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Leptospirosis as a risk factor for chronic kidney disease: A systematic review of observational studies

23 May 2019 - 9:00pm

by Rodrigo M. Carrillo-Larco, Carlos Altez-Fernandez, J. Gonzalo Acevedo-Rodriguez, Karol Ortiz-Acha, Cesar Ugarte-Gil

Background

Leptospirosis is a worldwide prevalent zoonosis and chronic kidney disease (CKD) is a leading global disease burden. Because of pathophysiological changes in the kidney, it has been suggested that these conditions may be associated. However, the extent of this interaction has not been synthetized. We aimed to systematically review and critically appraise the evidence on the association between leptospirosis and CKD.

Methodology/Principal findings

Observational studies with a control group were selected. Leptospirosis, confirmed with laboratory methods, and CKD also based on a laboratory assessment, were the exposures and outcomes of interest. The search was conducted in EMBASE, MEDLINE, Global Health, Scopus and Web of Science. Studies selected for qualitative synthesis were assessed for risk of bias following the Newcastle-Ottawa Scale. 5,981 reports were screened, and 2 (n = 3,534) were included for qualitative synthesis. The studies were conducted in Taiwan and Nicaragua; these reported cross-sectional and longitudinal estimates. In the general population, the mean estimated glomerular filtration rate (eGFR) was lower (p<0.001) in people testing positive for antileptospira antibodies (eGFR = 98.3) than in negative controls (eGFR = 100.8). Among sugarcane applicants with high creatinine, those who were seropositive had lower eGFR (mean difference: -10.08). In a prospective analysis, people with high antileptospira antibodies titer at baseline and follow-up, had worse eGFR (p<0.05).

Conclusion

Although the available evidence suggests there may be a positive association between leptospirosis and CKD, whereby leptospirosis could be a risk factor for CKD, it is still premature to draw conclusions. There is an urgent need for research on this association.

Insecticide resistance levels and mechanisms in <i>Aedes aegypti</i> populations in and around Ouagadougou, Burkina Faso

23 May 2019 - 9:00pm

by Athanase Badolo, Aboubacar Sombié, Patricia M. Pignatelli, Aboubakar Sanon, Félix Yaméogo, Dimitri W. Wangrawa, Antoine Sanon, Hirotaka Kanuka, Philip J. McCall, David Weetman

Background

Recent outbreaks of dengue and other Aedes aegypti-borne arboviruses highlight the importance of a rapid response for effective vector control. Data on insecticide resistance and underlying mechanisms are essential for outbreak preparedness, but are sparse in much of Africa. We investigated the levels and heterogeneity of insecticide resistance and mechanisms of Ae. aegypti from contrasting settings within and around Ouagadougou, Burkina Faso.

Methodology/Principal findings

Bioassays were performed on larvae and adults to diagnose prevalence of resistance, and to assess levels where resistance was detected. Investigation of resistance mechanisms was performed using synergist bioassays, knockdown resistance (kdr) target site mutation genotyping and quantitative PCR expression analysis of candidate P450 genes.Larval dose-response assays indicated susceptibility to the organophosphates tested. Adult females were also susceptible to organophosphates, but resistance to carbamates was suspected in urban and semi-urban localities. Females from all localities showed resistance to pyrethroids but resistance prevalence and level were higher in urban and especially in semi-urban areas, compared to the rural population. Environment was also associated with susceptibility: adults reared from larvae collected in tires from the semi-urban site were significantly less resistant to pyrethroids than those collected from large outdoor drinking water containers (‘drums’). Susceptibility to both pyrethroids tested was largely restored by pre-exposure to Piperonyl Butoxide (PBO), suggesting a strong metabolic basis to resistance.The 1534C kdr mutation was nearly fixed in semi-urban and urban areas but was far less common in the rural area, where the 1016I kdr mutation frequency was also significantly lower. P450 gene analysis detected limited over-expression of single candidates but significantly elevated average expression in the semi-urban site compared to both a susceptible laboratory colony, and females from the other collection sites.

Conclusions/Significance

Our results reveal pyrethroid resistance and paired kdr mutations in both urban and semi-urban sites at levels that are unprecedented for mainland Africa. The combination of target site and metabolic mechanisms is common in Ae. aegypti populations from other continents but is a worrying finding for African populations. However, organophosphate insecticides are still active against both larvae and adults of Ae. aegypti, providing useful insecticidal options for control and resistance management.

<i>Wuchereria bancrofti</i>-infected individuals harbor distinct IL-10-producing regulatory B and T cell subsets which are affected by anti-filarial treatment

23 May 2019 - 9:00pm

by Manuel Ritter, Jubin Osei-Mensah, Linda Batsa Debrah, Alexander Kwarteng, Yusif Mubarik, Alexander Y. Debrah, Kenneth Pfarr, Achim Hoerauf, Laura E. Layland

Despite worldwide mass drug administration, it is estimated that 68 million individuals are still infected with lymphatic filariasis with 19 million hydrocele and 17 million lymphedema reported cases. Despite the staggering number of pathology cases, the majority of LF-infected individuals do not develop clinical symptoms and present a tightly regulated immune system characterized by higher frequencies of regulatory T cells (Treg), suppressed proliferation and Th2 cytokine responses accompanied with increased secretion of IL-10, TGF-β and infection-specific IgG4. Nevertheless, the filarial-induced modulation of the host`s immune system and especially the role of regulatory immune cells like regulatory B (Breg) and Treg during an ongoing LF infection remains unknown. Thus, we analysed Breg and Treg frequencies in peripheral blood from Ghanaian uninfected endemic normals (EN), lymphedema (LE), asymptomatic patent (CFA+MF+) and latent (CFA+MF-) W. bancrofti-infected individuals as well as individuals who were previously infected with W. bancrofti (PI) but had cleared the infection due to the administration of ivermectin (IVM) and albendazole (ALB). In summary, we observed that IL-10-producing CD19+CD24highCD38dhigh Breg were specifically increased in patently infected (CFA+MF+) individuals. In addition, CD19+CD24highCD5+CD1dhigh and CD19+CD5+CD1dhighIL-10+ Breg as well as CD4+CD127-FOXP3+ Treg frequencies were significantly increased in both W. bancrofti-infected cohorts (CFA+MF+ and CFA+MF-). Interestingly, the PI cohort presented frequency levels of all studied regulatory immune cell populations comparable with the EN group. In conclusion, the results from this study show that an ongoing W. bancrofti infection induces distinct Breg and Treg populations in peripheral blood from Ghanaian volunteers. Those regulatory immune cell populations might contribute to the regulated state of the host immune system and are probably important for the survival and fertility (microfilaria release) of the helminth.

A single dose of antibody-drug conjugate cures a stage 1 model of African trypanosomiasis

23 May 2019 - 9:00pm

by Paula MacGregor, Andrea L. Gonzalez-Munoz, Fatoumatta Jobe, Martin C. Taylor, Steven Rust, Alan M. Sandercock, Olivia J. S. Macleod, Katrien Van Bocxlaer, Amanda F. Francisco, Francois D’Hooge, Arnaud Tiberghien, Conor S. Barry, Philip Howard, Matthew K. Higgins, Tristan J. Vaughan, Ralph Minter, Mark Carrington

Infections of humans and livestock with African trypanosomes are treated with drugs introduced decades ago that are not always fully effective and often have severe side effects. Here, the trypanosome haptoglobin-haemoglobin receptor (HpHbR) has been exploited as a route of uptake for an antibody-drug conjugate (ADC) that is completely effective against Trypanosoma brucei in the standard mouse model of infection. Recombinant human anti-HpHbR monoclonal antibodies were isolated and shown to be internalised in a receptor-dependent manner. Antibodies were conjugated to a pyrrolobenzodiazepine (PBD) toxin and killed T. brucei in vitro at picomolar concentrations. A single therapeutic dose (0.25 mg/kg) of a HpHbR antibody-PBD conjugate completely cured a T. brucei mouse infection within 2 days with no re-emergence of infection over a subsequent time course of 77 days. These experiments provide a demonstration of how ADCs can be exploited to treat protozoal diseases that desperately require new therapeutics.

First survey of <i>Enterocytozoon bieneusi</i> and dominant genotype Peru6 among ethnic minority groups in southwestern China’s Yunnan Province and assessment of risk factors

23 May 2019 - 9:00pm

by Baiyan Gong, Yaming Yang, Xiaohua Liu, Jianping Cao, Meng Xu, Ning Xu, Fengkun Yang, Fangwei Wu, Benfu Li, Aiqin Liu, Yujuan Shen

Background

Enterocytozoon bieneusi is the most common microsporidian species causing diarrhea and other intestinal disorders in humans and animals. Like other infectious diseases, microsporidiosis usually disproportionately affects poor populations. In China, some ethnic minority areas remain poor. Currently, no information of E. bieneusi infection is available in minority populations. The present aims were to understand occurrence and genetic characterizations of E. bieneusi in ethnic minority groups from a poverty-stricken ethnic township in Yunnan Province, and to assess risk factors for E. bieneusi infection.

Methodology/Principal findings

289 fecal specimens were collected from Yao people (one specimen each) with and without diarrhea, in Yunnan Province. E. bieneusi was identified and genotyped by PCR and sequence analysis of the ITS region of the rRNA gene. An average prevalence of 8.30% (24/289) was observed and four genotypes were identified—genotype Peru6 (n = 21) and three novel genotypes (one each). Genotype Peru6 was detected in two family members in each of three families. In a phylogenetic analysis, all of four genotypes fell into group 1 with zoonotic potential. The people owning individual pit toilets had a statistically higher prevalence of E. bieneusi (16.67%, 12/72) than those using public pit toilets (6.06%, 12/198).

Conclusions/Significance

This is the first report on occurrence and genetic characteristics of E. bieneusi in ethnic minority groups in China. Genotype Peru6 was found in humans in China for the first time and showed dominance in Yao people. The same genotype was found in some family members and all the genotypes fell into group 1, suggesting the possibility of anthroponotic and zoonotic transmissions. The majority (83.33%, 20/24) of E. bieneusi positive individuals did not present diarrhea. In any case, it is important to recognize their existence and the importance that asymptomatic individuals to E. bieneusi may have from an epidemiological point of view, as transmitters of this pathogen. The analysis of risk factors provides scientific evidence for the development of effective strategies for prevention and control of E. bieneusi infection.

Antibacterial mass drug administration for child mortality reduction: Opportunities, concerns, and possible next steps

23 May 2019 - 9:00pm

by Isaac I. Bogoch, Jürg Utzinger, Nathan C. Lo, Jason R. Andrews

Revisiting the taxonomy and evolution of pathogenicity of the genus <i>Leptospira</i> through the prism of genomics

23 May 2019 - 9:00pm

by Antony T. Vincent, Olivier Schiettekatte, Cyrille Goarant, Vasantha Kumari Neela, Eve Bernet, Roman Thibeaux, Nabilah Ismail, Mohd Khairul Nizam Mohd Khalid, Fairuz Amran, Toshiyuki Masuzawa, Ryo Nakao, Anissa Amara Korba, Pascale Bourhy, Frederic J. Veyrier, Mathieu Picardeau

The causative agents of leptospirosis are responsible for an emerging zoonotic disease worldwide. One of the major routes of transmission for leptospirosis is the natural environment contaminated with the urine of a wide range of reservoir animals. Soils and surface waters also host a high diversity of non-pathogenic Leptospira and species for which the virulence status is not clearly established. The genus Leptospira is currently divided into 35 species classified into three phylogenetic clusters, which supposedly correlate with the virulence of the bacteria. In this study, a total of 90 Leptospira strains isolated from different environments worldwide including Japan, Malaysia, New Caledonia, Algeria, mainland France, and the island of Mayotte in the Indian Ocean were sequenced. A comparison of average nucleotide identity (ANI) values of genomes of the 90 isolates and representative genomes of known species revealed 30 new Leptospira species. These data also supported the existence of two clades and 4 subclades. To avoid classification that strongly implies assumption on the virulence status of the lineages, we called them P1, P2, S1, S2. One of these subclades has not yet been described and is composed of Leptospira idonii and 4 novel species that are phylogenetically related to the saprophytes. We then investigated genome diversity and evolutionary relationships among members of the genus Leptospira by studying the pangenome and core gene sets. Our data enable the identification of genome features, genes and domains that are important for each subclade, thereby laying the foundation for refining the classification of this complex bacterial genus. We also shed light on atypical genomic features of a group of species that includes the species often associated with human infection, suggesting a specific and ongoing evolution of this group of species that will require more attention. In conclusion, we have uncovered a massive species diversity and revealed a novel subclade in environmental samples collected worldwide and we have redefined the classification of species in the genus. The implication of several new potentially infectious Leptospira species for human and animal health remains to be determined but our data also provide new insights into the emergence of virulence in the pathogenic species.

A bioeconomic model for the optimization of local canine rabies control

22 May 2019 - 9:00pm

by Aaron Anderson, Johann Kotzé, Stephanie A. Shwiff, Brody Hatch, Chris Slootmaker, Anne Conan, Darryn Knobel, Louis H. Nel

We present a new modeling tool that can be used to maximize the impact of canine rabies management resources that are available at the local level. The model is accessible through a web-based interface that allows for flexibility in the management strategies that can be investigated. Rabies vaccination, sterilization, chemo-contraception, and euthanasia can be specified and limited to specific demographic groups. Additionally, we allowed for considerable complexity in the specification of management costs. In many areas, the costs of contacting additional dogs increases as management effort increases, and this can have important strategic implications. We illustrated the application of the model by examining several alternative management strategies in an area of Mpumalanga Province, South Africa. Our results based on this dog population suggested that puppies should be vaccinated and sterilization would not be optimal if the spatial extent of management is not large (and perhaps not even then). Furthermore, given a sufficient budget, it was evident that vaccination campaigns should be repeated annually.

Pathogen blocking in <i>Wolbachia</i>-infected <i>Aedes aegypti</i> is not affected by Zika and dengue virus co-infection

20 May 2019 - 9:00pm

by Eric P. Caragata, Marcele N. Rocha, Thiago N. Pereira, Simone B. Mansur, Heverton L. C. Dutra, Luciano A. Moreira

Background

Wolbachia’s ability to restrict arbovirus transmission makes it a promising tool to combat mosquito-transmitted diseases. Wolbachia-infected Aedes aegypti are currently being released in locations such as Brazil, which regularly experience concurrent outbreaks of different arboviruses. A. aegypti can become co-infected with, and transmit multiple arboviruses with one bite, which can complicate patient diagnosis and treatment.

Methodology/principle findings

Using experimental oral infection of A. aegypti and then RT-qPCR, we examined ZIKV/DENV-1 and ZIKV/DENV-3 co-infection in Wolbachia-infected A. aegypti and observed that Wolbachia-infected mosquitoes experienced lower prevalence of infection and viral load than wildtype mosquitoes, even with an extra infecting virus. Critically, ZIKV/DENV co-infection had no significant impact on Wolbachia’s ability to reduce viral transmission. Wolbachia infection also strongly altered expression levels of key immune genes Defensin C and Transferrin 1, in a virus-dependent manner.

Conclusions/significance

Our results suggest that pathogen interference in Wolbachia-infected A. aegypti is not adversely affected by ZIKV/DENV co-infection, which suggests that Wolbachia-infected A. aegypti will likely prove suitable for controlling mosquito-borne diseases in environments with complex patterns of arbovirus transmission.

Characterization of a yeast interfering RNA larvicide with a target site conserved in the <i>synaptotagmin</i> gene of multiple disease vector mosquitoes

20 May 2019 - 9:00pm

by Keshava Mysore, Ping Li, Chien-Wei Wang, Limb K. Hapairai, Nicholas D. Scheel, Jacob S. Realey, Longhua Sun, Joseph B. Roethele, David W. Severson, Na Wei, Molly Duman-Scheel

New mosquito control strategies are vitally needed to address established and emerging arthropod-borne infectious diseases. Here we describe the characterization of a yeast interfering RNA larvicide that was developed through the genetic engineering of Saccharomyces cerevisiae (baker’s yeast) to express a short hairpin RNA targeting the Aedes aegypti synaptotagmin (Aae syt) gene. The larvicide effectively silences the Aae syt gene, causes defects at the larval neural synapse, and induces high rates of A. aegypti larval mortality in laboratory, simulated-field, and semi-field trials. Conservation of the interfering RNA target site in multiple mosquito species, but not in humans or other non-target species, suggested that it may function as a broad-range mosquito larvicide. In support of this, consumption of the yeast interfering RNA larvicide was also found to induce high rates of larval mortality in Aedes albopictus, Anopheles gambiae, and Culex quinquefasciatus mosquito larvae. The results of these studies suggest that this biorational yeast interfering RNA larvicide may represent a new intervention that can be used to combat multiple mosquito vectors of human diseases.

<i>Trypanosoma cruzi</i> surface mucins are involved in the attachment to the <i>Triatoma infestans</i> rectal ampoule

20 May 2019 - 9:00pm

by María de los Milagros Cámara, Virginia Balouz, Camila Centeno Cameán, Carmen R. Cori, Gustavo A. Kashiwagi, Santiago A. Gil, Natalia Paula Macchiaverna, Marta Victoria Cardinal, Francisco Guaimas, Maite Mabel Lobo, Rosa M. de Lederkremer, Carola Gallo-Rodríguez, Carlos A. Buscaglia

Background

Trypanosoma cruzi, the agent of Chagas disease, is a protozoan parasite transmitted to humans by blood-sucking triatomine vectors. However, and despite its utmost biological and epidemiological relevance, T. cruzi development inside the digestive tract of the insect remains a poorly understood process.

Methods/Principle findings

Here we showed that Gp35/50 kDa mucins, the major surface glycoproteins from T. cruzi insect-dwelling forms, are involved in parasite attachment to the internal cuticle of the triatomine rectal ampoule, a critical step leading to its differentiation into mammal-infective forms. Experimental evidence supporting this conclusion could be summarized as follows: i) native and recombinant Gp35/50 kDa mucins directly interacted with hindgut tissues from Triatoma infestans, as assessed by indirect immunofluorescence assays; ii) transgenic epimastigotes over-expressing Gp35/50 kDa mucins on their surface coat exhibited improved attachment rates (~2–3 fold) to such tissues as compared to appropriate transgenic controls and/or wild-type counterparts; and iii) certain chemically synthesized compounds derived from Gp35/50 kDa mucins were able to specifically interfere with epimastigote attachment to the inner lining of T. infestans rectal ampoules in ex vivo binding assays, most likely by competing with or directly blocking insect receptor(s). A solvent-exposed peptide (smugS peptide) from the Gp35/50 kDa mucins protein scaffolds and a branched, Galf-containing trisaccharide (Galfβ1–4[Galpβ1–6]GlcNAcα) from their O-linked glycans were identified as main adhesion determinants for these molecules. Interestingly, exogenous addition of a synthetic Galfβ1–4[Galpβ1–6]GlcNAcα derivative or of oligosaccharides containing this structure impaired the attachment of Dm28c but not of CL Brener epimastigotes to triatomine hindgut tissues; which correlates with the presence of Galf residues on the Gp35/50 kDa mucins’ O-glycans on the former but not the latter parasite clone.

Conclusion/Significance

These results provide novel insights into the mechanisms underlying T. cruzi-triatomine interplay, and indicate that inter-strain variations in the O-glycosylation of Gp35/50 kDa mucins may lead to differences in parasite differentiation and hence, in parasite transmissibility to the mammalian host. Most importantly, our findings point to Gp35/50 kDa mucins and/or the Galf biosynthetic pathway, which is absent in mammals and insects, as appealing targets for the development of T. cruzi transmission-blocking strategies.

Sexual reproduction in a natural <i>Trypanosoma cruzi</i> population

20 May 2019 - 9:00pm

by Alexander S. F. Berry, Renzo Salazar-Sánchez, Ricardo Castillo-Neyra, Katty Borrini-Mayorí, Claudia Chipana-Ramos, Melina Vargas-Maquera, Jenny Ancca-Juarez, César Náquira-Velarde, Michael Z. Levy, Dustin Brisson, the Chagas Disease Working Group in Arequipa

Background

Sexual reproduction provides an evolutionary advantageous mechanism that combines favorable mutations that have arisen in separate lineages into the same individual. This advantage is especially pronounced in microparasites as allelic reassortment among individuals caused by sexual reproduction promotes allelic diversity at immune evasion genes within individuals which is often essential to evade host immune systems. Despite these advantages, many eukaryotic microparasites exhibit highly-clonal population structures suggesting that genetic exchange through sexual reproduction is rare. Evidence supporting clonality is particularly convincing in the causative agent of Chagas disease, Trypanosoma cruzi, despite equally convincing evidence of the capacity to engage in sexual reproduction.

Methodology/ Principle Findings

In the present study, we investigated two hypotheses that can reconcile the apparent contradiction between the observed clonal population structure and the capacity to engage in sexual reproduction by analyzing the genome sequences of 123 T. cruzi isolates from a natural population in Arequipa, Peru. The distribution of polymorphic markers within and among isolates provides clear evidence of the occurrence of sexual reproduction. Large genetic segments are rearranged among chromosomes due to crossing over during meiosis leading to a decay in the genetic linkage among polymorphic markers compared to the expectations from a purely asexually-reproducing population. Nevertheless, the population structure appears clonal due to a high level of inbreeding during sexual reproduction which increases homozygosity, and thus reduces diversity, within each inbreeding lineage.

Conclusions/ Significance

These results effectively reconcile the apparent contradiction by demonstrating that the clonal population structure is derived not from infrequent sex in natural populations but from high levels of inbreeding. We discuss epidemiological consequences of this reproductive strategy on genome evolution, population structure, and phenotypic diversity of this medically important parasite.

El Niño southern Oscillation, overseas arrivals and imported chikungunya cases in Australia: A time series analysis

20 May 2019 - 9:00pm

by Xiaodong Huang, Wenbiao Hu, Laith Yakob, Gregor J. Devine, Elizabeth A. McGraw, Cassie C. Jansen, Helen M. Faddy, Francesca D. Frentiu

Background

Chikungunya virus (CHIKV) is an emerging mosquito-borne pathogen circulating in tropical and sub-tropical regions. Although autochthonous transmission has not been reported in Australia, there is a potential risk of local CHIKV outbreaks due to the presence of suitable vectors, global trade, frequent international travel and human adaptation to changes in climate.

Methodology/Principal findings

A time series seasonal decomposition method was used to investigate the seasonality and trend of monthly imported CHIKV cases. This pattern was compared with the seasonality and trend of monthly overseas arrivals. A wavelet coherence analysis was applied to examine the transient relationships between monthly imported CHIKV cases and southern oscillation index (SOI) in time-frequency space. We found that the number and geographical distribution of countries of acquisition for CHIKV in travellers to Australia has increased in recent years. The number of monthly imported CHIKV cases displayed an unstable increased trend compared with a stable linear increased trend in monthly overseas arrivals. Both imported CHIKV cases and overseas arrivals showed substantial seasonality, with the strongest seasonal effects in each January, followed by each October and July. The wavelet coherence analysis identified four significant transient relationships between monthly imported CHIKV cases and 6-month lagged moving average SOI, in the years 2009–2010, 2012, 2014 and 2015–2016.

Conclusion/Significance

High seasonal peaks of imported CHIKV cases were consistent with the high seasonal peaks of overseas arrivals into Australia. Our analysis also indicates that El Niño Southern Oscillation (ENSO) variation may impact CHIKV epidemics in endemic regions, in turn influencing the pattern of imported cases.

Effects of ‘The Vicious Worm’ educational tool on <i>Taenia solium</i> knowledge retention in Zambian primary school students after one year

20 May 2019 - 9:00pm

by Emma C. Hobbs, Kabemba Evans Mwape, Brecht Devleesschauwer, Inge Van Damme, Meryam Krit, Dirk Berkvens, Gideon Zulu, Moses Mambwe, Mwelwa Chembensofu, Chiara Trevisan, Jacoba Baauw, Isaac Khozozo Phiri, Niko Speybroeck, Jennifer Ketzis, Pierre Dorny, Arve Lee Willingham, Sarah Gabriël

Background

Taenia solium is a neglected zoonotic parasite endemic throughout many low-income countries worldwide, including Zambia, where it causes human and pig diseases with high health and socioeconomic burdens. Lack of knowledge is a recognized risk factor, and consequently targeted health educational programs can decrease parasite transmission and disease occurrence in endemic areas.Preliminary assessment of the computer-based education program ‘The Vicious Worm’ in rural areas of eastern Zambia indicated that it was effective at increasing knowledge of T. solium in primary school students. The aim of this study was to evaluate the impact of ‘The Vicious Worm’ on knowledge retention by re-assessing the same primary school students one year after the initial education workshops.

Methodology/Principal findings

Follow-up questionnaires were administered in the original three primary schools in eastern Zambia in 2017, 12 months after the original workshops. In total, 86 pupils participated in the follow-up sessions, representing 87% of the initial workshop respondents. Knowledge of T. solium at ‘follow-up’ was significantly higher than at the initial ‘pre’ questionnaire administered during the Vicious Worm workshop that took place one year earlier. While some specifics of the parasite’s life cycle were not completely understood, the key messages for disease prevention, such as the importance of hand washing and properly cooking pork, remained well understood by the students, even one year later.

Conclusions/Significance

Results of this study indicate that ‘The Vicious Worm’ may be an effective tool for both short- and long-term T. solium education of rural primary school students in Zambia. Inclusion of educational workshops using ‘The Vicious Worm’ could be recommended for integrated cysticercosis control/elimination programs in sub-Saharan Africa, particularly if the content is simplified to focus on the key messages for prevention of disease transmission.

Pharmacokinetics, safety, and efficacy of a single co-administered dose of diethylcarbamazine, albendazole and ivermectin in adults with and without <i>Wuchereria bancrofti</i> infection in Côte d’Ivoire

20 May 2019 - 9:00pm

by Constant Edi, Catherine M. Bjerum, Allassane F. Ouattara, Yashpal S. Chhonker, Louis K. Penali, Aboulaye Méité, Benjamin G. Koudou, Gary J. Weil, Christopher L. King, Daryl J. Murry

Background

A single co-administered dose of ivermectin (IVM) plus diethylcarbamazine (DEC) plus albendazole (ALB), or triple-drug therapy, was recently found to be more effective for clearing microfilariae (Mf) than standard DEC plus ALB currently used for mass drug administration programs for lymphatic filariasis (LF) outside of sub-Saharan Africa. Triple-drug therapy has not been previously tested in LF-uninfected individuals from Africa. This study evaluated the pharmacokinetics (PK), safety, and efficacy of triple-drug therapy in people with and without Wuchereria bancrofti infection in West Africa.

Methods

In this open-label cohort study, treatment-naïve microfilaremic (>50 mf/mL, n = 32) and uninfected (circulating filarial antigen negative, n = 24) adults residing in Agboville district, Côte d’Ivoire, were treated with a single dose of IVM plus DEC plus ALB, and evaluated for adverse events (AEs) until 7 days post treatment. Drug levels were assessed by liquid chromatography and mass spectrometry. Persons responsible for assessing AEs were blinded to participants’ infection status.

Findings

There was no difference in AUC0-inf or Cmax between LF-infected and uninfected participants (P>0.05 for all comparisons). All subjects experienced mild AEs; 28% and 25% of infected and uninfected participants experienced grade 2 AEs, respectively. There were no severe or serious adverse events. Only fever (16 of 32 versus 4 of 24, P<0.001) and scrotal pain/swelling in males (6 of 20 versus 0 of 12, P = 0.025) were more frequent in infected than uninfected participants. All LF positive participants were amicrofilaremic at 7 days post-treatment and 27 of 31 (87%) remained amicrofilaremic 12 months after treatment.

Conclusions

Moderate to heavy W. bancrofti infection did not affect PK parameters for IVM, DEC or ALB following a single co-administered dose of these drugs compared to uninfected individuals. The drugs were well tolerated. This study confirmed the efficacy of the triple-drug therapy for clearing W. bancrofti Mf and has added important information to support the use of this regimen in LF elimination programs in areas of Africa without co-endemic onchocerciasis or loiasis.

Trial registration

ClinicalTrials.gov NCT02845713.

Molecular characterization of <i>Brucella</i> species from Zimbabwe

20 May 2019 - 9:00pm

by Maphuti Betty Ledwaba, Calvin Gomo, Kgaugelo Edward Lekota, Philippe Le Flèche, Ayesha Hassim, Gilles Vergnaud, Henriette van Heerden

Brucella abortus and B. melitensis have been reported in several studies in animals in Zimbabwe but the extent of the disease remains poorly known. Thus, characterizing the circulating strains is a critical first step in understanding brucellosis in the country. In this study we used an array of molecular assays including AMOS-PCR, Bruce-ladder, multiple locus variable number tandem repeats analysis (MLVA) and single nucleotide polymorphisms from whole genome sequencing (WGS-SNP) to characterize Brucella isolates to the species, biovar, and individual strain level. Sixteen Brucella strains isolated in Zimbabwe at the Central Veterinary laboratory from various hosts were characterized using all or some of these assays. The strains were identified as B. ovis, B. abortus, B. canis and B. suis, with B. canis being the first report of this species in Zimbabwe. Zimbabwean strains identified as B. suis and B. abortus were further characterized with whole genome sequencing and were closely related to reference strains 1330 and 86/8/59, respectively. We demonstrate the range of different tests that can be performed from simple assays that can be run in laboratories lacking sophisticated instrumentation to whole genome analyses that currently require substantial expertise and infrastructure often not available in the developing world.

Coinfection with <i>Leishmania major</i> and <i>Staphylococcus aureus</i> enhances the pathologic responses to both microbes through a pathway involving IL-17A

20 May 2019 - 9:00pm

by Tiffany Y. Borbón, Breanna M. Scorza, Gwendolyn M. Clay, Fellipe Lima Nobre de Queiroz, Alan J. Sariol, Jayden L. Bowen, Yani Chen, Bayan Zhanbolat, Corey P. Parlet, Diogo G. Valadares, Suzanne L. Cassel, William M. Nauseef, Alexander R. Horswill, Fayyaz S. Sutterwala, Mary E. Wilson

Cutaneous leishmaniasis (CL) is a parasitic disease causing chronic, ulcerating skin lesions. Most humans infected with the causative Leishmania protozoa are asymptomatic. Leishmania spp. are usually introduced by sand flies into the dermis of mammalian hosts in the presence of bacteria from either the host skin, sand fly gut or both. We hypothesized that bacteria at the dermal inoculation site of Leishmania major will influence the severity of infection that ensues. A C57BL/6 mouse ear model of single or coinfection with Leishmania major, Staphylococcus aureus, or both showed that single pathogen infections caused localized lesions that peaked after 2–3 days for S. aureus and 3 weeks for L. major infection, but that coinfection produced lesions that were two-fold larger than single infection throughout 4 weeks after coinfection. Coinfection increased S. aureus burdens over 7 days, whereas L. major burdens (3, 7, 28 days) were the same in singly and coinfected ears. Inflammatory lesions throughout the first 4 weeks of coinfection had more neutrophils than did singly infected lesions, and the recruited neutrophils from early (day 1) lesions had similar phagocytic and NADPH oxidase capacities. However, most neutrophils were apoptotic, and transcription of immunomodulatory genes that promote efferocytosis was not upregulated, suggesting that the increased numbers of neutrophils may, in part, reflect defective clearance and resolution of the inflammatory response. In addition, the presence of more IL-17A-producing γδ and non-γδ T cells in early lesions (1–7 days), and L. major antigen-responsive Th17 cells after 28 days of coinfection, with a corresponding increase in IL-1β, may recruit more naïve neutrophils into the inflammatory site. Neutralization studies suggest that IL-17A contributed to an enhanced inflammatory response, whereas IL-1β has an important role in controlling bacterial replication. Taken together, these data suggest that coinfection of L. major infection with S. aureus exacerbates disease, both by promoting more inflammation and neutrophil recruitment and by increasing neutrophil apoptosis and delaying resolution of the inflammatory response. These data illustrate the profound impact that coinfecting microorganisms can exert on inflammatory lesion pathology and host adaptive immune responses.

The prevalence of <i>Leptospira</i> among invasive small mammals on Puerto Rican cattle farms

20 May 2019 - 9:00pm

by Kathryn M. Benavidez, Trina Guerra, Madison Torres, David Rodriguez, Joseph A. Veech, Dittmar Hahn, Robert J. Miller, Fred V. Soltero, Alejandro E. Pérez Ramírez, Adalberto Perez de León, Iván Castro-Arellano

Leptospirosis, an emerging infectious disease caused by bacteria of the genus Leptospira, is thought to be the most widespread zoonotic disease in the world. A first step in preventing the spread of Leptospira is delineating the animal reservoirs that maintain and disperse the bacteria. Quantitative PCR (qPCR) methods targeting the LipL32 gene were used to analyze kidney samples from 124 House mice (Mus musculus), 94 Black rats (Rattus rattus), 5 Norway rats (R. norvegicus), and 89 small Indian mongooses (Herpestes auropunctatus) from five cattle farms in Puerto Rico. Renal carriage of Leptospira was found in 38% of the sampled individuals, with 59% of the sampled mice, 34% of Black rats, 20% of Norway rats, and 13% of the mongooses. A heterogeneous distribution of prevalence was also found among sites, with the highest prevalence of Leptospira-positive samples at 52% and the lowest at 30%. Comparative sequence analysis of the LipL32 gene from positive samples revealed the presence of two species of Leptospira, L. borgpetersenii and L. interrogans in mice, detected in similar percentages in samples from four farms, while samples from the fifth farm almost exclusively harbored L. interrogans. In rats, both Leptospira species were found, while mongooses only harbored L. interrogans. Numbers tested for both animals, however, were too small (n = 7 each) to relate prevalence of Leptospira species to location. Significant associations of Leptospira prevalence with anthropogenic landscape features were observed at farms in Naguabo and Sabana Grande, where infected individuals were closer to human dwellings, milking barns, and ponds than were uninfected individuals. These results show that rural areas of Puerto Rico are in need of management and longitudinal surveillance of Leptospira in order to prevent continued infection of focal susceptible species (i.e. humans and cattle).

The characteristics of current natural foci of hemorrhagic fever with renal syndrome in Shandong Province, China, 2012-2015

20 May 2019 - 9:00pm

by Zhaolei Zheng, Peizhu Wang, Zhiqiang Wang, Dandan Zhang, Xu Wang, Shuqing Zuo, Xiujun Li

Background

Hemorrhagic fever with renal syndrome (HFRS), an infectious disease caused by hantaviruses, is endemic in China and remains a serious public health problem. Historically, Shandong Province has had the largest HFRS burden in China. However, we do not have a comprehensive and clear understanding of the current epidemic foci of HFRS in Shandong Province.

Methodology/principal findings

The incidence and mortality rates were calculated, and a phylogenetic analysis was performed after laboratory testing of the virus in rodents. Spatial epidemiology analysis was applied to investigate the epidemic foci, including their sources. A total of 6,206 HFRS cases and 59 related deaths were reported in Shandong Province. The virus carriage rates of the rodents Rattus norvegicus, Apodemus agrarius and Mus musculus were 10.24%, 6.31% and 0.27%, respectively. The phylogenetic analysis indicated that two novel viruses obtained from R. norvegicus in Anqiu City and Qingzhou City were dissimilar to the other strains, but closely related to strains previously isolated in northeastern China. Three epidemic foci were defined, two of which were derived from the Jining and Linyi epidemic foci, respectively, while the other was the residue of the Jining epidemic focus.

Conclusions/significance

The southeastern and central Shandong Province are current key HFRS epidemic foci dominated by A. agrarius and R. norvegicus, respectively. Our study could help local departments to strengthen prevention and control measures in key areas to reduce the hazards of HFRS.

Impairing the maintenance of germinative cells in <i>Echinococcus multilocularis</i> by targeting Aurora kinase

16 May 2019 - 9:00pm

by Zhe Cheng, Fan Liu, Huimin Tian, Zhijian Xu, Xiaoli Chai, Damin Luo, Yanhai Wang

Background

The tumor-like growth of the metacestode larvae of the tapeworm E. multilocularis causes human alveolar echinococcosis, a severe disease mainly affecting the liver. The germinative cells, a population of adult stem cells, are crucial for the larval growth and development of the parasite within the hosts. Maintenance of the germinative cell pools relies on their abilities of extensive proliferation and self-renewal, which requires accurate control of the cell division cycle. Targeting regulators of the cell division progression may impair germinative cell populations, leading to impeded parasite growth.

Methodology/Principal findings

In this study, we describe the characterization of EmAURKA and EmAURKB, which display significant similarity to the members of Aurora kinases that are essential mitotic kinases and play key roles in cell division. Our data suggest that EmAURKA and EmAURKB are actively expressed in the germinative cells of E. multilocularis. Treatment with low concentrations of MLN8237, a dual inhibitor of Aurora A and B, resulted in chromosomal defects in the germinative cells during mitosis, while higher concentrations of MLN8237 caused a failure in cytokinesis of the germinative cells, leading to multinucleated cells. Inhibition of the activities of Aurora kinases eventually resulted in depletion of the germinative cell populations in E. multilocularis, which in turn caused larval growth inhibition of the parasite.

Conclusions/Significance

Our data demonstrate the vital roles of Aurora kinases in the regulation of mitotic progression and maintenance of the germinative cells in E. multilocularis, and suggest Aurora kinases as promising druggable targets for the development of novel chemotherapeutics against human alveolar echinococcosis.

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