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by Alex P. McLatchie, Hollie Burrell-Saward, Elmarie Myburgh, Michael D. Lewis, Theresa H. Ward, Jeremy C. Mottram, Simon L. Croft, John M. Kelly, Martin C. TaylorBackground
Human African trypanosomiasis is caused by infection with parasites of the Trypanosoma brucei species complex, and threatens over 70 million people in sub-Saharan Africa. Development of new drugs is hampered by the limitations of current rodent models, particularly for stage II infections, which occur once parasites have accessed the CNS. Bioluminescence imaging of pathogens expressing firefly luciferase (emission maximum 562 nm) has been adopted in a number of in vivo models of disease to monitor dissemination, drug-treatment and the role of immune responses. However, lack of sensitivity in detecting deep tissue bioluminescence at wavelengths below 600 nm has restricted the wide-spread use of in vivo imaging to investigate infections with T. brucei and other trypanosomatids.Methodology/Principal findings
Here, we report a system that allows the detection of fewer than 100 bioluminescent T. brucei parasites in a murine model. As a reporter, we used a codon-optimised red-shifted Photinus pyralis luciferase (PpyRE9H) with a peak emission of 617 nm. Maximal expression was obtained following targeted integration of the gene, flanked by an upstream 5′-variant surface glycoprotein untranslated region (UTR) and a downstream 3′-tubulin UTR, into a T. brucei ribosomal DNA locus. Expression was stable in the absence of selective drug for at least 3 months and was not associated with detectable phenotypic changes. Parasite dissemination and drug efficacy could be monitored in real time, and brain infections were readily detectable. The level of sensitivity in vivo was significantly greater than achievable with a yellow firefly luciferase reporter.Conclusions/Significance
The optimised bioluminescent reporter line described here will significantly enhance the application of in vivo imaging to study stage II African trypanosomiasis in murine models. The greatly increased sensitivity provides a new framework for investigating host-parasite relationships, particularly in the context of CNS infections. It should be ideally suited to drug evaluation programmes.
Fascioliasis and Intestinal Parasitoses Affecting Schoolchildren in Atlixco, Puebla State, Mexico: Epidemiology and Treatment with Nitazoxanide
by José Lino Zumaquero-Ríos, Jorge Sarracent-Pérez, Raúl Rojas-García, Lázara Rojas-Rivero, Yaneth Martínez-Tovilla, María Adela Valero, Santiago Mas-ComaBackground
The Atlixco municipality, Puebla State, at a mean altitude of 1840 m, was selected for a study of Fasciola hepatica infection in schoolchildren in Mexico. This area presents permanent water collections continuously receiving thaw water from Popocatepetl volcano (5426 m altitude) through the community supply channels, conforming an epidemiological scenario similar to those known in hyperendemic areas of Andean countries.Methodology and Findings
A total of 865 6–14 year-old schoolchildren were analyzed with FasciDIG coproantigen test and Lumbreras rapid sedimentation technique, and quantitatively assessed with Kato-Katz. Fascioliasis prevalences ranged 2.94–13.33% according to localities (mean 5.78%). Intensities were however low (24–384 epg). The association between fascioliasis and the habit of eating raw vegetables was identified, including watercress and radish with pronouncedly higher relative risk than lettuce, corncob, spinach, alfalfa juice, and broccoli. Many F. hepatica-infected children were coinfected by other parasites. Entamoeba histolytica/dispar, Giardia intestinalis, Blastocystis hominis, Hymenolepis nana and Ascaris lumbricoides infection resulted in risk factors for F. hepatica infection. Nitazoxanide efficacy against fascioliasis was 94.0% and 100% after first and second treatment courses, respectively. The few children, for whom a second treatment course was needed, were concomitantly infected by moderate ascariasis burdens. Its efficacy was also very high in the treatment of E. histolytica/E. dispar, G. intestinalis, B. hominis, H. nana, A. lumbricoides, Trichuris trichiura, and Enterobius vermicularis. A second treatment course was needed for all children affected by ancylostomatids.Conclusions
Fascioliasis prevalences indicate this area to be mesoendemic, with isolated hyperendemic foci. This is the first time that a human fascioliasis endemic area is described in North America. Nitazoxanide appears as an appropriate alternative to triclabendazole, the present drug of choice for chronic fascioliasis. Its wide spectrum efficacy against intestinal protozooses and helminthiasis, usually coinfecting liver fluke infected subjects in human endemic areas, represents an important added value.
Pioneering Neglected Disease Research in Southern Mexico at the “Dr. Hideyo Noguchi” Regional Research Center
by Eric Dumonteil, Miguel Rosado-Vallado, Jorge E. Zavala-Castro
Severe South American Ocular Toxoplasmosis Is Associated with Decreased Ifn-γ/Il-17a and Increased Il-6/Il-13 Intraocular Levels
by Alejandra de-la-Torre, Arnaud Sauer, Alexander W. Pfaff, Tristan Bourcier, Julie Brunet, Claude Speeg-Schatz, Laurent Ballonzoli, Odile Villard, Daniel Ajzenberg, Natarajan Sundar, Michael E. Grigg, Jorge E. Gomez-Marin, Ermanno CandolfiIn a cross sectional study, 19 French and 23 Colombian cases of confirmed active ocular toxoplasmosis (OT) were evaluated. The objective was to compare clinical, parasitological and immunological responses and relate them to the infecting strains. A complete ocular examination was performed in each patient. The infecting strain was characterized by genotyping when intraocular Toxoplasma DNA was detectable, as well as by peptide-specific serotyping for each patient. To characterize the immune response, we assessed Toxoplasma protein recognition patterns by intraocular antibodies and the intraocular profile of cytokines, chemokines and growth factors. Significant differences were found for size of active lesions, unilateral macular involvement, unilateral visual impairment, vitreous inflammation, synechiae, and vasculitis, with higher values observed throughout for Colombian patients. Multilocus PCR-DNA sequence genotyping was only successful in three Colombian patients revealing one type I and two atypical strains. The Colombian OT patients possessed heterogeneous atypical serotypes whereas the French were uniformly reactive to type II strain peptides. The protein patterns recognized by intraocular antibodies and the cytokine patterns were strikingly different between the two populations. Intraocular IFN-γ and IL-17 expression was lower, while higher levels of IL-13 and IL-6 were detected in aqueous humor of Colombian patients. Our results are consistent with the hypothesis that South American strains may cause more severe OT due to an inhibition of the protective effect of IFN-γ.
by Roberta Rosa, Erica Azevedo Costa, Rafael Elias Marques, Taismara Simas Oliveira, Ronaldo Furtini, Maria Rosa Quaresma Bomfim, Mauro Martins Teixeira, Tatiane Alves Paixão, Renato Lima SantosSt. Louis encephalitis virus (SLEV) is a causative agent of encephalitis in humans in the Western hemisphere. SLEV is a positive-sense RNA virus that belongs to the Flavivirus genus, which includes West Nile encephalitis virus, Japanese encephalitis virus, Dengue virus and other medically important viruses. Recently, we isolated a SLEV strain from the brain of a horse with neurological signs in the countryside of Minas Gerais, Brazil. The SLEV isolation was confirmed by reverse-transcription RT-PCR and sequencing of the E protein gene. Virus identity was also confirmed by indirect immunofluorescence using commercial antibodies against SLEV. To characterize this newly isolated strain in vivo, serial passages in newborn mice were performed and led to hemorrhagic manifestations associated with recruitment of inflammatory cells into the central nervous system of newborns. In summary this is the first isolation of SLEV from a horse with neurological signs in Brazil.
by Monica K. Borucki, Haiyin Chen-Harris, Victoria Lao, Gilda Vanier, Debra A. Wadford, Sharon Messenger, Jonathan E. AllenOne of the hurdles to understanding the role of viral quasispecies in RNA virus cross-species transmission (CST) events is the need to analyze a densely sampled outbreak using deep sequencing in order to measure the amount of mutation occurring on a small time scale. In 2009, the California Department of Public Health reported a dramatic increase (350) in the number of gray foxes infected with a rabies virus variant for which striped skunks serve as a reservoir host in Humboldt County. To better understand the evolution of rabies, deep-sequencing was applied to 40 unpassaged rabies virus samples from the Humboldt outbreak. For each sample, approximately 11 kb of the 12 kb genome was amplified and sequenced using the Illumina platform. Average coverage was 17,448 and this allowed characterization of the rabies virus population present in each sample at unprecedented depths. Phylogenetic analysis of the consensus sequence data demonstrated that samples clustered according to date (1995 vs. 2009) and geographic location (northern vs. southern). A single amino acid change in the G protein distinguished a subset of northern foxes from a haplotype present in both foxes and skunks, suggesting this mutation may have played a role in the observed increased transmission among foxes in this region. Deep-sequencing data indicated that many genetic changes associated with the CST event occurred prior to 2009 since several nonsynonymous mutations that were present in the consensus sequences of skunk and fox rabies samples obtained from 20032010 were present at the sub-consensus level (as rare variants in the viral population) in skunk and fox samples from 1995. These results suggest that analysis of rare variants within a viral population may yield clues to ancestral genomes and identify rare variants that have the potential to be selected for if environment conditions change.
Whole Genome Sequencing of Field Isolates Reveals a Common Duplication of the Duffy Binding Protein Gene in Malagasy Plasmodium vivax Strains
by Didier Menard, Ernest R. Chan, Christophe Benedet, Arsène Ratsimbasoa, Saorin Kim, Pheaktra Chim, Catherine Do, Benoit Witkowski, Remy Durand, Marc Thellier, Carlo Severini, Eric Legrand, Lise Musset, Bakri Y. M. Nour, Odile Mercereau-Puijalon, David Serre, Peter A. ZimmermanBackground
Plasmodium vivax is the most prevalent human malaria parasite, causing serious public health problems in malaria-endemic countries. Until recently the Duffy-negative blood group phenotype was considered to confer resistance to vivax malaria for most African ethnicities. We and others have reported that P. vivax strains in African countries from Madagascar to Mauritania display capacity to cause clinical vivax malaria in Duffy-negative people. New insights must now explain Duffy-independent P. vivax invasion of human erythrocytes.Methods/Principal Findings
Through recent whole genome sequencing we obtained ≥70× coverage of the P. vivax genome from five field-isolates, resulting in ≥93% of the Sal I reference sequenced at coverage greater than 20×. Combined with sequences from one additional Malagasy field isolate and from five monkey-adapted strains, we describe here identification of DNA sequence rearrangements in the P. vivax genome, including discovery of a duplication of the P. vivax Duffy binding protein (PvDBP) gene. A survey of Malagasy patients infected with P. vivax showed that the PvDBP duplication was present in numerous locations in Madagascar and found in over 50% of infected patients evaluated. Extended geographic surveys showed that the PvDBP duplication was detected frequently in vivax patients living in East Africa and in some residents of non-African P. vivax-endemic countries. Additionally, the PvDBP duplication was observed in travelers seeking treatment of vivax malaria upon returning home. PvDBP duplication prevalence was highest in west-central Madagascar sites where the highest frequencies of P. vivax-infected, Duffy-negative people were reported.Conclusions/Significance
The highly conserved nature of the sequence involved in the PvDBP duplication suggests that it has occurred in a recent evolutionary time frame. These data suggest that PvDBP, a merozoite surface protein involved in red cell adhesion is rapidly evolving, possibly in response to constraints imposed by erythrocyte Duffy negativity in some human populations.
A Review of Factors That Influence Individual Compliance with Mass Drug Administration for Elimination of Lymphatic Filariasis
by Alison Krentel, Peter U. Fischer, Gary J. WeilBackground
The success of programs to eliminate lymphatic filariasis (LF) depends in large part on their ability to achieve and sustain high levels of compliance with mass drug administration (MDA). This paper reports results from a comprehensive review of factors that affect compliance with MDA.Methodology/Principal Findings
Papers published between 2000 and 2012 were considered, and 79 publications were included in the final dataset for analysis after two rounds of selection. While results varied in different settings, some common features were associated with successful programs and with compliance by individuals. Training and motivation of drug distributors is critically important, because these people directly interact with target populations, and their actions can affect MDA compliance decisions by families and individuals. Other important programmatic issues include thorough preparation of personnel, supplies, and logistics for implementation and preparation of the population for MDA. Demographic factors (age, sex, income level, and area of residence) are often associated with compliance by individuals, but compliance decisions are also affected by perceptions of the potential benefits of participation versus the risk of adverse events. Trust and information can sometimes offset fear of the unknown. While no single formula can ensure success MDA in all settings, five key ingredients were identified: engender trust, tailor programs to local conditions, take actions to minimize the impact of adverse events, promote the broader benefits of the MDA program, and directly address the issue of systematic non-compliance, which harms communities by prolonging their exposure to LF.Conclusions/Significance
This review has identified factors that promote coverage and compliance with MDA for LF elimination across countries. This information may be helpful for explaining results that do not meet expectations and for developing remedies for ailing MDA programs. Our review has also identified gaps in understanding and suggested priority areas for further research.
Cholera Vaccination Campaign Contributes to Improved Knowledge Regarding Cholera and Improved Practice Relevant to Waterborne Disease in Rural Haiti
by Omowunmi Aibana, Molly Franke, Jessica Teng, Johanne Hilaire, Max Raymond, Louise C. IversBackground
Haiti's cholera epidemic has been devastating partly due to underlying weak infrastructure and limited clean water and sanitation. A comprehensive approach to cholera control is crucial, yet some have argued that oral cholera vaccination (OCV) might result in reduced hygiene practice among recipients. We evaluated the impact of an OCV campaign on knowledge and health practice in rural Haiti.Methodology/Principal Findings
We administered baseline surveys on knowledge and practice relevant to cholera and waterborne disease to every 10th household during a census in rural Haiti in February 2012 (N = 811). An OCV campaign occurred from May–June 2012 after which we administered identical surveys to 518 households randomly chosen from the same region in September 2012. We compared responses pre- and post-OCV campaign.Post-vaccination, there was improved knowledge with significant increase in percentage of respondents with ≥3 correct responses on cholera transmission mechanisms (odds ratio[OR] 1.91; 95% confidence interval[CI] 1.52–2.40), preventive methods (OR 1.83; 95% CI 1.46–2.30), and water treatment modalities (OR 2.75; 95% CI 2.16–3.50). Relative to pre-vaccination, participants were more likely post-OCV to report always treating water (OR 1.62; 95% CI 1.28–2.05). Respondents were also more likely to report hand washing with soap and water >4 times daily post-vaccine (OR 1.30; 95% CI 1.03–1.64). Knowledge of treating water as a cholera prevention measure was associated with practice of always treating water (OR 1.47; 95% CI 1.14–1.89). Post-vaccination, knowledge was associated with frequent hand washing (OR 2.47; 95% CI 1.35–4.51).Conclusion
An OCV campaign in rural Haiti was associated with significant improvement in cholera knowledge and practices related to waterborne disease. OCV can be part of comprehensive cholera control and reinforce, not detract from, other control efforts in Haiti.
NTDs V.2.0: “Blue Marble Health”—Neglected Tropical Disease Control and Elimination in a Shifting Health Policy Landscape
by Peter J. HotezThe concept of the neglected tropical diseases (NTDs) was established in the aftermath of the Millennium Development Goals. Here, we summarize the emergence of several new post-2010 global health documents and policies, and how they may alter the way we frame the world's major NTDs since they were first highlighted. These documents include a new Global Burden of Disease 2010 Study that identifies visceral leishmaniasis and food-borne trematode infections as priority diseases beyond the seven NTDs originally targeted by preventive chemotherapy, a London Declaration for access to essential medicines, and a 2013 World Health Assembly resolution on NTDs. Additional information highlights an emerging dengue fever pandemic. New United Nations resolutions on women and the non-communicable diseases (NCDs) have not yet embraced NTDs, which may actually be the most common afflictions of girls and women and represent a stealth cause of NCDs. NTDs also have important direct and collateral effects on HIV/AIDS and malaria, and there is now a robust evidence base and rationale for incorporating NTDs into the Global Fund to Fight AIDS, Tuberculosis, and Malaria. “Blue marble health” is an added concept that recognizes a paradoxical NTD disease burden among the poor living in G20 (Group of Twenty) and other wealthy countries, requiring these nations to take greater ownership for both disease control and research and development. As we advance past the year 2015, it will be essential to incorporate global NTD elimination into newly proposed Sustainable Development Goals.
by Ganesh R. Pant, Rachel Lavenir, Frank Y. K. Wong, Andrea Certoma, Florence Larrous, Dwij R. Bhatta, Hervé Bourhy, Vittoria Stevens, Laurent DacheuxRabies is a zoonotic disease that is endemic in many parts of the developing world, especially in Africa and Asia. However its epidemiology remains largely unappreciated in much of these regions, such as in Nepal, where limited information is available about the spatiotemporal dynamics of the main etiological agent, the rabies virus (RABV). In this study, we describe for the first time the phylogenetic diversity and evolution of RABV circulating in Nepal, as well as their geographical relationships within the broader region. A total of 24 new isolates obtained from Nepal and collected from 2003 to 2011 were full-length sequenced for both the nucleoprotein and the glycoprotein genes, and analysed using neighbour-joining and maximum-likelihood phylogenetic methods with representative viruses from all over the world, including new related RABV strains from neighbouring or more distant countries (Afghanistan, Greenland, Iran, Russia and USA). Despite Nepal's limited land surface and its particular geographical position within the Indian subcontinent, our study revealed the presence of a surprising wide genetic diversity of RABV, with the co-existence of three different phylogenetic groups: an Indian subcontinent clade and two different Arctic-like sub-clades within the Arctic-related clade. This observation suggests at least two independent episodes of rabies introduction from neighbouring countries. In addition, specific phylogenetic and temporal evolution analysis of viruses within the Arctic-related clade has identified a new recently emerged RABV lineage we named as the Arctic-like 3 (AL-3) sub-clade that is already widely spread in Nepal.
Molecular Cloning and Characterization of Taurocyamine Kinase from Clonorchis sinensis: A Candidate Chemotherapeutic Target
by Jing-ying Xiao, Ji-Yun Lee, Shinji Tokuhiro, Mitsuru Nagataki, Blanca R. Jarilla, Haruka Nomura, Tae Im Kim, Sung-Jong Hong, Takeshi AgatsumaBackground
Adult Clonorchis sinensis lives in the bile duct and causes endemic clonorchiasis in East Asian countries. Phosphagen kinases (PK) constitute a highly conserved family of enzymes, which play a role in ATP buffering in cells, and are potential targets for chemotherapeutic agents, since variants of PK are found only in invertebrate animals, including helminthic parasites. This work is conducted to characterize a PK from C. sinensis and to address further investigation for future drug development.Methology/Principal findings
A cDNA clone encoding a putative polypeptide of 717 amino acids was retrieved from a C. sinensis transcriptome. This polypeptide was homologous to taurocyamine kinase (TK) of the invertebrate animals and consisted of two contiguous domains. C. sinensis TK (CsTK) gene was reported and found consist of 13 exons intercalated with 12 introns. This suggested an evolutionary pathway originating from an arginine kinase gene group, and distinguished annelid TK from the general CK phylogenetic group. CsTK was found not to have a homologous counterpart in sequences analysis of its mammalian hosts from public databases. Individual domains of CsTK, as well as the whole two-domain enzyme, showed enzymatic activity and specificity toward taurocyamine substrate. Of the CsTK residues, R58, I60 and Y84 of domain 1, and H60, I63 and Y87 of domain 2 were found to participate in binding taurocyamine. CsTK expression was distributed in locomotive and reproductive organs of adult C. sinensis. Developmentally, CsTK was stably expressed in both the adult and metacercariae stages. Recombinant CsTK protein was found to have low sensitivity and specificity toward C. sinensis and platyhelminth-infected human sera on ELISA.Conclusion
CsTK is a promising anti-C. sinensis drug target since the enzyme is found only in the C. sinensis and has a substrate specificity for taurocyamine, which is different from its mammalian counterpart, creatine.
Disseminated Histoplasmosis in HIV-Infected Patients in South America: A Neglected Killer Continues on Its Rampage
by Mathieu Nacher, Antoine Adenis, Sigrid Mc Donald, Margarete Do Socorro Mendonca Gomes, Shanti Singh, Ivina Lopes Lima, Rosilene Malcher Leite, Sandra Hermelijn, Merril Wongsokarijo, Marja Van Eer, Silvia Marques Da Silva, Maurimelia Mesquita Da Costa, Marizette Silva, Maria Calvacante, Terezinha do Menino Jesus Silva Leitao, Beatriz L. Gómez, Angela Restrepo, Angela Tobon, Cristina E. Canteros, Christine Aznar, Denis Blanchet, Vincent Vantilcke, Cyrille Vautrin, Rachida Boukhari, Tom Chiller, Christina Scheel, Angela Ahlquist, Monika Roy, Olivier Lortholary, Bernard Carme, Pierre Couppié, Stephen Vreden
Gene Amplification and Point Mutations in Pyrimidine Metabolic Genes in 5-Fluorouracil Resistant Leishmania infantum
by Jean-François Ritt, Frédéric Raymond, Philippe Leprohon, Danielle Légaré, Jacques Corbeil, Marc OuelletteBackground
The human protozoan parasites Leishmania are prototrophic for pyrimidines with the ability of both de novo biosynthesis and uptake of pyrimidines.Methodology/Principal Findings
Five independent L. infantum mutants were selected for resistance to the pyrimidine analogue 5-fluorouracil (5-FU) in the hope to better understand the metabolism of pyrimidine in Leishmania. Analysis of the 5-FU mutants by comparative genomic hybridization and whole genome sequencing revealed in selected mutants the amplification of DHFR-TS and a deletion of part of chromosome 10. Point mutations in uracil phosphorybosyl transferase (UPRT), thymidine kinase (TK) and uridine phosphorylase (UP) were also observed in three individual resistant mutants. Transfection experiments confirmed that these point mutations were responsible for 5-FU resistance. Transport studies revealed that one resistant mutant was defective for uracil and 5-FU import.Conclusion/Significance
This study provided further insights in pyrimidine metabolism in Leishmania and confirmed that multiple mutations can co-exist and lead to resistance in Leishmania.
Fecal Occult Blood and Fecal Calprotectin as Point-of-Care Markers of Intestinal Morbidity in Ugandan Children with Schistosoma mansoni Infection
by Amaya L. Bustinduy, José C. Sousa-Figueiredo, Moses Adriko, Martha Betson, Alan Fenwick, Narcis Kabatereine, J. Russell StothardBackground
Calprotectin is a calcium-binding cytoplasmic protein found in neutrophils and increasingly used as a marker of bowel inflammation. Fecal occult blood (FOB) is also a dependable indicator of bowel morbidity. The objective of our study was to determine the applicability of these tests as surrogate markers of Schistosoma mansoni intestinal morbidity before and after treatment with praziquantel (PZQ).Methods
216 children (ages 3–9 years old) from Buliisa District in Lake Albert, Uganda were examined and treated with PZQ at baseline in October 2012 with 211 of them re-examined 24 days later for S. mansoni and other soil transmitted helminths (STH). POC calprotectin and FOB assays were performed at both time points on a subset of children. Associations between the test results and infection were analysed by logistic regression.Results
Fecal calprotectin concentrations of 150–300 µg/g were associated with S. mansoni egg patent infection both at baseline and follow up (OR: 12.5 P = 0.05; OR: 6.8 P = 0.02). FOB had a very strong association with baseline anemia (OR: 9.2 P = 0.03) and medium and high egg intensity schistosomiasis at follow up (OR: 6.6 P = 0.03; OR: 51.3 P = 0.003). Both tests were strongly associated with heavy intensity S. mansoni infections. There was a significant decrease in FOB and calprotectin test positivity after PZQ treatment in those children who had egg patent schistosomiasis at baseline.Conclusions
Both FOB and calprotectin rapid assays were found to correlate positively and strongly with egg patent S. mansoni infection with a positive ameloriation response after PZQ treatment indicative of short term reversion of morbidity. Both tests were appropriate for use in the field with excellent operational performance and reliability. Due to its lower-cost which makes its scale-up of use affordable, FOB could be immediately adopted as a monitoring tool for PC campaigns for efficacy evaluation before and after treatment.
by Christopher M. Barker, Tianchan Niu, William K. Reisen, David M. HartleyRift Valley Fever virus (RVFV) is an enzootic virus that causes extensive morbidity and mortality in domestic ruminants in Africa, and it has shown the potential to invade other areas such as the Arabian Peninsula. Here, we develop methods for linking mathematical models to real-world data that could be used for continent-scale risk assessment given adequate data on local host and vector populations. We have applied the methods to a well-studied agricultural region of California with 1 million dairy cattle, abundant and competent mosquito vectors, and a permissive climate that has enabled consistent transmission of West Nile virus and historically other arboviruses. Our results suggest that RVFV outbreaks could occur from February–November, but would progress slowly during winter–early spring or early fall and be limited spatially to areas with early increases in vector abundance. Risk was greatest in summer, when the areas at risk broadened to include most of the dairy farms in the study region, indicating the potential for considerable economic losses if an introduction were to occur. To assess the threat that RVFV poses to North America, including what-if scenarios for introduction and control strategies, models such as this one should be an integral part of the process; however, modeling must be paralleled by efforts to address the numerous remaining gaps in data and knowledge for this system.
Trypanosoma cruzi Disrupts Thymic Homeostasis by Altering Intrathymic and Systemic Stress-Related Endocrine Circuitries
by Ailin Lepletier, Vinicius Frias de Carvalho, Patricia Machado Rodrigues e Silva, Silvina Villar, Ana Rosa Pérez, Wilson Savino, Alexandre MorrotWe have previously shown that experimental infection caused by Trypanosoma cruzi is associated with changes in the hypothalamus-pituitary-adrenal axis. Increased glucocorticoid (GC) levels are believed to be protective against the effects of acute stress during infection but result in depletion of CD4+CD8+ thymocytes by apoptosis, driving to thymic atrophy. However, very few data are available concerning prolactin (PRL), another stress-related hormone, which seems to be decreased during T. cruzi infection. Considering the immunomodulatory role of PRL upon the effects caused by GC, we investigated if intrathymic cross-talk between GC and PRL receptors (GR and PRLR, respectively) might influence T. cruzi-induced thymic atrophy. Using an acute experimental model, we observed changes in GR/PRLR cross-activation related with the survival of CD4+CD8+ thymocytes during infection. These alterations were closely related with systemic changes, characterized by a stress hormone imbalance, with progressive GC augmentation simultaneously to PRL reduction. The intrathymic hormone circuitry exhibited an inverse modulation that seemed to counteract the GC-related systemic deleterious effects. During infection, adrenalectomy protected the thymus from the increase in apoptosis ratio without changing PRL levels, whereas an additional inhibition of circulating PRL accelerated the thymic atrophy and led to an increase in corticosterone systemic levels. These results demonstrate that the PRL impairment during infection is not caused by the increase of corticosterone levels, but the opposite seems to occur. Accordingly, metoclopramide (MET)-induced enhancement of PRL secretion protected thymic atrophy in acutely infected animals as well as the abnormal export of immature and potentially autoreactive CD4+CD8+ thymocytes to the periphery. In conclusion, our findings clearly show that Trypanosoma cruzi subverts mouse thymus homeostasis by altering intrathymic and systemic stress-related endocrine circuitries with major consequences upon the normal process of intrathymic T cell development.
Genomic Characterisation of Invasive Non-Typhoidal Salmonella enterica Subspecies enterica Serovar Bovismorbificans Isolates from Malawi
by Christina Bronowski, Maria C. Fookes, Ruth Gilderthorp, Kevin E. Ashelford, Simon R. Harris, Amos Phiri, Neil Hall, Melita A. Gordon, John Wain, Charles A. Hart, Paul Wigley, Nicholas R. Thomson, Craig WinstanleyBackground
Invasive Non-typhoidal Salmonella (iNTS) are an important cause of bacteraemia in children and HIV-infected adults in sub-Saharan Africa. Previous research has shown that iNTS strains exhibit a pattern of gene loss that resembles that of host adapted serovars such as Salmonella Typhi and Paratyphi A. Salmonella enterica serovar Bovismorbificans was a common serovar in Malawi between 1997 and 2004.Methodology
We sequenced the genomes of 14 Malawian bacteraemia and four veterinary isolates from the UK, to identify genomic variations and signs of host adaptation in the Malawian strains.Principal Findings
Whole genome phylogeny of invasive and veterinary S. Bovismorbificans isolates showed that the isolates are highly related, belonging to the most common international S. Bovismorbificans Sequence Type, ST142, in contrast to the findings for S. Typhimurium, where a distinct Sequence Type, ST313, is associated with invasive disease in sub-Saharan Africa. Although genome degradation through pseudogene formation was observed in ST142 isolates, there were no clear overlaps with the patterns of gene loss seen in iNTS ST313 isolates previously described from Malawi, and no clear distinction between S. Bovismorbificans isolates from Malawi and the UK.The only defining differences between S. Bovismorbificans bacteraemia and veterinary isolates were prophage-related regions and the carriage of a S. Bovismorbificans virulence plasmid (pVIRBov).Conclusions
iNTS S. Bovismorbificans isolates, unlike iNTS S. Typhiumrium isolates, are only distinguished from those circulating elsewhere by differences in the mobile genome. It is likely that these strains have entered a susceptible population and are able to take advantage of this niche. There are tentative signs of convergent evolution to a more human adapted iNTS variant. Considering its importance in causing disease in this region, S. Bovismorbificans may be at the beginning of this process, providing a reference against which to compare changes that may become fixed in future lineages in sub-Saharan Africa.
by Ruth Rottbeck, Jules Fidèle Nshimiyimana, Pierrot Tugirimana, Uta E. Düll, Janko Sattler, Jean-Claudien Hategekimana, Janvier Hitayezu, Irmengard Bruckmaier, Matthias Borchert, Jean Bosco Gahutu, Sebastian Dieckmann, Gundel Harms, Frank P. Mockenhaupt, Ralf IgnatiusBackground
Neurocysticercosis (NCC), the central nervous system infection by Taenia solium larvae, is a preventable and treatable cause of epilepsy. In Sub-Saharan Africa, the role of NCC in epilepsy differs geographically and, overall, is poorly defined. We aimed at contributing specific, first data for Rwanda, assessing factors associated with NCC, and evaluating a real-time PCR assay to diagnose NCC in cerebrospinal fluid (CSF).Methodology/Principal findings
At three healthcare facilities in southern Rwanda, 215 people with epilepsy (PWE) and 51 controls were clinically examined, interviewed, and tested by immunoblot for cysticerci-specific serum antibodies. Additionally, CSF samples from PWE were tested for anticysticercal antibodies by ELISA and for parasite DNA by PCR. Cranial computer tomography (CT) scans were available for 12.1% of PWE with additional symptoms suggestive of NCC. The Del Brutto criteria were applied for NCC diagnosis. Cysticerci-specific serum antibodies were found in 21.8% of PWE and 4% of controls (odds ratio (OR), 6.69; 95% confidence interval (95%CI), 1.6–58.7). Seropositivity was associated with age and lack of safe drinking water. Fifty (23.3%) PWE were considered NCC cases (definitive, based on CT scans, 7.4%; probable, mainly based on positive immunoblots, 15.8%). In CSF samples from NCC cases, anticysticercal antibodies were detected in 10% (definitive cases, 25%) and parasite DNA in 16% (definitive cases, 44%). Immunoblot-positive PWE were older (medians, 30 vs. 22 years), more frequently had late-onset epilepsy (at age >25 years; 43.5% vs. 8.5%; OR, 8.30; 95%CI, 3.5–20.0), and suffered from significantly fewer episodes of seizures in the preceding six months than immunoblot-negative PWE.Conclusions/Significance
NCC is present and contributes to epilepsy in southern Rwanda. Systematic investigations into porcine and human cysticercosis as well as health education and hygiene measures for T. solium control are needed. PCR might provide an additional, highly specific tool in NCC diagnosis.
by Nicolas Veziris, Aurélie Chauffour, Sylvie Escolano, Sarah Henquet, Masanori Matsuoka, Vincent Jarlier, Alexandra Aubry
Multidrug resistant leprosy, defined as resistance to rifampin, dapsone and fluoroquinolones (FQ), has been described in Mycobacterium leprae. However, the in vivo impact of fluoroquinolone resistance, mainly mediated by mutations in DNA gyrase (GyrA2GyrB2), has not been precisely assessed. Our objective was to measure the impact of a DNA gyrase mutation whose implication in fluoroquinolone resistance has been previously demonstrated through biochemical studies, on the in vivo activity of 3 fluoroquinolones: ofloxacin, moxifloxacin and garenoxacin.Methodology/Principal Findings
We used the proportional bactericidal method. 210 four-week-old immunodeficient female Nude mice (NMRI-Foxn1nu/Foxn1nu) were inoculated in the left hind footpad with 0.03 ml of bacterial suspension containing 5×103, 5×102, 5×101, and 5×100 M. leprae AFB organisms of strain Hoshizuka-4 which is a multidrug resistant strain harboring a GyrA A91V substitution. An additional subgroup of 10 mice was inoculated with 5×10−1 bacilli in the untreated control group. The day after inoculation, subgroups of mice were treated with a single dose of ofloxacin, moxifloxacin, garenoxacin or clarithromycin at 150 mg/kg dosing. 12 months later mice were sacrificed and M. leprae bacilli were numbered in the footpad. The results from the untreated control group indicated that the infective inoculum contained 23% of viable M. leprae. The results from the moxifloxacin and garenoxacin groups indicated that a single dose of these drugs reduced the percentage of viable M. leprae by 90%, similarly to the reduction observed after a single dose of the positive control drug clarithromycin. Conversely, ofloxacin was less active than clarithromycin.Conclusion/Significance
DNA gyrase mutation is not always synonymous of lack of in vivo fluoroquinolone activity in M. leprae. As for M. tuberculosis, in vivo studies allow to measure residual antibiotic activity in case of target mutations in M. leprae.