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Preview: PLoS Neglected Tropical Diseases: New Articles

PLOS Neglected Tropical Diseases: New Articles



A Peer-Reviewed Open-Access Journal



Updated: 2018-04-25T22:17:01Z

 



(XML) Aminopeptidase secreted by Chromobacterium sp. Panama inhibits dengue virus infection by degrading the E protein

2018-04-25T21:00:00Z

by Raúl G. Saraiva, Jingru Fang, Seokyoung Kang, Yesseinia I. Angleró-Rodríguez, Yuemei Dong, George Dimopoulos

Dengue virus (DENV) is the most prevalent and burdensome arbovirus transmitted by Aedes mosquitoes, against which there is only a limited licensed vaccine and no approved drug treatment. A Chromobacterium species, C. sp. Panama, isolated from the midgut of A. aegypti is able to inhibit DENV replication within the mosquito and in vitro. Here we show that C. sp. Panama mediates its anti-DENV activity through secreted factors that are proteinous in nature. The inhibitory effect occurs prior to virus attachment to cells, and is attributed to a factor that destabilizes the virion by promoting the degradation of the viral envelope protein. Bioassay-guided fractionation, coupled with mass spectrometry, allowed for the identification of a C. sp. Panama-secreted neutral protease and an aminopeptidase that are co-expressed and appear to act synergistically to degrade the viral envelope (E) protein and thus prevent viral attachment and subsequent infection of cells. This is the first study characterizing the anti-DENV activity of a common soil and mosquito-associated bacterium, thereby contributing towards understanding how such bacteria may limit disease transmission, and providing new tools for dengue prevention and therapeutics.(image)



(XML) Data quality and timeliness of outbreak reporting system among countries in Greater Mekong subregion: Challenges for international data sharing

2018-04-25T21:00:00Z

by Saranath Lawpoolsri, Jaranit Kaewkungwal, Amnat Khamsiriwatchara, Ly Sovann, Bun Sreng, Bounlay Phommasack, Viengsavanh Kitthiphong, Soe Lwin Nyein, Nyan Win Myint, Nguyen Dang Vung, Pham Hung, Mark S. Smolinski, Adam W. Crawley, Moe Ko Oo

Cross-border disease transmission is a key challenge for prevention and control of outbreaks. Variation in surveillance structure and national guidelines used in different countries can affect their data quality and the timeliness of outbreak reports. This study aimed to evaluate timeliness and data quality of national outbreak reporting for four countries in the Mekong Basin Disease Surveillance network (MBDS). Data on disease outbreaks occurring from 2010 to 2015 were obtained from the national disease surveillance reports of Cambodia, Lao PDR, Myanmar, and Vietnam. Data included total cases, geographical information, and dates at different timeline milestones in the outbreak detection process. Nine diseases or syndromes with public health importance were selected for the analysis including: dengue, food poisoning & diarrhea, severe diarrhea, diphtheria, measles, H5N1 influenza, H1N1 influenza, rabies, and pertussis. Overall, 2,087 outbreaks were reported from the four countries. The number of outbreaks and number of cases per outbreak varied across countries and diseases, depending in part on the outbreak definition used in each country. Dates on index onset, report, and response were >95% complete in all countries, while laboratory confirmation dates were 10%-100% incomplete in most countries. Inconsistent and out of range date data were observed in 1%-5% of records. The overall timeliness of outbreak report, response, and public communication was within 1–15 days, depending on countries and diseases. Diarrhea and severe diarrhea outbreaks showed the most rapid time to report and response, whereas diseases such as rabies, pertussis and diphtheria required a longer time to report and respond. The hierarchical structure of the reporting system, data collection method, and country’s resources could affect the data quality and timeliness of the national outbreak reporting system. Differences in data quality and timeliness of outbreak reporting system among member countries should be considered when planning data sharing strategies within a regional network.(image)



(XML) Zika virus infection and microcephaly: Evidence regarding geospatial associations

2018-04-25T21:00:00Z

by João Ricardo Nickenig Vissoci, Thiago Augusto Hernandes Rocha, Núbia Cristina da Silva, Rejane Christine de Sousa Queiroz, Erika Bárbara Abreu Fonseca Thomaz, Pedro Vasconcelos Maia Amaral, Adriana Lein, Maria dos Remédios Freitas Carvalho Branco, José Aquino Junior, Zulimar Márita Ribeiro Rodrigues, Antônio Augusto Moura da Silva, Catherine Staton

Background

Although the Zika virus (ZIKV) epidemic ceased to be a public health emergency by the end of 2016, studies to improve knowledge about this emerging disease are still needed, especially those investigating a causal relationship between ZIKV in pregnant women and microcephaly in neonates. However, there are still many challenges in describing the relationship between ZIKV and microcephaly. The few studies focusing on the epidemiological profile of ZIKV and its changes over time are largely limited to systematic reviews of case reports and dispersal mapping of ZIKV spread over time without quantitative methods to analyze patterns and their covariates. Since Brazil has been at the epicenter of the ZIKV epidemic, this study examines the geospatial association between ZIKV and microcephaly in Brazil.

Methods

Our study is categorized as a retrospective, ecological study based on secondary databases. Data were obtained from January to December 2016, from the following data sources: Brazilian System for Epidemiological Surveillance, Disease Notification System, System for Specialized Management Support, and Brazilian Institute of Geography and Statistics. Data were aggregated by municipality. Incidence rates were estimated per 100,000 inhabitants. Analyses consisted of mapping the aggregated incidence rates of ZIKV and microcephaly, followed by a Getis-Ord-Gi spatial cluster analysis and a Bivariate Local Moran’s I analysis.

Results

The incidence of ZIKV cases is changing the virus’s spatial pattern, shifting from Brazil’s Northeast region to the Midwest and North regions. The number of municipalities in clusters of microcephaly incidence is also shifting from the Northeast region to the Midwest and North, after a time lag is considered. Our findings suggest an increase in microcephaly incidence in the Midwest and North regions, associated with high levels of ZIKV infection months before.

Conclusion

The greatest burden of microcephaly shifted from the Northeast to other Brazilian regions at the beginning of 2016. Brazil’s Midwest region experienced an increase in microcephaly incidence associated with ZIKV incidence. This finding highlights an association between an increase in ZIKV infection with a rise in microcephaly cases after approximately three months.

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(XML) Impact of confinement housing on study end-points in the calf model of cryptosporidiosis

2018-04-25T21:00:00Z

by Geneva Graef, Natalie J. Hurst, Lance Kidder, Tracy L. Sy, Laura B. Goodman, Whitney D. Preston, Samuel L. M. Arnold, Jennifer A. Zambriski

Background

Diarrhea is the second leading cause of death in children < 5 years globally and the parasite genus Cryptosporidium is a leading cause of that diarrhea. The global disease burden attributable to cryptosporidiosis is substantial and the only approved chemotherapeutic, nitazoxanide, has poor efficacy in HIV positive children. Chemotherapeutic development is dependent on the calf model of cryptosporidiosis, which is the best approximation of human disease. However, the model is not consistently applied across research studies. Data collection commonly occurs using two different methods: Complete Fecal Collection (CFC), which requires use of confinement housing, and Interval Collection (IC), which permits use of box stalls. CFC mimics human challenge model methodology but it is unknown if confinement housing impacts study end-points and if data gathered via this method is suitable for generalization to human populations.

Methods

Using a modified crossover study design we compared CFC and IC and evaluated the impact of housing on study end-points. At birth, calves were randomly assigned to confinement (n = 14) or box stall housing (n = 9), or were challenged with 5 x 107 C. parvum oocysts, and followed for 10 days. Study end-points included fecal oocyst shedding, severity of diarrhea, degree of dehydration, and plasma cortisol.

Findings

Calves in confinement had no significant differences in mean log oocysts enumerated per gram of fecal dry matter between CFC and IC samples (P = 0.6), nor were there diurnal variations in oocyst shedding (P = 0.1). Confinement housed calves shed significantly more oocysts (P = 0.05), had higher plasma cortisol (P = 0.001), and required more supportive care (P = 0.0009) than calves in box stalls.

Conclusion

Housing method confounds study end-points in the calf model of cryptosporidiosis. Due to increased stress data collected from calves in confinement housing may not accurately estimate the efficacy of chemotherapeutics targeting C. parvum.

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(XML) Cryosurgery for the treatment of cutaneous sporotrichosis in four pregnant women

2018-04-23T21:00:00Z

by Vivian Fichman, Antonio Carlos Francesconi do Valle, Priscila Marques de Macedo, Dayvison Francis Saraiva Freitas, Manoel Marques Evangelista de Oliveira, Rodrigo Almeida-Paes, Maria Clara Gutierrez-Galhardo

Background

Pregnant women with sporotrichosis should not receive systemic antifungal therapy except in severe cases when amphotericin B is recommended. Thermotherapy is the most reported treatment described in this group of patients. It entails weeks of daily self-application of heat to the lesions, requires that the patient faithfully apply it, and it could cause skin burns. Cryosurgery is a useful therapeutic tool for many cutaneous infectious diseases, safe for pregnant women, but not well evaluated for sporotrichosis treatment in this group.

Methodology

The authors conducted a retrospective study describing epidemiological, clinical, and therapeutic data related to four pregnant patients with sporotrichosis treated with cryosurgery. The authors reviewed the clinical records of four pregnant patients diagnosed with cutaneous sporotrichosis and treated with cryosurgery. The sessions were carried out monthly up to clinical cure. Molecular identification of the Sporothrix species was performed in two cases using T3B PCR fingerprinting assays.

Principal findings

All patients were in the second trimester of pregnancy and their age ranged from 18 to 34 years. With regard to clinical presentation, two patients had lymphocutaneous and two had the fixed form. S. brasiliensis was identified in two cases as the causative agent. Cryosurgery was well tolerated and the number of sessions ranged from 1 to 3. All the patients reached a complete clinical cure.

Conclusions

Cryosurgery was a safe, easy to perform and well tolerated method, and therefore it is suggested to be a suitable option for the treatment of cutaneous sporotrichosis in pregnant women.

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(XML) Entomopathogenic fungal infection leads to temporospatial modulation of the mosquito immune system

2018-04-23T21:00:00Z

by José L. Ramirez, Christopher A. Dunlap, Ephantus J. Muturi, Ana B. F. Barletta, Alejandro P. Rooney

Alternative methods of mosquito control are needed to tackle the rising burden of mosquito-borne diseases while minimizing the use of synthetic insecticides, which are threatened by the rapid increase in insecticide resistance in mosquito populations. Fungal biopesticides show great promise as potential alternatives because of their ecofriendly nature and ability to infect mosquitoes on contact. Here we describe the temporospatial interactions between the mosquito Aedes aegypti and several entomopathogenic fungi. Fungal infection assays followed by the molecular assessment of infection-responsive genes revealed an intricate interaction between the mosquito immune system and entomopathogenic fungi. We observed contrasting tissue and time-specific differences in the activation of immune signaling pathways and antimicrobial peptide expression. In addition, these antifungal responses appear to vary according to the fungal entomopathogen used in the infection. Enzyme activity-based assays coupled with gene expression analysis of prophenoloxidase genes revealed a reduction in phenoloxidase (PO) activity in mosquitoes infected with the most virulent fungal strains at 3 and 6d post-fungal infection. Moreover, fungal infection led to an increase in midgut microbiota that appear to be attributed in part to reduced midgut reactive oxygen species (ROS) activity. This indicates that the fungal infection has far reaching effects on other microbes naturally associated with mosquitoes. This study also revealed that despite fungal recognition and immune elicitation by the mosquito, it is unable to successfully eliminate the entomopathogenic fungal infection. Our study provides new insights into this intricate multipartite interaction and contributes to a better understanding of mosquito antifungal immunity.(image)



(XML) Behavioral responses of Rhodnius prolixus to volatile organic compounds released in vitro by bacteria isolated from human facial skin

2018-04-23T21:00:00Z

by Marcela Tabares, Mario Ortiz, Mabel Gonzalez, Chiara Carazzone, Martha J. Vives Florez, Jorge Molina

Background

Previous studies have demonstrated the role of volatile organic compounds (VOCs) produced by skin microbiota in the attraction of mosquitoes to humans. Recently, behavioral experiments confirmed the importance of VOCs released by skin microbiota in the attraction of Rhodnius prolixus (Hemiptera: Triatominae), a vector of Chagas disease.

Methods/Findings

In this study, we screened for VOCs released in vitro by bacteria isolated from human facial skin that were able to elicit behavioral responses in R. prolixus. The VOCs released in vitro by eight bacterial species during two growth phases were tested with adult Rhodnius prolixus insects using a dual-choice “T”-shaped olfactometer. In addition, the VOCs released by the bacteria were analyzed with headspace solid-phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC-MS). The VOCs produced by Staphylococcus capitis 11C, Staphylococcus warneri and Staphylococcus epidermidis 1 were attractive to R. prolixus, while the VOCs released by Citrobacter koseri 6P, Brevibacterium epidermidis and Micrococcus luteus 23 were non-attractive.

Conclusions

The results shown here indicate that VOCs released by bacteria isolated from human facial skin have a potential for biotechnological uses as a strategy to prevent the vectorial transmission of Chagas disease mediated by Rhodnius prolixus.

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(XML) Laboratory and molecular surveillance of paediatric typhoidal Salmonella in Nepal: Antimicrobial resistance and implications for vaccine policy

2018-04-23T21:00:00Z

by Carl D. Britto, Zoe A. Dyson, Sebastian Duchene, Michael J. Carter, Meeru Gurung, Dominic F. Kelly, David R. Murdoch, Imran Ansari, Stephen Thorson, Shrijana Shrestha, Neelam Adhikari, Gordon Dougan, Kathryn E. Holt, Andrew J. Pollard

Background

Children are substantially affected by enteric fever in most settings with a high burden of the disease, including Nepal. However pathogen population structure and transmission dynamics are poorly delineated in young children, the proposed target group for immunization programs. Here we present whole genome sequencing and antimicrobial susceptibility data on 198 S. Typhi and 66 S. Paratyphi A isolated from children aged 2 months to 15 years of age during blood culture surveillance at Patan Hospital, Nepal, 2008–2016.

Principal findings

S. Typhi was the dominant agent and comprised several distinct genotypes, dominated by 4.3.1 (H58). The heterogeneity of genotypes in children under five was reduced compared to data from 2005–2006, attributable to ongoing clonal expansion of H58. Most isolates (86%) were non-susceptible to fluoroquinolones, associated mainly with S. Typhi H58 Lineage II and S. Paratyphi A harbouring mutations in the quinolone resistance-determining region (QRDR); non-susceptible strains from these groups accounted for 50% and 25% of all isolates. Multi-drug resistance (MDR) was rare (3.5% of S. Typhi, 0 S. Paratyphi A) and restricted to chromosomal insertions of resistance genes in H58 lineage I strains. Temporal analyses revealed a shift in dominance from H58 Lineage I to H58 Lineage II, with the latter being significantly more common after 2010. Comparison to global data sets showed the local S. Typhi and S. Paratyphi A strains had close genetic relatives in other South Asian countries, indicating regional strain circulation. Multiple imports from India of ciprofloxacin-resistant H58 Lineage II strains were identified, but these were rare and showed no evidence of clonal replacement of local S. Typhi.

Significance

These data indicate that enteric fever in Nepal continues to be a major public health issue with ongoing inter- and intra-country transmission, and highlights the need for regional coordination of intervention strategies. The absence of a S. Paratyphi A vaccine is cause for concern, given its prevalence as a fluoroquinolone resistant enteric fever agent in this setting.

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(XML) Plasma and memory B cell responses targeting O-specific polysaccharide (OSP) are associated with protection against Vibrio cholerae O1 infection among household contacts of cholera patients in Bangladesh

2018-04-23T21:00:00Z

by Amena Aktar, M. Arifur Rahman, Sadia Afrin, Aklima Akter, Taher Uddin, Tahirah Yasmin, Md. Israk Nur Sami, Pinki Dash, Sultana Rownok Jahan, Fahima Chowdhury, Ashraful I. Khan, Regina C. LaRocque, Richelle C. Charles, Taufiqur Rahman Bhuiyan, Anjali Mandlik, Meagan Kelly, Pavol Kováč, Peng Xu, Stephen B. Calderwood, Jason B. Harris, Firdausi Qadri, Edward T. Ryan

Background

The mediators of protection against cholera, a severe dehydrating illness of humans caused by Vibrio cholerae, are unknown. We have previously shown that plasma IgA as well as memory B IgG cells targeting lipopolysaccharide (LPS) of Vibrio cholerae O1 correlate with protection against V. cholerae O1 infection among household contacts of cholera patients. Protection against cholera is serogroup specific, and serogroup specificity is defined by the O-specific polysaccharide (OSP) component of LPS. Therefore, we prospectively followed household contacts of cholera patients to determine whether OSP-specific immune responses present at the time of enrollment are associated with protection against V. cholerae infection.

Methodology

In this study, we enrolled two hundred forty two household contacts of one hundred fifty index patients who were infected with Vibrio cholerae. We determined OSP-specific memory B cells and plasma IgA, IgG and IgM antibody responses on study entry (day 2).

Principle findings

The presence of OSP-specific plasma IgA, IgM, and IgG antibody responses on study entry were associated with a decrease in the risk of infection in household contacts (IgA, p = 0.015; IgM, p = 0.01, and IgG, p = 0.024). In addition, the presence of OSP-specific IgG memory B cell responses in peripheral blood on study entry was also associated with a decreased risk of infection (44% reduction; 95% CI: 31.1 to 99.8) in contacts. No protection was associated with cholera toxin B subunit (CtxB)-specific memory B cell responses.

Conclusion

These results suggest that immune responses that target OSP, both in plasma and memory responses, may be important in mediating protection against infection with V. cholerae O1.

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(XML) Open label comparative trial of mono versus dual antibiotic therapy for Typhoid Fever in adults

2018-04-23T21:00:00Z

by Niv Zmora, Sudeep Shrestha, Ami Neuberger, Yael Paran, Rajendra Tamrakar, Ashish Shrestha, Surendra K. Madhup, T. R. S. Bedi, Rajendra Koju, Eli Schwartz

Background

Emerging resistance to antibiotics renders therapy of Typhoid Fever (TF) increasingly challenging. The current single-drug regimens exhibit prolonged fever clearance time (FCT), imposing a great burden on both patients and health systems, and potentially contributing to the development of antibiotic resistance and the chronic carriage of the pathogens. The aim of our study was to assess the efficacy of combining third-generation cephalosporin therapy with azithromycin on the outcomes of TF in patients living in an endemic region.

Methods

An open-label, comparative trial was conducted at Dhulikhel Hospital, Nepal, between October 2012 and October 2014. Only culture-confirmed TF cases were eligible. Patients were alternately allocated to one of four study arms: hospitalized patients received either intravenous ceftriaxone or a combination of ceftriaxone and oral azithromycin, while outpatients received either oral azithromycin or a combination of oral azithromycin and cefexime. The primary outcome evaluated was FCT and the secondary outcomes included duration of bacteremia.

Results

105 blood culture-confirmed patients, of whom 51 were treated as outpatients, were eligible for the study. Of the 88 patients who met the inclusion criteria for FCT analysis 41 patients received a single-agent regimen, while 47 patients received a combined regimen. Results showed that FCT was significantly shorter for the latter (95 versus 88 hours, respectively, p = 0·004), and this effect was exhibited in both the hospitalized and the outpatient sub-groups. Repeat blood cultures, drawn on day 3, were positive for 8/47 (17%) patients after monotherapy, versus 2/51 (4%) after combination therapy (p = 0·045). No severe complications or fatalities occurred in any of the groups.

Conclusions

Combined therapy of third-generation cephalosporins and azithromycin for TF may surpass monotherapy in terms of FCT and time to elimination of bacteremia.

Trial registration

Trial registration number: NCT02224040.

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(XML) First cases of European bat lyssavirus type 1 in Iberian serotine bats: Implications for the molecular epidemiology of bat rabies in Europe

2018-04-23T21:00:00Z

by Patricia Mingo-Casas, Virginia Sandonís, Elena Obón, José M. Berciano, Sonia Vázquez-Morón, Javier Juste, Juan E. Echevarría

Previous studies have shown that EBLV-1 strains exclusively hosted by Eptesicus isabellinus bats in the Iberian Peninsula cluster in a specific monophyletic group that is related to the EBLV-1b lineage found in the rest of Europe. More recently, enhanced passive surveillance has allowed the detection of the first EBLV-1 strains associated to Eptesicus serotinus south of the Pyrenees. The aim of this study is the reconstruction of the EBLV-1 phylogeny and phylodynamics in the Iberian Peninsula in the context of the European continent. We have sequenced 23 EBLV-1 strains detected on nine E. serotinus and 14 E. isabellinus. Phylogenetic analyses were performed on the first 400-bp-5’ fragment of the Nucleoprotein (N) gene together with other 162 sequences from Europe. Besides, fragments of the variable region of the phosphoprotein (P) gene and the glycoprotein-polymerase (G-L) intergenic region were studied on Spanish samples. Phylogenies show that two of the new EBLV-1a strains from Iberian E. serotinus clustered together with French strains from the North of the Pyrenees, suggesting a recent expansion southwards of this subtype. The remaining seven Iberian strains from E. serotinus grouped, instead, within the cluster linked, so far, to E. isabellinus, indicating that spatial distribution prevails over species specificity in explaining rabies distribution and supporting interspecific transmission. The structure found within the Iberian Peninsula for EBLV-1b is in concordance with that described previously for E. isabellinus. Finally, we have found that the current EBLV-1 European strains could have emerged only 175 years ago according to our evolutionary dynamics analyses.(image)



(XML) SmSP2: A serine protease secreted by the blood fluke pathogen Schistosoma mansoni with anti-hemostatic properties

2018-04-20T21:00:00Z

by Adrian Leontovyč, Lenka Ulrychová, Anthony J. O’Donoghue, Jiří Vondrášek, Lucie Marešová, Martin Hubálek, Pavla Fajtová, Marta Chanová, Zhenze Jiang, Charles S. Craik, Conor R. Caffrey, Michael Mareš, Jan Dvořák, Martin Horn

Background

Serine proteases are important virulence factors for many pathogens. Recently, we discovered a group of trypsin-like serine proteases with domain organization unique to flatworm parasites and containing a thrombospondin type 1 repeat (TSR-1). These proteases are recognized as antigens during host infection and may prove useful as anthelminthic vaccines, however their molecular characteristics are under-studied. Here, we characterize the structural and proteolytic attributes of serine protease 2 (SmSP2) from Schistosoma mansoni, one of the major species responsible for the tropical infectious disease, schistosomiasis.

Methodology/Principal findings

SmSP2 comprises three domains: a histidine stretch, TSR-1 and a serine protease domain. The cleavage specificity of recombinant SmSP2 was determined using positional scanning and multiplex combinatorial libraries and the determinants of specificity were identified with 3D homology models, demonstrating a trypsin-like endopeptidase mode of action. SmSP2 displayed restricted proteolysis on protein substrates. It activated tissue plasminogen activator and plasminogen as key components of the fibrinolytic system, and released the vasoregulatory peptide, kinin, from kininogen. SmSP2 was detected in the surface tegument, esophageal glands and reproductive organs of the adult parasite by immunofluorescence microscopy, and in the excretory/secretory products by immunoblotting.

Conclusions/Significance

The data suggest that SmSP2 is secreted, functions at the host-parasite interface and contributes to the survival of the parasite by manipulating host vasodilatation and fibrinolysis. SmSP2 may be, therefore, a potential target for anti-schistosomal therapy.

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(XML) Morphophysiological changes in the splenic extracellular matrix of Leishmania infantum-naturally infected dogs is associated with alterations in lymphoid niches and the CD4+ T cell frequency in spleens

2018-04-20T21:00:00Z

by Aurea Virginia Andrade da Silva, Fabiano Borges Figueiredo, Rodrigo Caldas Menezes, Arthur Augusto Mendes-Junior, Luisa Helena Monteiro de Miranda, Elisa Cupolillo, Renato Porrozzi, Fernanda Nazaré Morgado

The spleen is one of the main affected organs in canine visceral leishmaniasis (CVL). Disorganization of the splenic white pulp (SWP) has been associated with immunosuppression and disease progression. This study aims to assess structural and cellular changes in the splenic extracellular matrix of dogs with CVL, correlating these changes with the parasite load and clinical signs. Splenic fragments were collected from 41 naturally infected animals for parasite load quantification by quantitative PCR, histopathological analysis and immunohistochemistry for CD3+, CD4+, and CD8+ T cells; CD21+ B cells; Ki-67+, IFN-γ+, and IL-10+ cells; and the MMP-9 and ADAM-10 enzymes. Laminin, collagen and fibronectin deposition were also evaluated. The animals were grouped according to the level of SWP organization. SWP disorganization was accompanied by a reduction in the quantity of lymphoid follicles/mm2 (p > 0.0001). Animals with moderate to intense SWP disorganization showed more clinical signs (p = 0.021), higher laminin (p = 0.045) and collagen deposition (p = 0.036), higher MMP-9 expression (p = 0.035) and lower numbers of CD4+ T cells (p = 0.027) in the spleen than the animals with organized SWP. These data suggest that splenic structure and function are drastically altered and compromised during CVL.(image)



(XML) Implications of current therapeutic restrictions for primaquine and tafenoquine in the radical cure of vivax malaria

2018-04-20T21:00:00Z

by James Watson, Walter R. J. Taylor, Germana Bancone, Cindy S. Chu, Podjanee Jittamala, Nicholas J. White

Background

The 8-aminoquinoline antimalarials, the only drugs which prevent relapse of vivax and ovale malaria (radical cure), cause dose-dependent oxidant haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Patients with <30% and <70% of normal G6PD activity are not given standard regimens of primaquine and tafenoquine, respectively. Both drugs are currently considered contraindicated in pregnant and lactating women.

Methods

Quantitative G6PD enzyme activity data from 5198 individuals were used to estimate the proportions of heterozygous females who would be ineligible for treatment at the 30% and 70% activity thresholds, and the relationship with the severity of the deficiency. This was used to construct a simple model relating allele frequency in males to the potential population coverage of tafenoquine and primaquine under current prescribing restrictions.

Findings

Independent of G6PD deficiency, the current pregnancy and lactation restrictions will exclude ~13% of females from radical cure treatment. This could be reduced to ~4% if 8-aminoquinolines can be prescribed to women breast-feeding infants older than 1 month. At a 30% activity threshold, approximately 8–19% of G6PD heterozygous women are ineligible for primaquine treatment; at a 70% threshold, 50–70% of heterozygous women and approximately 5% of G6PD wild type individuals are ineligible for tafenoquine treatment. Thus, overall in areas where the G6PDd allele frequency is >10% more than 15% of men and more than 25% of women would be unable to receive tafenoquine. In vivax malaria infected patients these proportions will be lowered by any protective effect against P. vivax conferred by G6PD deficiency.

Conclusion

If tafenoquine is deployed for radical cure, primaquine will still be needed to obtain high population coverage. Better radical cure antimalarial regimens are needed.

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(XML) Progress in the pharmacological treatment of human cystic and alveolar echinococcosis: Compounds and therapeutic targets

2018-04-20T21:00:00Z

by Mar Siles-Lucas, Adriano Casulli, Roberto Cirilli, David Carmena

Human cystic and alveolar echinococcosis are helmintic zoonotic diseases caused by infections with the larval stages of the cestode parasites Echinococcus granulosus and E. multilocularis, respectively. Both diseases are progressive and chronic, and often fatal if left unattended for E. multilocularis. As a treatment approach, chemotherapy against these orphan and neglected diseases has been available for more than 40 years. However, drug options were limited to the benzimidazoles albendazole and mebendazole, the only chemical compounds currently licensed for treatment in humans. To compensate this therapeutic shortfall, new treatment alternatives are urgently needed, including the identification, development, and assessment of novel compound classes and drug targets. Here is presented a thorough overview of the range of compounds that have been tested against E. granulosus and E. multilocularis in recent years, including in vitro and in vivo data on their mode of action, dosage, administration regimen, therapeutic outcomes, and associated clinical symptoms. Drugs covered included albendazole, mebendazole, and other members of the benzimidazole family and their derivatives, including improved formulations and combined therapies with other biocidal agents. Chemically synthetized molecules previously known to be effective against other infectious and non-infectious conditions such as anti-virals, antibiotics, anti-parasites, anti-mycotics, and anti-neoplastics are addressed. In view of their increasing relevance, natural occurring compounds derived from plant and fungal extracts are also discussed. Special attention has been paid to the recent application of genomic science on drug discovery and clinical medicine, particularly through the identification of small inhibitor molecules tackling key metabolic enzymes or signalling pathways.(image)



(XML) A 2015 outbreak of flea-borne rickettsiosis in San Gabriel Valley, Los Angeles County, California

2018-04-20T21:00:00Z

by Kimberly Nelson, Alice N. Maina, Angela Brisco, Chelsea Foo, Curtis Croker, Van Ngo, Rachel Civen, Allen L. Richards, Kenn Fujioka, J. Wakoli Wekesa

Although flea-borne rickettsiosis is endemic in Los Angeles County, outbreaks are rare. In the spring of 2015 three human cases of flea-borne rickettsiosis among residents of a mobile home community (MHC) prompted an investigation. Fleas were ubiquitous in common areas due to presence of flea-infested opossums and overabundant outdoor cats and dogs. The MHC was summarily abated in June 2015, and within five months, flea control and removal of animals significantly reduced the flea population. Two additional epidemiologically-linked human cases of flea-borne rickettsiosis detected at the MHC were suspected to have occurred before control efforts began. Molecular testing of 106 individual and 85 pooled cat fleas, blood and ear tissue samples from three opossums and thirteen feral cats using PCR amplification and DNA sequencing detected rickettsial DNA in 18.8% of the fleas. Seventeen percent of these cat fleas tested positive for R. felis-specific DNA compared to under two (<2) percent for Candidatus R. senegalensis-specific DNA. In addition, serological testing of 13 cats using a group-specific IgG-ELISA detected antibodies against typhus group rickettsiae and spotted fever group rickettsiae in six (46.2%) and one (7.7%) cat, respectively. These results indicate that cats and their fleas may have played an active role in the epidemiology of the typhus group and/or spotted fever group rickettsial disease(s) in this outbreak.(image)



(XML) Vector competence of Italian Aedes albopictus populations for the chikungunya virus (E1-226V)

2018-04-19T21:00:00Z

by Francesco Severini, Daniela Boccolini, Claudia Fortuna, Marco Di Luca, Luciano Toma, Antonello Amendola, Eleonora Benedetti, Giada Minelli, Roberto Romi, Giulietta Venturi, Giovanni Rezza, Maria Elena Remoli

Background

Chikungunya virus (CHIKV) is an emerging arbovirus, belonging to the Togaviridae family, Alphavirus genus, transmitted by Aedes spp. mosquitoes. Since 2007, two different CHIKV stains (E1-226A and E1-226V) have been responsible for outbreaks in European countries, including Italy, sustained by Ae. albopictus mosquitoes.

Findings

In this study, we assessed the susceptibility to the CHIKV E1-226V, strain responsible for the Italian 2007 outbreak, of eight Ae. albopictus populations collected in Northern, Central, Southern, and Island Italy, by experimental infections. Vector competence was evaluated by estimating infection, dissemination, and transmission rates (IR, DR, TR), through detection of the virus in the bodies, legs plus wings, and saliva, respectively. Additionally, vertical transmission was evaluated by the detection of the virus in the offspring. The results of our study demonstrated that the Italian populations of Ae. albopictus tested were susceptible to CHIKV infection, and can disseminate the virus outside the midgut barrier with high values of IR and DR. Viral infectious RNA was detected in the saliva of three populations from Central, Southern, and Island Italy, also tested for TR and population transmission rate (PTR) values. No progeny of the first and second gonotrophic cycle were positive for CHIKV.

Conclusions

This study strongly confirms the role of Ae. albopictus as a potential CHIKV vector in Italy. This may represent a threat, especially considering both the high density of this species, which is widespread throughout the country, and the increasing number of cases of imported arbovirus.

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(XML) Nucleobases and corresponding nucleosides display potent antiviral activities against dengue virus possibly through viral lethal mutagenesis

2018-04-19T21:00:00Z

by Li Qiu, Steven E. Patterson, Laurent F. Bonnac, Robert J. Geraghty

Dengue virus affects millions of people worldwide each year. To date, there is no drug for the treatment of dengue-associated disease. Nucleosides are effective antivirals and work by inhibiting the accurate replication of the viral genome. Nucleobases offer a cheaper alternative to nucleosides for broad antiviral applications. Metabolic activation of nucleobases involves condensation with 5-phosphoribosyl-1-pyrophosphate to give the corresponding nucleoside-5’-monophosphate. This could provide an alternative to phosphorylation of a nucleoside, a step that is often rate limiting and inefficient in activation of nucleosides. We evaluated more than 30 nucleobases and corresponding nucleosides for their antiviral activity against dengue virus. Five nucleobases and two nucleosides were found to induce potent antiviral effects not previously described. Our studies further revealed that nucleobases were usually more active with a better tissue culture therapeutic index than their corresponding nucleosides. The development of viral lethal mutagenesis, an antiviral approach that takes into account the quasispecies behavior of RNA viruses, represents an exciting prospect not yet studied in the context of dengue replication. Passage of the virus in the presence of the nucleobase 3a (T-1105) and corresponding nucleoside 3b (T-1106), favipiravir derivatives, induced an increase in apparent mutations, indicating lethal mutagenesis as a possible antiviral mechanism. A more concerted and widespread screening of nucleobase libraries is a very promising approach to identify dengue virus inhibitors including those that may act as viral mutagens.(image)



(XML) Point-of-care tests for syphilis and yaws in a low-income setting – A qualitative study of healthcare worker and patient experiences

2018-04-19T21:00:00Z

by Michael Marks, Tommy Esau, Rowena Asugeni, Relmah Harrington, Jason Diau, Hilary Toloka, James Asugeni, Eimhin Ansbro, Anthony W. Solomon, David Maclaren, Michelle Redman-Maclaren, David C. W. Mabey

Introduction

The human treponematoses comprise venereal syphilis and the three non-venereal or endemic treponematoses yaws, bejel, and pinta. Serological assays remain the most common diagnostic method for all treponemal infections.Point-of-care tests (POCTs) for syphilis and yaws allow testing without further development of infrastructure in populations where routine laboratory facilities are not available. Alongside the test’s performance characteristics assessed through diagnostic evaluation, it is important to consider broader issues when rolling out a POCT. Experience with malaria POCT roll-out in sub-Saharan Africa has demonstrated that both healthcare worker and patient beliefs may play a major role in shaping the real-world use of POCTs. We conducted a qualitative study evaluating healthcare worker and patient perceptions of using a syphilis/yaws POCT in clinics in the East Malaita region of Malaita province in the Solomon Islands. Prior to the study serology was only routinely available at the local district hospital.

Methods

The POCT was deployed in the outpatient and ante-natal departments of a district hospital and four rural health clinics served by the hospital. Each site was provided with training and an SOP on the performance, interpretation and recording of results. Treatment for those testing positive was provided, in line with Solomon Islands Ministry of Health and Medical Services’ guidelines for syphilis and yaws respectively. Alongside the implementation of the POCT we facilitated semi-structured interviews with both nurses and patients to explore individuals’ experiences and beliefs in relation to use of the POCT.

Results and discussion

Four main themes emerged in the interviews: 1) training and ease of performing the test; 2) time taken and ability to fit the test into a clinical workflow; 3) perceived reliability and trustworthiness of the test; and 4) level of the health care system the test was most usefully deployed. Many healthcare workers related their experience with the POCT to their experience using similar tests for malaria. Although the test was considered to take a relatively long time to perform the benefits of improved access to testing were considered positive by most healthcare workers. Qualitative data is needed to help inform better training packages to support the implementation of POCT in low-resource settings.

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(XML) Rodent-borne diseases and their public health importance in Iran

2018-04-19T21:00:00Z

by Mohammad Hasan Rabiee, Ahmad Mahmoudi, Roohollah Siahsarvie, Boris Kryštufek, Ehsan Mostafavi

Background

Rodents are reservoirs and hosts for several zoonotic diseases such as plague, leptospirosis, and leishmaniasis. Rapid development of industry and agriculture, as well as climate change throughout the globe, has led to change or increase in occurrence of rodent-borne diseases. Considering the distribution of rodents throughout Iran, the aim of this review is to assess the risk of rodent-borne diseases in Iran.

Methodology/Principal finding

We searched Google Scholar, PubMed, Science Direct, Scientific Information Database (SID), and Magiran databases up to September 2016 to obtain articles reporting occurrence of rodent-borne diseases in Iran and extract information from them. Out of 70 known rodent-borne diseases, 34 were reported in Iran: 17 (50%) parasitic diseases, 13 (38%) bacterial diseases, and 4 (12%) viral diseases. Twenty-one out of 34 diseases were reported from both humans and rodents. Among the diseases reported in the rodents of Iran, plague, leishmaniasis, and hymenolepiasis were the most frequent. The most infected rodents were Rattus norvegicus (16 diseases), Mus musculus (14 diseases), Rattus rattus (13 diseases), Meriones persicus (7 diseases), Apodemus spp. (5 diseases), Tatera indica (4 diseases), Meriones libycus (3 diseases), Rhombomys opimus (3 diseases), Cricetulus migratorius (3 diseases), and Nesokia indica (2 diseases).

Conclusions/Significance

The results of this review indicate the importance of rodent-borne diseases in Iran. Considering notable diversity of rodents and their extensive distribution throughout the country, it is crucial to pay more attention to their role in spreading infectious diseases for better control of the diseases.

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(XML) Use of primaquine and glucose-6-phosphate dehydrogenase deficiency testing: Divergent policies and practices in malaria endemic countries

2018-04-19T21:00:00Z

by Judith Recht, Elizabeth A. Ashley, Nicholas J. White

Primaquine is the only available antimalarial drug that kills dormant liver stages of Plasmodium vivax and Plasmodium ovale malarias and therefore prevents their relapse (‘radical cure’). It is also the only generally available antimalarial that rapidly sterilises mature P. falciparum gametocytes. Radical cure requires extended courses of primaquine (usually 14 days; total dose 3.5–7 mg/kg), whereas transmissibility reduction in falciparum malaria requires a single dose (formerly 0.75 mg/kg, now a single low dose [SLD] of 0.25 mg/kg is recommended). The main adverse effect of primaquine is dose-dependent haemolysis in glucose 6-phosphate dehydrogenase (G6PD) deficiency, the most common human enzymopathy. X-linked mutations conferring varying degrees of G6PD deficiency are prevalent throughout malaria-endemic regions. Phenotypic screening tests usually detect <30% of normal G6PD activity, identifying nearly all male hemizygotes and female homozygotes and some heterozygotes. Unfortunately, G6PD deficiency screening is usually unavailable at point of care, and, as a consequence, radical cure is greatly underused. Both haemolytic risk (determined by the prevalence and severity of G6PD deficiency polymorphisms) and relapse rates vary, so there has been considerable uncertainty in both policies and practices related to G6PD deficiency testing and use of primaquine for radical cure. Review of available information on the prevalence and severity of G6PD variants together with countries’ policies for the use of primaquine and G6PD deficiency testing confirms a wide range of practices. There remains lack of consensus on the requirement for G6PD deficiency testing before prescribing primaquine radical cure regimens. Despite substantially lower haemolytic risks, implementation of SLD primaquine as a P. falciparum gametocytocide also varies. In Africa, a few countries have recently adopted SLD primaquine, yet many with areas of low seasonal transmission do not use primaquine as an antimalarial at all. Most countries that recommended the higher 0.75 mg/kg single primaquine dose for falciparum malaria (e.g., most countries in the Americas) have not changed their recommendation. Some vivax malaria–endemic countries where G6PD deficiency testing is generally unavailable have adopted the once-weekly radical cure regimen (0.75 mg/kg/week for 8 weeks), known to be safer in less severe G6PD deficiency variants. There is substantial room for improvement in radical cure policies and practices.(image)



(XML) Could violent conflict derail the London Declaration on NTDs?

2018-04-19T21:00:00Z

by Rebecca Y. Du, Jeffrey D. Stanaway, Peter J. Hotez

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(XML) Activation of host transient receptor potential (TRP) channels by praziquantel stereoisomers

2018-04-18T21:00:00Z

by Gihan S. Gunaratne, Nawal Yahya, Peter I. Dosa, Jonathan S. Marchant

The anthelmintic praziquantel (±PZQ) serves as a highly effective antischistosomal therapy. ±PZQ causes a rapid paralysis of adult schistosome worms and deleterious effects on the worm tegument. In addition to these activities against the parasite, ±PZQ also modulates host vascular tone in blood vessels where the adult worms reside. In resting mesenteric arteries ±PZQ causes a constriction of basal tone, an effect mediated by (R)-PZQ activation of endogenous serotoninergic G protein coupled receptors (GPCRs). Here, we demonstrate a novel vasodilatory action of ±PZQ in mesenteric vessels that are precontracted by high potassium-evoked depolarization, an effect previously reported to be associated with agonists of the transient receptor potential melastatin 8 channel (TRPM8). Pharmacological profiling a panel of 17 human TRPs demonstrated ±PZQ activity against a subset of human TRP channels. Several host TRP channels (hTRPA1, hTRPC3, hTRPC7) were activated by both (R)-PZQ and (S)-PZQ over a micromolar range whereas hTRPM8 showed stereoselective activation by (S)-PZQ. The relaxant effect of ±PZQ in mesenteric arteries was caused by (S)-PZQ, not (R)-PZQ, and mimicked by TRPM8 agonists. However, persistence of both (S)-PZQ and TRPM8 agonist evoked vessel relaxation in TRPM8 knockout tissue suggested that canonical TRPM8 does not mediate this (S)-PZQ effect. We conclude that (S)-PZQ is vasoactive over the micromolar range in mesenteric arteries although the molecular mediators of this effect remain to be identified. These data expand our knowledge of the polypharmacology and host vascular efficacy of this clinically important anthelmintic.(image)



(XML) Establishment of a mouse model for the complete mosquito-mediated transmission cycle of Zika virus

2018-04-18T21:00:00Z

by Yi-Ping Kuo, Kuen-Nan Tsai, Yin-Chiu Luo, Pei-Jung Chung, Yu-Wen Su, Yu Teng, Ming-Sian Wu, Yu-Feng Lin, Chao-Yang Lai, Tsung-Hsien Chuang, Shih-Syong Dai, Fan-Chen Tseng, Cheng-Han Hsieh, De-Jiun Tsai, Wan-Ting Tsai, Chun-Hong Chen, Guann-Yi Yu

Zika virus (ZIKV) is primarily transmitted by Aedes mosquitoes in the subgenus Stegomyia but can also be transmitted sexually and vertically in humans. STAT1 is an important downstream factor that mediates type I and II interferon signaling. In the current study, we showed that mice with STAT1 knockout (Stat1-/-) were highly susceptible to ZIKV infection. As low as 5 plaque-forming units of ZIKV could cause viremia and death in Stat1-/- mice. ZIKV replication was initially detected in the spleen but subsequently spread to the brain with concomitant reduction of the virus in the spleen in the infected mice. Furthermore, ZIKV could be transmitted from mosquitoes to Stat1-/- mice back to mosquitoes and then to naïve Stat1-/- mice. The 50% mosquito infectious dose of viremic Stat1-/- mouse blood was close to 810 focus-forming units (ffu)/ml. Our further studies indicated that the activation of macrophages and conventional dendritic cells were likely critical for the resolution of ZIKV infection. The newly developed mouse and mosquito transmission models for ZIKV infection will be useful for the evaluation of antiviral drugs targeting the virus, vector, and host.(image)



(XML) Similarities and differences between helminth parasites and cancer cell lines in shaping human monocytes: Insights into parallel mechanisms of immune evasion

2018-04-18T21:00:00Z

by Prakash Babu Narasimhan, Leor Akabas, Sameha Tariq, Naureen Huda, Sasisekhar Bennuru, Helen Sabzevari, Robert Hofmeister, Thomas B. Nutman, Roshanak Tolouei Semnani

A number of features at the host-parasite interface are reminiscent of those that are also observed at the host-tumor interface. Both cancer cells and parasites establish a tissue microenvironment that allows for immune evasion and may reflect functional alterations of various innate cells. Here, we investigated how the phenotype and function of human monocytes is altered by exposure to cancer cell lines and if these functional and phenotypic alterations parallel those induced by exposure to helminth parasites. Thus, human monocytes were exposed to three different cancer cell lines (breast, ovarian, or glioblastoma) or to live microfilariae (mf) of Brugia malayi–a causative agent of lymphatic filariasis. After 2 days of co-culture, monocytes exposed to cancer cell lines showed markedly upregulated expression of M1-associated (TNF-α, IL-1β), M2-associated (CCL13, CD206), Mreg-associated (IL-10, TGF-β), and angiogenesis associated (MMP9, VEGF) genes. Similar to cancer cell lines, but less dramatically, mf altered the mRNA expression of IL-1β, CCL13, and TGM2 and MMP9. When surface expression of the inhibitory ligands PDL1 and PDL2 was assessed, monocytes exposed to both cancer cell lines and to live mf significantly upregulated PDL1 and PDL2 expression. In contrast to exposure to mf, exposure to cancer cell lines increased the phagocytic ability of monocytes and reduced their ability to induce T cell proliferation and to expand Granzyme A+ CD8+ T cells. Our data suggest that despite the fact that helminth parasites and cancer cell lines are extraordinarily disparate, they share the ability to alter the phenotype of human monocytes.(image)



(XML) Genetic profiling of Mycobacterium bovis strains from slaughtered cattle in Eritrea

2018-04-17T21:00:00Z

by Michael Kahsay Ghebremariam, Tiny Hlokwe, Victor P. M. G. Rutten, Alberto Allepuz, Simeon Cadmus, Adrian Muwonge, Suelee Robbe-Austerman, Anita L. Michel

Mycobacterium bovis (M.bovis) is the main causative agent for bovine tuberculosis (BTB) and can also be the cause of zoonotic tuberculosis in humans. In view of its zoonotic nature, slaughterhouse surveillance, potentially resulting in total or partial condemnation of the carcasses and organs, is conducted routinely.Spoligotyping, VNTR profiling, and whole genome sequencing (WGS)ofM. bovis isolated from tissues with tuberculosis-like lesions collected from 14 cattle at Eritrea’s largest slaughterhouse in the capital Asmara, were conducted.The 14 M. bovisisolates were classified into three different spoligotype patterns (SB0120, SB0134 and SB0948) and six VNTR profiles. WGSresults matched those of the conventional genotyping methodsand further discriminatedthe six VNTR profiles into 14 strains.Furthermore, phylogenetic analysis of the M. bovisisolates suggests two independent introductions of BTB into Eritrea possibly evolving from a common ancestral strain in Europe.This molecular study revealed the most important strains of M. bovis in Eritrea and their (dis)similarities with the strains generally present in East Africa and Europe, as well as potential routes of introduction of M. bovis. Though the sample size is small, the current study provides important information as well as platform for future in-depth molecular studies on isolates from both the dairy and the traditional livestock sectors in Eritrea and the region. This study provides information onthe origin of some of the M. bovis strains in Eritrea, its genetic diversity, evolution and patterns of spread between dairy herds. Such information is essential in the development and implementation of future BTB control strategy for Eritrea.(image)



(XML) Body lice of homeless people reveal the presence of several emerging bacterial pathogens in northern Algeria

2018-04-17T21:00:00Z

by Meriem Louni, Nassima Mana, Idir Bitam, Mustapha Dahmani, Philippe Parola, Florence Fenollar, Didier Raoult, Oleg Mediannikov

Background

Human lice, Pediculus humanus, are obligate blood-sucking parasites. Body lice, Pediculus h. humanus, occur in two divergent mitochondrial clades (A and D) each exhibiting a particular geographic distribution. Currently, the body louse is recognized as the only vector for louse-borne diseases. In this study, we aimed to study the genetic diversity of body lice collected from homeless populations in three localities of northern Algeria, and to investigate louse-borne pathogens in these lice.

Methodology/Principal findings

In this study, 524 body lice specimens were collected from 44 homeless people in three localities: Algiers, Tizi Ouzou and Boumerdès located in northern Algeria. Duplex clade specific real-time PCRs (qPCR) and Cytochrome b (cytb) mitochondrial DNA (mtDNA) analysis were performed in order to identify the mitochondrial clade. Screening of louse-borne pathogens bacteria was based on targeting specific genes for each pathogen using qPCR supplemented by sequencing. All body lice belong to clade A. Through amplification and sequencing of the cytb gene we confirmed the presence of three haplotypes: A5, A9 and A63, which is novel. The molecular investigation of the 524 body lice samples revealed the presence of four human pathogens: Bartonella quintana (13.35%), Coxiella burnetii (10.52%), Anaplasma phagocytophilum (0.76%) and Acinetobacter species (A. baumannii, A. johnsonii, A. berezeniae, A. nosocomialis and A. variabilis, in total 46.94%).

Conclusions/Significance

To the best of our knowledge, our study is the first to show the genetic diversity and presence of several emerging pathogenic bacteria in homeless’ body lice from Algeria. We also report for the first time, the presence of several species of Acinetobacter in human body lice. Our results highlight the fact that body lice may be suspected as being a much broader vector of several pathogenic agents than previously thought. Nevertheless, other studies are needed to encourage epidemiological investigations and surveys of louse-associated infections.

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(XML) Profiling extracellular vesicle release by the filarial nematode Brugia malayi reveals sex-specific differences in cargo and a sensitivity to ivermectin

2018-04-16T21:00:00Z

by Hiruni Harischandra, Wang Yuan, Hannah J. Loghry, Mostafa Zamanian, Michael J. Kimber

The filarial nematode Brugia malayi is an etiological agent of Lymphatic Filariasis. The capability of B. malayi and other parasitic nematodes to modulate host biology is recognized but the mechanisms by which such manipulation occurs are obscure. An emerging paradigm is the release of parasite-derived extracellular vesicles (EV) containing bioactive proteins and small RNA species that allow secretion of parasite effector molecules and their potential trafficking to host tissues. We have previously described EV release from the infectious L3 stage B. malayi and here we profile vesicle release across all intra-mammalian life cycle stages (microfilariae, L3, L4, adult male and female worms). Nanoparticle Tracking Analysis was used to quantify and size EVs revealing discrete vesicle populations and indicating a secretory process that is conserved across the life cycle. Brugia EVs are internalized by murine macrophages with no preference for life stage suggesting a uniform mechanism for effector molecule trafficking. Further, the use of chemical uptake inhibitors suggests all life stage EVs are internalized by phagocytosis. Proteomic profiling of adult male and female EVs using nano-scale LC-MS/MS described quantitative and qualitative differences in the adult EV proteome, helping define the biogenesis of Brugia EVs and revealing sexual dimorphic characteristics in immunomodulatory cargo. Finally, ivermectin was found to rapidly inhibit EV release by all Brugia life stages. Further this drug effect was also observed in the related filarial nematode, the canine heartworm Dirofilaria immitis but not in an ivermectin-unresponsive field isolate of that parasite, highlighting a potential mechanism of action for this drug and suggesting new screening platforms for anti-filarial drug development.(image)



(XML) In vitro assessment of cytotoxic activities of Lachesis muta muta snake venom

2018-04-16T21:00:00Z

by Stephanie Stransky, Fernanda Costal-Oliveira, Letícia Lopes-de-Souza, Clara Guerra-Duarte, Carlos Chávez-Olórtegui, Vania Maria Martin Braga

Envenomation by the bushmaster snake Lachesis muta muta is considered severe, characterized by local effects including necrosis, the main cause of permanent disability. However, cellular mechanisms related to cell death and tissue destruction, triggered by snake venoms, are poorly explored. The purpose of this study was to investigate the cytotoxic effect caused by L. m. muta venom in normal human keratinocytes and to identify the cellular processes involved in in cellulo envenomation. In order to investigate venom effect on different cell types, Alamar Blue assay was performed to quantify levels of cellular metabolism as a readout of cell viability. Apoptosis, necrosis and changes in mitochondrial membrane potential were evaluated by flow cytometry, while induction of autophagy was assessed by expression of GFP-LC3 and analyzed using fluorescence microscopy. The cytotoxic potential of the venom is shown by reduced cell viability in a concentration-dependent manner. It was also observed the sequential appearance of cells undergoing autophagy (by 6 hours), apoptosis and necrosis (12 and 24 hours). Morphologically, incubation with L. m. muta venom led to a significant cellular retraction and formation of cellular aggregates. These results indicate that L. m. muta venom is cytotoxic to normal human keratinocytes and other cell lines, and this toxicity involves the integration of distinct modes of cell death. Autophagy as a cell death mechanism, in addition to apoptosis and necrosis, can help to unravel cellular pathways and mechanisms triggered by the venom. Understanding the mechanisms that underlie cellular damage and tissue destruction will be useful in the development of alternative therapies against snakebites.(image)



(XML) The impact of school water, sanitation, and hygiene improvements on infectious disease using serum antibody detection

2018-04-16T21:00:00Z

by Anna N. Chard, Victoria Trinies, Delynn M. Moss, Howard H. Chang, Seydou Doumbia, Patrick J. Lammie, Matthew C. Freeman

Background

Evidence from recent studies assessing the impact of school water, sanitation and hygiene (WASH) interventions on child health has been mixed. Self-reports of disease are subject to bias, and few WASH impact evaluations employ objective health measures to assess reductions in disease and exposure to pathogens. We utilized antibody responses from dried blood spots (DBS) to measure the impact of a school WASH intervention on infectious disease among pupils in Mali.

Methodology/Principal findings

We randomly selected 21 beneficiary primary schools and their 21 matched comparison schools participating in a matched-control trial of a comprehensive school-based WASH intervention in Mali. DBS were collected from 20 randomly selected pupils in each school (n = 807). We analyzed eluted IgG from the DBS using a Luminex multiplex bead assay to 28 antigens from 17 different pathogens. Factor analysis identified three distinct latent variables representing vector-transmitted disease (driven primarily by dengue), food/water-transmitted enteric disease (driven primarily by Escherichia coli and Vibrio cholerae), and person-to-person transmitted enteric disease (driven primarily by norovirus). Data were analyzed using a linear latent variable model. Antibody evidence of food/water-transmitted enteric disease (change in latent variable mean (β) = -0.24; 95% CI: -0.53, -0.13) and person-to-person transmitted enteric disease (β = -0.17; 95% CI: -0.42, -0.04) was lower among pupils attending beneficiary schools. There was no difference in antibody evidence of vector-transmitted disease (β = 0.11; 95% CI: -0.05, 0.33).

Conclusions/Significance

Evidence of enteric disease was lower among pupils attending schools benefitting from school WASH improvements than students attending comparison schools. These findings support results from the parent study, which also found reduced incidence of self-reported diarrhea among pupils of beneficiary schools. DBS collection was feasible in this resource-poor field setting and provided objective evidence of disease at a low cost per antigen analyzed, making it an effective measurement tool for the WASH field.

Trial registration

The trial was registered at ClinicalTrials.gov (NCT01787058)

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