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IL-10 and NOS2 Modulate Antigen-Specific Reactivity and Nerve Infiltration by T Cells in Experimental Leprosy
by Deanna A. Hagge, David M. Scollard, Nashone A. Ray, Vilma T. Marks, Angelina T. Deming, John S. Spencer, Linda B. AdamsBackground
Although immunopathology dictates clinical outcome in leprosy, the dynamics of early and chronic infection are poorly defined. In the tuberculoid region of the spectrum, Mycobacterium leprae growth is restricted yet a severe granulomatous lesion can occur. The evolution and maintenance of chronic inflammatory processes like those observed in the leprosy granuloma involve an ongoing network of communications via cytokines. IL-10 has immunosuppressive properties and IL-10 genetic variants have been associated with leprosy development and reactions.Methodology/Principal Findings
The role of IL-10 in resistance and inflammation in leprosy was investigated using Mycobacterium leprae infection of mice deficient in IL-10 (IL-10−/−), as well as mice deficient in both inducible nitric oxide synthase (NOS2−/−) and IL-10 (10NOS2−/−). Although a lack of IL-10 did not affect M. leprae multiplication in the footpads (FP), inflammation increased from C57Bl/6 (B6)M. leprae cell wall, membrane, and cytosol antigens and ML2028 (Ag85B) were significantly increased in the evolved granuloma in NOS2−/− FP compared to B6 and IL-10−/− during early and peak phases. In 10NOS2−/− FP, CD4+CD44+ and especially CD8+CD44+ responses were augmented even further to these antigens as well as to ML0380 (GroES), ML2038 (bacterioferritin), and ML1877 (EF-Tu). Moreover, fragmented nerves containing CD4+ cells were present in 10NOS2−/− FP.Conclusions/Significance
The 10NOS2−/− strain offers insight on the regulation of granuloma formation and maintenance by immune modulators in the resistant forms of leprosy and presents a new model for investigating the pathogenesis of neurological involvement.
Direct Comparison of the Efficacy and Safety of Oral Treatments with Oleylphosphocholine (OlPC) and Miltefosine in a Mouse Model of L. major Cutaneous Leishmaniasis
by Anny Fortin, Diana P. Caridha, Susan Leed, Franklyn Ngundam, Jenell Sena, Tom Bosschaerts, Sandi Parriott, Mark R. Hickman, Thomas H. Hudson, Max GroglBackground
Cutaneous leishmaniasis (CL) represents a range of skin diseases caused by infection with Leishmania parasites and associated with tissue inflammation and skin ulceration. CL is clinically widespread in both the Old and New World but lacks treatments that are well tolerated, effective and inexpensive. Oleylphosphocholine (OlPC) is a new orally bioavailable drug of the alkylphosphocholine family with potent antileishmanial activity against a broad range of Leishmania species/strains.Methodology/principal findings
The potential of OlPC against Old World CL was evaluated in a mouse model of Leishmania (L.) major infection in BALB/c mice. Initial dose-response experiments showed that an oral daily dose of 40 mg/kg of OlPC was needed to impact time to cure and lesion sizes. This dose was then used to directly compare the efficacy of OlPC to the efficacy of the antileishmanial drugs miltefosine (40 mg/kg/day), fluconazole (160 mg/kg/day) and amphotericin B (25 mg/kg/day). OlPC, miltefosine and fluconazole were given orally for 21 days while amphotericin B was administered intraperitoneally for 10 days. Ulcer sizes and animal weights were followed up on a weekly basis and parasitemia was determined by means of a real-time in vivo imaging system which detects luminescence emitted from luciferase-expressing infecting L. major parasites. Amphotericin B and OlPC showed excellent efficacy against L. major lesions in terms of reduction of parasitic loads and by inducing complete healing of established lesions. In contrast, treatment with miltefosine did not significantly affect parasitemia and lesion sizes, while fluconazole was completely ineffective at the dose regimen tested.Conclusions/Significance
Given the data showing the outstanding efficacy and tolerability of OlPC, our results suggest that OlPC is a promising new drug candidate to improve and simplify current clinical management of L. major CL.
by Michael Marks, Adriana Goncalves, Ventis Vahi, Oliver Sokana, Elliot Puiahi, Zaixing Zhang, Tenneth Dalipanda, Christian Bottomley, David Mabey, Anthony W. SolomonYaws is a non-venereal treponemal infection caused by Treponema pallidum ssp. pertenue. The WHO has launched a worldwide control programme, which aims to eradicate yaws by 2020. The development of a rapid diagnostic test (RDT) for serological diagnosis in the isolated communities affected by yaws is a key requirement for the successful implementation of the WHO strategy. We conducted a study to evaluate the utility of the DPP test in screening for yaws, utilizing samples collected as part of a community prevalence survey conducted in the Solomon Islands. 415 serum samples were tested using both traditional syphilis serology (TPPA and quantitative RPR) and the Chembio DPP Syphilis Screen and Confirm RDT. We calculated the sensitivity and specificity of the RDT as compared to gold standard serology. The sensitivity of the RDT against TPPA was 58.5% and the specificity was 97.6%. The sensitivity of the RDT against RPR was 41.7% and the specificity was 95.2%. The sensitivity of the DPP was strongly related to the RPR titre with a sensitivity of 92.0% for an RPR titre of >1/16. Wider access to DPP testing would improve our understanding of worldwide yaws case reporting and the test may play a key role in assessing patients presenting with yaws like lesions in a post-mass drug administration (MDA) setting.
Co-infection of Long-Term Carriers of Plasmodium falciparum with Schistosoma haematobium Enhances Protection from Febrile Malaria: A Prospective Cohort Study in Mali
by Safiatou Doumbo, Tuan M. Tran, Jules Sangala, Shanping Li, Didier Doumtabe, Younoussou Kone, Abdrahamane Traoré, Aboudramane Bathily, Nafomon Sogoba, Michel E. Coulibaly, Chiung-Yu Huang, Aissata Ongoiba, Kassoum Kayentao, Mouctar Diallo, Zongo Dramane, Thomas B. Nutman, Peter D. Crompton, Ogobara Doumbo, Boubacar TraoreBackground
Malaria and schistosomiasis often overlap in tropical and subtropical countries and impose tremendous disease burdens; however, the extent to which schistosomiasis modifies the risk of febrile malaria remains unclear.Methods
We evaluated the effect of baseline S. haematobium mono-infection, baseline P. falciparum mono-infection, and co-infection with both parasites on the risk of febrile malaria in a prospective cohort study of 616 children and adults living in Kalifabougou, Mali. Individuals with S. haematobium were treated with praziquantel within 6 weeks of enrollment. Malaria episodes were detected by weekly physical examination and self-referral for 7 months. The primary outcome was time to first or only malaria episode defined as fever (≥37.5°C) and parasitemia (≥2500 asexual parasites/µl). Secondary definitions of malaria using different parasite densities were also explored.Results
After adjusting for age, anemia status, sickle cell trait, distance from home to river, residence within a cluster of high S. haematobium transmission, and housing type, baseline P. falciparum mono-infection (n = 254) and co-infection (n = 39) were significantly associated with protection from febrile malaria by Cox regression (hazard ratios 0.71 and 0.44; P = 0.01 and 0.02; reference group: uninfected at baseline). Baseline S. haematobium mono-infection (n = 23) did not associate with malaria protection in the adjusted analysis, but this may be due to lack of statistical power. Anemia significantly interacted with co-infection (P = 0.009), and the malaria-protective effect of co-infection was strongest in non-anemic individuals. Co-infection was an independent negative predictor of lower parasite density at the first febrile malaria episode.Conclusions
Co-infection with S. haematobium and P. falciparum is significantly associated with reduced risk of febrile malaria in long-term asymptomatic carriers of P. falciparum. Future studies are needed to determine whether co-infection induces immunomodulatory mechanisms that protect against febrile malaria or whether genetic, behavioral, or environmental factors not accounted for here explain these findings.
Innovative Approaches to Clinical Data Management in Resource Limited Settings Using Open-Source Technologies
by Raymond Omollo, Michael Ochieng, Brian Mutinda, Truphosa Omollo, Rhoda Owiti, Seth Okeyo, Monique Wasunna, Tansy Edwards
by Rafael Van den Bergh, Jo A. Van Ginderachter, Elio Schouppe, Belete A. Desimmie, Asrat Hailu, Patrick De Baetselier, Johan van Griensven
Impact of a Community-Based Lymphedema Management Program on Episodes of Adenolymphangitis (ADLA) and Lymphedema Progression - Odisha State, India
by Katherine E. Mues, Michael Deming, David G. Kleinbaum, Philip J. Budge, Mitch Klein, Juan S. Leon, Aishya Prakash, Jonathan Rout, LeAnne M. FoxBackground
Lymphedema management programs have been shown to decrease episodes of adenolymphangitis (ADLA), but the impact on lymphedema progression and of program compliance have not been thoroughly explored. Our objectives were to determine the rate of ADLA episodes and lymphedema progression over time for patients enrolled in a community-based lymphedema management program. We explored the association between program compliance and ADLA episodes as well as lymphedema progression.Methodology/Principal Findings
A lymphedema management program was implemented in Odisha State, India from 2007–2010 by the non-governmental organization, Church's Auxiliary for Social Action, in consultation with the Centers for Disease Control and Prevention. A cohort of patients was followed over 24 months. The crude 30-day rate of ADLA episodes decreased from 0.35 episodes per person-month at baseline to 0.23 at 24 months. Over the study period, the percentage of patients who progressed to more severe lymphedema decreased (P-value = 0.0004), while those whose lymphedema regressed increased over time (P-value<0.0001). Overall compliance to lymphedema management, lagged one time point, appeared to have little to no association with the frequency of ADLA episodes among those without entry lesions (RR = 0.87 (0.69, 1.10)) and was associated with an increased rate (RR = 1.44 (1.11, 1.86)) among those with entry lesions. Lagging compliance two time points, it was associated with a decrease in the rate of ADLA episodes among those with entry lesions (RR = 0.77 (95% CI: 0.59, 0.99)) and was somewhat associated among those without entry lesions (RR = 0.83 (95% CI: 0.64, 1.06)). Compliance to soap was associated with a decreased rate of ADLA episodes among those without inter-digital entry lesions.Conclusions/Significance
These results indicate that a community-based lymphedema management program is beneficial for lymphedema patients for both ADLA episodes and lymphedema. It is one of the first studies to demonstrate an association between program compliance and rate of ADLA episodes.
Sensitivity and Specificity of Multiple Kato-Katz Thick Smears and a Circulating Cathodic Antigen Test for Schistosoma mansoni Diagnosis Pre- and Post-repeated-Praziquantel Treatment
by Poppy H. L. Lamberton, Narcis B. Kabatereine, David W. Oguttu, Alan Fenwick, Joanne P. WebsterBackground
Two Kato-Katz thick smears (Kato-Katzs) from a single stool are currently recommended for diagnosing Schistosoma mansoni infections to map areas for intervention. This ‘gold standard’ has low sensitivity at low infection intensities. The urine point-of-care circulating cathodic antigen test (POC-CCA) is potentially more sensitive but how accurately they detect S. mansoni after repeated praziquantel treatments, their suitability for measuring drug efficacy and their correlation with egg counts remain to be fully understood. We compared the accuracies of one to six Kato-Katzs and one POC-CCA for the diagnosis of S. mansoni in primary-school children who have received zero to ten praziquantel treatments. We determined the impact each diagnostic approach may have on monitoring and evaluation (M&E) and drug-efficacy findings.Method/Principle Findings
In a high S. mansoni endemic area of Uganda, three days of consecutive stool samples were collected from primary school-aged children (six - 12 years) at five time-points in year one: baseline, one-week-post-, four-weeks-post-, six-months-post-, and six-months-one-week-post-praziquantel and three time-points in years two and three: pre-, one-week-post- and four-weeks-post-praziquantel-treatment/retreatment (n = 1065). Two Kato-Katzs were performed on each stool. In parallel, one urine sample was collected and a single POC-CCA evaluated per child at each time-point in year one (n = 367). At baseline, diagnosis by two Kato-Katzs (sensitivity = 98.6%) or one POC-CCA (sensitivity = 91.7%, specificity = 75.0%) accurately predicted S. mansoni infections. However, one year later, a minimum of three Kato-Katzs, and two years later, five Kato-Katzs were required for accurate diagnosis (sensitivity >90%) and drug-efficacy evaluation. The POC-CCA was as sensitive as six Kato-Katzs four-weeks-post and six-months-post-treatment, if trace readings were classified as positive.Conclusions/Significance
Six Kato-Katzs (two/stool from three stools) and/or one POC-CCA are required for M&E or drug-efficacy studies. Although unable to measure egg reduction rates, one POC-CCA appears to be more sensitive than six Kato-Katzs at four-weeks-post-praziquantel (drug efficacy) and six-months-post-praziquantel (M&E).
by Piraya Bhoomiboonchoo, Robert V. Gibbons, Angkana Huang, In-Kyu Yoon, Darunee Buddhari, Ananda Nisalak, Natkamol Chansatiporn, Mathuros Thipayamongkolgul, Siripen Kalanarooj, Timothy Endy, Alan L. Rothman, Anon Srikiatkhachorn, Sharone Green, Mammen P. Mammen, Derek A. Cummings, Henrik SaljeBackground
Dengue is endemic to the rural province of Kamphaeng Phet, Northern Thailand. A decade of prospective cohort studies has provided important insights into the dengue viruses and their generated disease. However, as elsewhere, spatial dynamics of the pathogen remain poorly understood. In particular, the spatial scale of transmission and the scale of clustering are poorly characterized. This information is critical for effective deployment of spatially targeted interventions and for understanding the mechanisms that drive the dispersal of the virus.Methodology/Principal Findings
We geocoded the home locations of 4,768 confirmed dengue cases admitted to the main hospital in Kamphaeng Phet province between 1994 and 2008. We used the phi clustering statistic to characterize short-term spatial dependence between cases. Further, to see if clustering of cases led to similar temporal patterns of disease across villages, we calculated the correlation in the long-term epidemic curves between communities. We found that cases were 2.9 times (95% confidence interval 2.7–3.2) more likely to live in the same village and be infected within the same month than expected given the underlying spatial and temporal distribution of cases. This fell to 1.4 times (1.2–1.7) for individuals living in villages 1 km apart. Significant clustering was observed up to 5 km. We found a steadily decreasing trend in the correlation in epidemics curves by distance: communities separated by up to 5 km had a mean correlation of 0.28 falling to 0.16 for communities separated between 20 km and 25 km. A potential explanation for these patterns is a role for human movement in spreading the pathogen between communities. Gravity style models, which attempt to capture population movement, outperformed competing models in describing the observed correlations.Conclusions
There exists significant short-term clustering of cases within individual villages. Effective spatially and temporally targeted interventions deployed within villages may target ongoing transmission and reduce infection risk.
by Seth E. O'Neal, Luz M. Moyano, Viterbo Ayvar, Silvia Rodriguez, Cesar Gavidia, Patricia P. Wilkins, Robert H. Gilman, Hector H. Garcia, Armando E. Gonzalez, for The Cysticercosis Working Group in PeruBackground
Taenia solium is a major cause of preventable epilepsy in developing nations. Screening and treatment of human intestinal stage infection (taeniasis) within high-risk foci may reduce transmission and prevent epilepsy by limiting human exposure to infective eggs. We piloted a ring-strategy that involves screening and treatment for taeniasis among households located nearby pigs heavily-infected with the larval stage (cysticercosis). These pigs mark areas of increased transmission and can be identified by tongue examination.Methodology
We selected two villages in northern Peru for a controlled prospective interventional cohort pilot study. In the intervention village (1,058 residents) we examined the tongues of all pigs every 4 months for nodules characteristic of cysticercosis. We then screened all residents living within 100-meters of any tongue-positive pig using enzyme-linked immunosorbent assay to detect Taenia antigens in stool. Residents with taeniasis were treated with niclosamide. In both the intervention and control (753 residents) we measured incidence of exposure by sampling the pig population every 4 months for serum antibodies against cysticercosis using enzyme-linked immunoelectrotransfer blot.Principal Findings
Baseline seroincidence among pigs born during the study was 22.6 cases per 100 pigs per-month (95% confidence interval [CI] 17.0–30.0) in the intervention and 18.1 (95% CI 12.7–25.9) in the control. After one year we observed a 41% reduction in seroincidence in the intervention village compared to baseline (incidence rate ratio 0.59, 95% CI 0.41–0.87) while the seroincidence in the control village remained unchanged. At study end, the prevalence of taeniasis was nearly 4 times lower in the intervention than in the control (prevalence ratio 0.28, 95% CI 0.08–0.91).Conclusions/Significance
Ring-screening reduced transmission of T. solium in this pilot study and may provide an effective and practical approach for regions where resources are limited. However, this strategy requires validation in larger populations over a greater period of time.
Does Mass Azithromycin Distribution Impact Child Growth and Nutrition in Niger? A Cluster-Randomized Trial
by Abdou Amza, Sun N. Yu, Boubacar Kadri, Baido Nassirou, Nicole E. Stoller, Zhaoxia Zhou, Sheila K. West, Robin L. Bailey, Bruce D. Gaynor, Jeremy D. Keenan, Travis C. Porco, Thomas M. LietmanBackground
Antibiotic use on animals demonstrates improved growth regardless of whether or not there is clinical evidence of infectious disease. Antibiotics used for trachoma control may play an unintended benefit of improving child growth.Methodology
In this sub-study of a larger randomized controlled trial, we assess anthropometry of pre-school children in a community-randomized trial of mass oral azithromycin distributions for trachoma in Niger. We measured height, weight, and mid-upper arm circumference (MUAC) in 12 communities randomized to receive annual mass azithromycin treatment of everyone versus 12 communities randomized to receive biannual mass azithromycin treatments for children, 3 years after the initial mass treatment. We collected measurements in 1,034 children aged 6–60 months of age.Principal Findings
We found no difference in the prevalence of wasting among children in the 12 annually treated communities that received three mass azithromycin distributions compared to the 12 biannually treated communities that received six mass azithromycin distributions (odds ratio = 0.88, 95% confidence interval = 0.53 to 1.49).Conclusions/Significance
We were unable to demonstrate a statistically significant difference in stunting, underweight, and low MUAC of pre-school children in communities randomized to annual mass azithromycin treatment or biannual mass azithromycin treatment. The role of antibiotics on child growth and nutrition remains unclear, but larger studies and longitudinal trials may help determine any association.
by Ary A. Hoffmann, Inaki Iturbe-Ormaetxe, Ashley G. Callahan, Ben L. Phillips, Katrina Billington, Jason K. Axford, Brian Montgomery, Andrew P. Turley, Scott L. O'NeillThe wMel infection of Drosophila melanogaster was successfully transferred into Aedes aegypti mosquitoes where it has the potential to suppress dengue and other arboviruses. The infection was subsequently spread into two natural populations at Yorkeys Knob and Gordonvale near Cairns, Queensland in 2011. Here we report on the stability of the infection following introduction and we characterize factors influencing the ongoing dynamics of the infection in these two populations. While the Wolbachia infection always remained high and near fixation in both locations, there was a persistent low frequency of uninfected mosquitoes. These uninfected mosquitoes showed weak spatial structure at both release sites although there was some clustering around two areas in Gordonvale. Infected females from both locations showed perfect maternal transmission consistent with patterns previously established pre-release in laboratory tests. After >2 years under field conditions, the infection continued to show complete cytoplasmic incompatibility across multiple gonotrophic cycles but persistent deleterious fitness effects, suggesting that host effects were stable over time. These results point to the stability of Wolbachia infections and their impact on hosts following local invasion, and also highlight the continued persistence of uninfected individuals at a low frequency most likely due to immigration.
A Model for a Chikungunya Outbreak in a Rural Cambodian Setting: Implications for Disease Control in Uninfected Areas
by Marguerite Robinson, Anne Conan, Veasna Duong, Sowath Ly, Chantha Ngan, Philippe Buchy, Arnaud Tarantola, Xavier RodóFollowing almost 30 years of relative silence, chikungunya fever reemerged in Kenya in 2004. It subsequently spread to the islands of the Indian Ocean, reaching Southeast Asia in 2006. The virus was first detected in Cambodia in 2011 and a large outbreak occurred in the village of Trapeang Roka Kampong Speu Province in March 2012, in which 44% of the villagers had a recent infection biologically confirmed. The epidemic curve was constructed from the number of biologically-confirmed CHIKV cases per day determined from the date of fever onset, which was self-reported during a data collection campaign conducted in the village after the outbreak. All individuals participating in the campaign had infections confirmed by laboratory analysis, allowing for the identification of asymptomatic cases and those with an unreported date of fever onset. We develop a stochastic model explicitly including such cases, all of whom do not appear on the epidemic curve. We estimate the basic reproduction number of the outbreak to be 6.46 (95% C.I. [6.24, 6.78]). We show that this estimate is particularly sensitive to changes in the biting rate and mosquito longevity. Our model also indicates that the infection was more widespread within the population on the reported epidemic start date. We show that the exclusion of asymptomatic cases and cases with undocumented onset dates can lead to an underestimation of the reproduction number which, in turn, could negatively impact control strategies implemented by public health authorities. We highlight the need for properly documenting newly emerging pathogens in immunologically naive populations and the importance of identifying the route of disease introduction.
Serological Diagnosis of Paracoccidioidomycosis: High Rate of Inter-laboratorial Variability among Medical Mycology Reference Centers
by Monica Scarpelli Martinelli Vidal, Gilda Maria Barbaro Del Negro, Adriana Pardini Vicentini, Teresinha Inez Estivalet Svidzinski, Maria Jose Mendes-Giannini, Ana Marisa Fusco Almeida, Roberto Martinez, Zoilo Pires de Camargo, Carlos Pelleschi Taborda, Gil BenardBackground
Serological tests have long been established as rapid, simple and inexpensive tools for the diagnosis and follow-up of PCM. However, different protocols and antigen preparations are used and the few attempts to standardize the routine serological methods have not succeeded.Methodology/Principal findings
We compared the performance of six Brazilian reference centers for serological diagnosis of PCM. Each center provided 30 sera of PCM patients, with positive high, intermediate and low titers, which were defined as the “reference” titers. Each center then applied its own antigen preparation and serological routine test, either semiquantitative double immunodifusion or counterimmmunoelectrophoresis, in the 150 sera from the other five centers blindly as regard to the “reference” titers. Titers were transformed into scores: 0 (negative), 1 (healing titers), 2 (active disease, low titers) and 3 (active disease, high titers) according to each center's criteria. Major discordances were considered between scores indicating active disease and scores indicating negative or healing titers; such discordance when associated with proper clinical and other laboratorial data, may correspond to different approaches to the patient's treatment. Surprisingly, all centers exhibited a high rate of “major” discordances with a mean of 31 (20%) discordant scores. Alternatively, when the scores given by one center to their own sera were compared with the scores given to their sera by the remaining five other centers, a high rate of major discordances was also found, with a mean number of 14.8 sera in 30 presenting a discordance with at least one other center. The data also suggest that centers that used CIE and pool of isolates for antigen preparation performed better.Conclusion
There are inconsistencies among the laboratories that are strong enough to result in conflicting information regarding the patients' treatment. Renewed efforts should be promoted to improve standardization of the serological diagnosis of PCM.
by Evaristus Chibunna Mbanefo, Nguyen Tien Huy, Anita Akpeedje Wadagni, Christine Ifeoma Eneanya, Obioma Nwaorgu, Kenji HirayamaBackground
Schistosomiasis is still a major public health burden in the tropics and subtropics. Although there is an effective chemotherapy (Praziquantel) for this disease, reinfection occurs rapidly after mass drug administration (MDA). Because the entire population do not get reinfected at the same rate, it is possible that host factors may play a dominant role in determining resistance or susceptibility to reinfection with schistosomes. Here, we systematically reviewed and meta-analyzed studies that reported associations between reinfection with the principal human-infecting species (S. mansoni, S. japonicum and S. haematobium) and host socio-demographic, epidemiological, immunological and genetic factors.Methodology/Principal Findings
PubMed, Scopus, Google Scholar, Cochrane Review Library and African Journals Online public databases were searched in October 2013 to retrieve studies assessing association of host factors with reinfection with schistosomes. Meta-analysis was performed to generate pooled odds ratios and standardized mean differences as overall effect estimates for dichotomous and continuous variables, respectively. Quality assessment of included studies, heterogeneity between studies and publication bias were also assessed. Out of the initial 2739 records, 109 studies were included in the analyses, of which only 32 studies with 37 data sets were eligible for quantitative data synthesis. Among several host factors identified, strong positive association was found with age and pre-treatment intensity, and only slightly for gender. These factors are major determinants of exposure and disease transmission. Significant positive association was found with anti-SWA IgG4 level, and a negative overall effect for association with IgE levels. This reconfirmed the concept that IgE/IgG4 balance is a major determinant of protective immunity against schistosomiasis. Other identified determinants were reported by a small number of studies to enable interpretation.Conclusions
Our data contribute to the understanding of host-parasite interaction as it affects reinfection, and is a potential tool to guide planning and tailoring of community interventions to target high-risk groups.
Predicting the Mosquito Species and Vertebrate Species Involved in the Theoretical Transmission of Rift Valley Fever Virus in the United States
by Andrew J. Golnar, Michael J. Turell, A. Desiree LaBeaud, Rebekah C. Kading, Gabriel L. HamerRift Valley fever virus (RVFV) is a mosquito-borne virus in the family Bunyaviridiae that has spread throughout continental Africa to Madagascar and the Arabian Peninsula. The establishment of RVFV in North America would have serious consequences for human and animal health in addition to a significant economic impact on the livestock industry. Published and unpublished data on RVFV vector competence, vertebrate host competence, and mosquito feeding patterns from the United States were combined to quantitatively implicate mosquito vectors and vertebrate hosts that may be important to RVFV transmission in the United States. A viremia-vector competence relationship based on published mosquito transmission studies was used to calculate a vertebrate host competence index which was then combined with mosquito blood feeding patterns to approximate the vector and vertebrate amplification fraction, defined as the relative contribution of the mosquito or vertebrate host to pathogen transmission. Results implicate several Aedes spp. mosquitoes and vertebrates in the order Artiodactyla as important hosts for RVFV transmission in the U.S. Moreover, this study identifies critical gaps in knowledge which would be necessary to complete a comprehensive analysis identifying the different contributions of mosquitoes and vertebrates to potential RVFV transmission in the U.S. Future research should focus on (1) the dose-dependent relationship between viremic exposure and the subsequent infectiousness of key mosquito species, (2) evaluation of vertebrate host competence for RVFV among North American mammal species, with particular emphasis on the order Artiodactyla, and (3) identification of areas with a high risk for RVFV introduction so data on local vector and host populations can help generate geographically appropriate amplification fraction estimates.
Differential Spatial Repositioning of Activated Genes in Biomphalaria glabrata Snails Infected with Schistosoma mansoni
by Halime D. Arican-Goktas, Wannaporn Ittiprasert, Joanna M. Bridger, Matty KnightSchistosomiasis is an infectious disease infecting mammals as the definitive host and fresh water snails as the intermediate host. Understanding the molecular and biochemical relationship between the causative schistosome parasite and its hosts will be key to understanding and ultimately treating and/or eradicating the disease. There is increasing evidence that pathogens that have co-evolved with their hosts can manipulate their hosts' behaviour at various levels to augment an infection. Bacteria, for example, can induce beneficial chromatin remodelling of the host genome. We have previously shown in vitro that Biomphalaria glabrata embryonic cells co-cultured with schistosome miracidia display genes changing their nuclear location and becoming up-regulated. This also happens in vivo in live intact snails, where early exposure to miracidia also elicits non-random repositioning of genes. We reveal differences in the nuclear repositioning between the response of parasite susceptible snails as compared to resistant snails and with normal or live, attenuated parasites. Interestingly, the stress response gene heat shock protein (Hsp) 70 is only repositioned and then up-regulated in susceptible snails with the normal parasite. This movement and change in gene expression seems to be controlled by the parasite. Other differences in the behaviour of genes support the view that some genes are responding to tissue damage, for example the ferritin genes move and are up-regulated whether the snails are either susceptible or resistant and upon exposure to either normal or attenuated parasite. This is the first time host genome reorganisation has been seen in a parasitic host and only the second time for any pathogen. We believe that the parasite elicits a spatio-epigenetic reorganisation of the host genome to induce favourable gene expression for itself and this might represent a fundamental mechanism present in the human host infected with schistosome cercariae as well as in other host-pathogen relationships.
Hunting, Swimming, and Worshiping: Human Cultural Practices Illuminate the Blood Meal Sources of Cave Dwelling Chagas Vectors (Triatoma dimidiata) in Guatemala and Belize
by Lori Stevens, M. Carlota Monroy, Antonieta Guadalupe Rodas, Patricia L. DornBackground
Triatoma dimidiata, currently the major Central American vector of Trypanosoma cruzi, the parasite that causes Chagas disease, inhabits caves throughout the region. This research investigates the possibility that cave dwelling T. dimidiata might transmit the parasite to humans and links the blood meal sources of cave vectors to cultural practices that differ among locations.Methodology/Principal Findings
We determined the blood meal sources of twenty-four T. dimidiata collected from two locations in Guatemala and one in Belize where human interactions with the caves differ. Blood meal sources were determined by cloning and sequencing PCR products amplified from DNA extracted from the vector abdomen using primers specific for the vertebrate 12S mitochondrial gene. The blood meal sources were inferred by ≥99% identity with published sequences. We found 70% of cave-collected T. dimidiata positive for human DNA. The vectors had fed on 10 additional vertebrates with a variety of relationships to humans, including companion animal (dog), food animals (pig, sheep/goat), wild animals (duck, two bat, two opossum species) and commensal animals (mouse, rat). Vectors from all locations fed on humans and commensal animals. The blood meal sources differ among locations, as well as the likelihood of feeding on dog and food animals. Vectors from one location were tested for T. cruzi infection, and 30% (3/10) tested positive, including two positive for human blood meals.Conclusions/Significance
Cave dwelling Chagas disease vectors feed on humans and commensal animals as well as dog, food animals and wild animals. Blood meal sources were related to human uses of the caves. We caution that just as T. dimidiata in caves may pose an epidemiological risk, there may be other situations where risk is thought to be minimal, but is not.
by Paolo di Procolo, Claudio JommiThis paper scrutinises pipelines for Neglected Diseases (NDs), through freely accessible and at-least-weekly updated trials databases. It updates to 2012 data provided by recent publications, and integrates these analyses with information on location of trials coordinators and patients recruitment status. Additionally, it provides (i) disease-specific information to better understand the rational of investments in NDs, (ii) yearly data, to understand the investment trends. The search identified 650 clinical studies. Leishmaniasis, Arbovirus infection, and Dengue are the top three diseases by number of clinical studies. Disease diffusion risk seems to be the most important driver of the clinical trials target choice, whereas the role played by disease prevalence and unmet need is controversial. Number of trials is stable between 2005 and 2010, with an increase in the last two years. Patient recruitment was completed for most studies (57.6%), and Phases II and III account for 35% and 28% of trials, respectively. The primary purpose of clinical investigations is prevention (49.3%), especially for infectious diseases with mosquitoes and sand flies as the vector, and treatment (43.2%), which is the primary target for parasitic diseases Research centres and public organisations are the most important clinical studies sponsors (58.9%), followed by the pharmaceutical industry (24.1%), foundations and non-governmental organisations (9.3%). Many coordinator centres are located in less affluent countries (43.7%), whereas OECD countries and BRICS account for 34.7% and 17.5% of trials, respectively. Information was partially missing for some parameters. Notwithstanding, and despite its descriptive nature, this research has enhanced the evidence of the literature on pipelines for NDs. Future contributions may further investigate whether trials metrics are consistent with the characteristics of the interested countries and the explicative variables of trials location, target (disease) choice, and the object of the trials.
by Jordi Landier, Jean Gaudart, Kevin Carolan, Danny Lo Seen, Jean-François Guégan, Sara Eyangoh, Arnaud Fontanet, Gaëtan TexierBackground
Buruli ulcer (BU) is an extensively damaging skin infection caused by Mycobacterium ulcerans, whose transmission mode is still unknown. The focal distribution of BU and the absence of interpersonal transmission suggest a major role of environmental factors, which remain unidentified. This study provides the first description of the spatio-temporal variations of BU in an endemic African region, in Akonolinga, Cameroon. We quantify landscape-associated risk of BU, and reveal local patterns of endemicity.Methodology/Principal Findings
From January 2002 to May 2012, 787 new BU cases were recorded in 154 villages of the district of Akonolinga. Incidence per village ranged from 0 (n = 59 villages) to 10.4 cases/1000 person.years (py); median incidence was 0.4 cases/1,000py. Villages neighbouring the Nyong River flood plain near Akonolinga town were identified as the highest risk zone using the SPODT algorithm. We found a decreasing risk with increasing distance to the Nyong and identified 4 time phases with changes in spatial distribution. We classified the villages into 8 groups according to landscape characteristics using principal component analysis and hierarchical clustering. We estimated the incidence ratio (IR) associated with each landscape using a generalised linear model. BU risk was highest in landscapes with abundant wetlands, especially cultivated ones (IR = 15.7, 95% confidence interval [95%CI] = 15.7[4.2–59.2]), and lowest in reference landscape where primary and secondary forest cover was abundant. In intermediate-risk landscapes, risk decreased with agriculture pressure (from IR[95%CI] = 7.9[2.2–28.8] to 2.0[0.6–6.6]). We identified landscapes where endemicity was stable and landscapes where incidence increased with time.Conclusion/Significance
Our study on the largest series of BU cases recorded in a single endemic region illustrates the local evolution of BU and identifies the Nyong River as the major driver of BU incidence. Local differences along the river are explained by wetland abundance and human modification of the environment.