and 10 percent of the RDT negatives to determine Ov16 and Wb123 IgG4 antibodies through enzyme-linked immunosorbent assay (ELISA). Skin snips were collected from RDT positives. Filarial detection was performed by PCR in positives and indeterminate sera. Black fly collection was carried out in traditional breeding sites. A total of 7,052 children, ranging from 5 to 9 years of age, were included in the study. Four children (0.06%) were Ov16 IgG4 RDT positives, but negative by ELISA Ov16, while 6 RDT negative children tested positive by ELISA. A total of 1,230 children from the Riaba and Baney districts were tested for LF. One child was Wb123 RDT positive (0.08%), but ELISA negative, while 3 RDT negative children were positive by Wb123 ELISA. All positive samples were negative by PCR for onchocerciasis and LF (in blood spot and skin snip). All fly collections and larval prospections in the traditional catching and prospection sites were negative.

Conclusions/Significance

WHO criteria have been met, therefore MDA in Bioko Island can be stopped. Three years of post-treatment surveillance should be implemented to identify any new occurrences of exposure or infection.

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