Life Sciences Commons^™

Differential Spatial Repositioning Of Activated Genes In Biomphalaria Glabrata Snails Infected With Schistosoma Mansoni, Halime D. Arican-Goktas, Wannaporn Ittiprasert, Joanna M. Bridger, Matty Knight

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Schistosomiasis 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 thatBiomphalaria glabrata embryonic cells co-cultured with schistosome miracidia display genes changing their …

Urinary Estrogen Metabolites And Self-Reported Infertility In Women Infected With Schistosoma Haematobium, Julio Santos, Maria Joao Gouveia, Nuno Vale, Maria De Lurdes Delgado, Ana Goncalves, Gabriel Rinaldi, Paul J. Brindley, +10 Additional Authors

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Background

Schistosomiasis is a neglected tropical disease, endemic in 76 countries, that afflicts more than 240 million people. The impact of schistosomiasis on infertility may be underestimated according to recent literature. Extracts of Schistosoma haematobium include estrogen-like metabolites termed catechol-estrogens that down regulate estrogen receptors alpha and beta in estrogen responsive cells. In addition, schistosome derived catechol-estrogens induce genotoxicity that result in estrogen-DNA adducts. These catechol estrogens and the catechol-estrogen-DNA adducts can be isolated from sera of people infected with S. haematobium. The aim of this study was to study infertility in females infected with S. haematobium and its …

Suppression Of Basophil Histamine-Release And Other Ige-Dependent Responses In Childhood Schistosoma Mansoni Hookworm Co-Infection, Angela Pinot De Moira, Colin M. Fitzsimmons, Frances M. Jones, Shona Wilson, Pierre Cahen, Edridah Tukahebwa, Harriet Mpairwe, Joseph K. Mwatha, Jeffrey M. Bethony, Per S. Skov, Narcis B. Kabatereine, David W. Dunne

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Background. The poor correlation between allergen-specific-IgE (asIgE) and clinical signs of allergy in helminth infected populations suggests that helminth infections could protect against allergy by uncoupling asIgE from its effector mechanisms. We investigated this hypothesis in Ugandan schoolchildren coinfected with Schistosoma mansoni and hookworm.

Methods. Skin prick test (SPT) sensitivity to house dust mite allergen (HDM) and current wheeze were assessed pre-anthelmintic treatment. Non-specific (anti-IgE), helminth-specific and HDM-allergen-specific basophil histamine release (HR), plus helminth- and HDM-specific IgE and IgG4 responses were measured pre- and post-treatment.

Results. Non-specific- and helminth-specific-HR, and associations between helminth-specific-IgE and helminth-specific-HR increased post-treatment. Hookworm infection appeared …

An Immunomics Approach To Schistosome Antigen Discovery: Antibody Signatures Of Naturally Resistant And Chronically Infected Individuals From Endemic Areas, Soraya Gaze, Patrick Driguez, Mark S. Pearson, Tiago Mendes, Denise L. Doolan, Jeffrey M. Bethony, +14 Additional Authors

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Schistosomiasis is a neglected tropical disease that is responsible for almost 300,000 deaths annually. Mass drug administration (MDA) is used worldwide for the control of schistosomiasis, but chemotherapy fails to prevent reinfection with schistosomes, so MDA alone is not sufficient to eliminate the disease, and a prophylactic vaccine is required. Herein, we take advantage of recent advances in systems biology and longitudinal studies in schistosomiasis endemic areas in Brazil to pilot an immunomics approach to the discovery of schistosomiasis vaccine antigens. We selected mostly surface-derived proteins, produced them using an in vitro rapid translation system and then printed them to …

Genome Of The Human Hookworm Necator Americanus, Yat T. Tang, Xin Gao, Bruce A. Rosa, Sahar Abubucker, Kymberlie Hallsworth-Pepin, Peter J. Hotez, Jeffrey M. Bethony, +23 Additional Authors

Microbiology, Immunology, and Tropical Medicine Faculty Publications

The hookworm Necator americanus is the predominant soil-transmitted human parasite. Adult worms feed on blood in the small intestine, causing iron-deficiency anemia, malnutrition, growth and development stunting in children, and severe morbidity and mortality during pregnancy in women. We report sequencing and assembly of the N. americanus genome (244 Mb, 19,151 genes). Characterization of this first hookworm genome sequence identified genes orchestrating the hookworm's invasion of the human host, genes involved in blood feeding and development, and genes encoding proteins that represent new potential drug targets against hookworms. N. americanus has undergone a considerable and unique expansion of immunomodulator proteins, …

A Melanin-Independent Interaction Between Mc1r And Met Signalling Pathways Is Required For Hgf-Dependent Melanoma, Agnieszka Wolnicka-Głubisz, Faith M. Strickland, Albert Wielgus, Miriam Anver, Glenn Merlino, Edward C. De Fabo, Frances P. Noonan

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Melanocortin 1 receptor (MC1R) signaling stimulates black eumelanin production through a cAMP-dependent pathway. MC1R polymorphisms can impair this process, resulting in a predominance of red phaeomelanin. The red hair, fair skin and UV sensitive phenotype is a well-described melanoma risk factor. MC1R polymorphisms also confer melanoma risk independent of pigment. We investigated the effect of Mc1r deficiency in a mouse model of UV-induced melanoma. C57BL/6-Mc1r+/+-HGF transgenic mice have a characteristic hyperpigmented black phenotype with extra-follicular dermal melanocytes located at the dermal/epidermal junction. UVB induces melanoma, independent of melanin pigmentation, but UVA-induced and spontaneous melanomas are dependent on black eumelanin. We …

Helminth.Net: Expansions To Nematode.Net And An Introduction To Trematode.Net, John Martin, Bruce A. Rosa, Philip Ozersky, Kymberlie Hallsworth-Pepin, Xu Zhang, Veena Bhonagiri-Palsikar, Rahul Tyagi, Qi Wang, Young-Jun Choi, Xin Gao, Samantha N. Mcnulty, Paul J. Brindley, Makedonka Mitreva

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Helminth.net (http://www.helminth.net) is the new moniker for a collection of databases: Nematode.net and Trematode.net. Within this collection we provide services and resources for parasitic roundworms (nematodes) and flatworms (trematodes), collectively known as helminths. For over a decade we have provided resources for studying nematodes via our veteran site Nematode.net (http://nematode.net). In this article, (i) we provide an update on the expansions of Nematode.net that hosts omics data from 84 species and provides advanced search tools to the broad scientific community so that data can be mined in a useful and user-friendly manner and (ii) we …

Suppression Of Aquaporin, A Mediator Of Water Channel Control In The Carcinogenic Liver Fluke, Opisthorchis Viverrini, Sirikanda Thanasuwan, Supawadee Piratae, Paul J. Brindley, Alex Loukas, Sasithorn Kaewkes, Thewarach Laha

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Background

Opisthorchiasis and Opisthorchis viverrini-associated bile duct cancer represent major public health threats in Thailand and Laos. The tegument of this food borne fluke plays pivotal roles in parasite metabolism, homeostasis and osmoregulation. Excretory/secretory products also pass from the fluke to the biliary environment, products that likely underlie pathogenesis of liver fluke infection. Aquaporins (AQPs), belong to the major intrinsic protein superfamily of integral plasma membrane channel proteins that selectively transport water across cell membranes. AQPs play key roles as water and ion transport channels through the tegument of helminth parasites.

Methods

Here, two forms of AQP mRNAs from the …

Schistosomes And Snails: A Molecular Encounter, Matty Knight, Halime D. Arican-Goktas, Wannaporn Ittiprasert, Edwin C. Odoemelam, Andre N. Miller, Joanna M. Bridger

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Biomphalaria glabrata snails play an integral role in the transmission of Schistosoma mansoni, the causative agent for human schistosomiasis in the Western hemisphere. For the past two decades, tremendous advances have been made in research aimed at elucidating the molecular basis of the snail/parasite interaction. The growing concern that there is no vaccine to prevent schistosomiasis and only one effective drug in existence provides the impetus to develop new control strategies based on eliminating schistosomes at the snail-stage of the life cycle. To elucidate why a given snail is not always compatible to each and every schistosome it encounters, B. …

Schistosome And Liver Fluke Derived Catechol-Estrogens And Helminth Associated Cancers., José M. Correia Da Costa, Nuno Vale, Maria J. Gouveia, Mónica C. Botelho, Banchob Sripa, Lúcio L. Santos, Júlio H. Santos, Gabriel Rinaldi, Paul J. Brindley

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Infection with helminth parasites remains a persistent public health problem in developing countries. Three of these pathogens, the liver flukes Clonorchis sinensis, Opisthorchis viverrini and the blood fluke Schistosoma haematobium, are of particular concern due to their classification as Group 1 carcinogens: infection with these worms is carcinogenic. Using liquid chromatography-mass spectrometry (LC-MS/MS) approaches, we identified steroid hormone like (e.g., oxysterol-like, catechol estrogen quinone-like, etc.) metabolites and related DNA-adducts, apparently of parasite origin, in developmental stages including eggs of S. haematobium, in urine of people with urogenital schistosomiasis, and in the adult stage of O. viverrini. Since these kinds of …

Septins Of Platyhelminths: Identification, Phylogeny, Expression And Localization Among Developmental Stages Of Schistosoma Mansoni, Ana E. Zeraik, Gabriel Rinaldi, Victoria H. Mann, Anastas Popratiloff, Ana P.U. Araujo, Ricardo Demarco, Paul J. Brindley

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Septins are a family of eukaryotic GTP binding proteins conserved from yeasts to humans. Originally identified in mutants of budding yeast, septins participate in diverse cellular functions including cytokinesis, organization of actin networks, cell polarity, vesicle trafficking and many others. Septins assemble into heteroligomers to form filaments and rings. Here, four septins of Schistosoma mansoni are described, which appear to be conserved within the phylum Platyhelminthes. These orthologues were related to the SEPT5, SEPT10 and SEPT7 septins of humans, and hence we have termed the schistosome septins SmSEPT5, SmSEPT10, SmSEPT7.1 and SmSEPT7.2. Septin transcripts were detected throughout the developmental cycle …

Spatially Explicit Modeling Of Schistosomiasis Risk In Eastern China Based On A Synthesis Of Epidemiological, Environmental, And Intermediate Host Genetic Data, Matthias Schrader, Torsten Hauffe, Zhijie Zhang, George M. Davis, Fred Jopp, Justin V. Remais, Thomas Wilke

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Schistosomiasis japonica is a major parasitic disease threatening millions of people in China. Though overall prevalence was greatly reduced during the second half of the past century, continued persistence in some areas and cases of re-emergence in others remain major concerns. As many regions in China are approaching disease elimination, obtaining quantitative data on Schistosoma japonicum parasites is increasingly difficult. This study examines the distribution of schistosomiasis in eastern China, taking advantage of the fact that the single intermediate host serves as a major transmission bottleneck. Epidemiological, population-genetic and high-resolution ecological data are combined to construct a predictive model capable …

Microproteinuria During Opisthorchis Viverrini Infection: A Biomarker For Advanced Renal And Hepatobiliary Pathologies From Chronic Opisthorchiasis, Prasert Saichua, Paiboon Sithithaworn, Amar R. Jariwala, David J. Diemert, Jiraporn Sithithaworn, Banchob Sripa, Thewarach Laha, Eimorn Mairiang, Chawalit Pairojkul, Maria V. Periago, Narong Khuntikeo, Jason Mulvenna, Jeffrey M. Bethony

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Approximately 680 million people are at risk of infection with Opisthorchis viverrini (OV) andClonorchis sinensis, with an estimated 10 million infected with OV in Southeast Asia alone. While opisthorchiasis is associated with hepatobiliary pathologies, such as advanced periductal fibrosis (APF) and cholangiocarcinoma (CCA), animal models of OV infection show that immune-complex glomerulonephritis is an important renal pathology that develops simultaneously with hepatobiliary pathologies. A cardinal sign of immune-complex glomerulonephritis is the urinary excretion of immunoglobulin G (IgG) (microproteinuria). In community-based studies in OV endemic areas along the Chi River in northeastern Thailand, we observed that over half of …

Break Out: Urogenital Schistosomiasis And Schistosoma Haematobium Infection In The Post-Genomic Era, Paul J. Brindley, Peter J. Hotez

Microbiology, Immunology, and Tropical Medicine Faculty Publications

No abstract provided.

Effects Of Treatment On Ige Responses Against Parasite Allergen-Like Proteins And Immunit To Reinfection In Childhood Schistosome And Hookworm Coinfections, Angela Pinot De Moira, Frances M. Jones, Shona Wilson, Edridah Tukahebwa, Colin M. Fitzsimmons, Joseph K. Mwatha, Jeffrey M. Bethony, Narcis B. Kabatereine, David W. Dunne

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Naturally occurring human immunity to both schistosomiasis and hookworm infection has been associated with IgE responses against parasite allergen-like proteins. Since the two helminths frequently coinfect the same individuals, there is growing advocacy for their concurrent treatment. However, both helminths are known to exert strong immunomodulatory effects; therefore, coinfected individuals could have immune responses different from those characteristically seen in monoinfected individuals. In this study, we measured changes in IgE, IgG1, and IgG4 responses to schistosome and hookworm antigens, including the allergen-like proteins Schistosoma mansoni tegumental-allergen-like 1 protein (SmTAL1), SmTAL2, and Necator americanus Ancylostoma-secreted protein-2 (Na-ASP-2), following concurrent …

Transcriptional Responses Of In Vivo Praziquantel Exposure In Schistosomes Identifies A Functional Role For Calcium Signalling Pathway Member Camkii, Hong You, Donald P. Mcmanus, Wei Hu, Michael J. Smout, Paul J. Brindley, Geoffrey N. Gobert

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Treatment for clinical schistosomiasis has relied centrally on the broad spectrum anthelmintic praziquantel; however, there is limited information on its mode of action or the molecular response of the parasite. This paper presents a transcriptional and functional approach to defining the molecular responses of schistosomes to praziquantel. Differential gene expression in Schistosoma japonicum was investigated by transcriptome-wide microarray analysis of adult worms perfused from infected mice after 0.5 to 24 hours after oral administration of sub-lethal doses of praziquantel. Genes up-regulated initially in male parasites were associated with “Tegument/Muscle Repair” and “Lipid/Ion Regulation” functions and were followed by “Drug Resistance” …

Molecular Characterization Of A Tetraspanin From The Human Liver Fluke, Opisthorchis Viverrini, Supawadee Piratae, Smarn Tesana, Malcolm K. Jones, Paul J. Brindley, Alex Loukas, Erica Lovas, Veerachai Eursitthichai, Banchob Sripa, Sirikanda Thanasuwan, Thewarach Laha

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Background

The human liver fluke, Opisthorchis viverrini, is designated as a group 1 carcinogen, and is the major risk factor for cholangiocarcinoma in endemic countries throughout Southeast Asia. Proteins in the excretory-secretory products and tegumental surface membranes of the fluke have been proposed to play pivotal roles in parasite survival in the host, and subsequent pathogenesis. These macromolecules are therefore valid targets for the development of vaccines and new drugs to control the infection. Tetraspanins (TSP) are prominent components of the tegument of blood flukes where they are essential for tegument formation, are directly exposed to the immune system, …

Germline Transgenesis And Insertional Mutagenesis In Schistosoma Mansoni Mediated By Murine Leukemia Virus, Gabriel Rinaldi, Sabine E. Eckert, Isheng J. Tsai, Suttas Suttiprapa, Kristine J. Kines, Jose F. Tort, Victoria H. Mann, Daniel J. Turner, Matthew Berriman, Paul J. Brindley

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Functional studies will facilitate characterization of role and essentiality of newly available genome sequences of the human schistosomes, Schistosoma mansoni, S. japonicum and S. haematobium. To develop transgenesis as a functional approach for these pathogens, we previously demonstrated that pseudotyped murine leukemia virus (MLV) can transduce schistosomes leading to chromosomal integration of reporter transgenes and short hairpin RNA cassettes. Here we investigated vertical transmission of transgenes through the developmental cycle of S. mansoni after introducing transgenes into eggs. Although MLV infection of schistosome eggs from mouse livers was efficient in terms of snail infectivity, >10-fold higher transgene copy …

Gastrointestinal Cell Mediated Immunity And The Microsporidia, Magali M. Moretto, Imtiaz A. Khan, Louis M. Weiss

Microbiology, Immunology, and Tropical Medicine Faculty Publications

No abstract provided.

Vasa-Like Dead-Box Rna Helicases Of Schistosoma Mansoni, Danielle E. Skinner, Gabriel Rinaldi, Sutas Suttiprapa, Victoria H. Mann, Pablo Smircich, Alexis A. Cogswell, David L. Williams, Paul J. Brindley

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Genome sequences are available for the human blood flukes, Schistosoma japonicum, S. mansoni and S. haematobium. Functional genomic approaches could aid in identifying the role and importance of these newly described schistosome genes. Transgenesis is established for functional genomics in model species, which can lead to gain- or loss-of-functions, facilitate vector-based RNA interference, and represents an effective forward genetics tool for insertional mutagenesis screens. Progress toward routine transgenesis in schistosomes might be expedited if germ cells could be reliably localized in cultured schistosomes. Vasa, a member of the ATP-dependent DEAD-box RNA helicase family, is a prototypic marker of …

Elevated Plasma Il-6 Associates With Increased Risk Of Advanced Fibrosis And Cholangiocarcinoma In Individuals Infected By Opisthorchis Viverrini, Banchob Sripa, Bandit Thinkhamrop, Eimorn Mairiang, Thewarach Laha, Sasithorn Kaewkes, Paiboon Sithithaworn, Maria V. Periago, Vajarabhongsa Bhudhisawasdi, Ponlapat Yonglitthipagon, Jason Mulvenna, Paul J. Brindley, Alex Loukas, Jeffrey M. Bethony

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Opisthorchis viverrini is considered among the most important of the food-borne trematodes due to its strong association with advanced periductal fibrosis and bile duct cancer (cholangiocarcinoma). We investigated the relationship between plasma levels of Interleukin (IL)-6 and the risk of developing advanced fibrosis and bile duct cancer from chronic Opisthorchis infection. We show that IL-6 circulates in plasma at concentrations 58 times higher in individuals with advanced fibrosis than age, sex, and nearest-neighbor matched controls and 221 times higher in individuals with bile duct cancer than controls. We also observed a dose-response relationship between increasing levels of plasma IL-6 and …

Five-Year Longitudinal Assessment Of The Downstream Impact On Schistosomiasis Transmission Following Closure Of The Three Gorges Dam., Darren J. Gray, Aaron P. Thrift, Gail M. Williams, Feng Zheng, Yue-Sheng Li, Jiagang Guo, Honggen Chen, Tianping Wang, Xin J. Xu, Rong Zhu, Hongqing Zhu, Chun Li Cao, Dan D. Lin, Zhen Y. Zhao, Robert S. Li, George M. Davis, Donald P. Mcmanus

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Background

Schistosoma japonicum is a major public health concern in the Peoples' Republic of China (PRC), with about 800,000 people infected and another 50 million living in areas at risk of infection. Based on ecological, environmental, population genetic and molecular factors, schistosomiasis transmission in PRC can be categorised into four discrete ecosystems or transmission modes. It is predicted that, long-term, the Three Gorges Dam (TGD) will impact upon the transmission of schistosomiasis in the PRC, with varying degree across the four transmission modes.

Methodology/Principal Findings

We undertook longitudinal surveillance from 2002 to 2006 in sentinel villages of the three transmission …

Enhanced Protective Efficacy Of A Chimeric Form Of The Schistosomiasis Vaccine Antigen Sm-Tsp-2, Mark S. Pearson, Darren A. Pickering, Henry J. Mcsorley, Jeffrey M. Bethony, Leon Tribolet, Annette M. Dougall, Peter J. Hotez, Alex Loukas

Microbiology, Immunology, and Tropical Medicine Faculty Publications

The large extracellular loop of the Schistosoma mansoni tetraspanin, Sm-TSP-2, when fused to a thioredoxin partner and formulated with Freund's adjuvants, has been shown to be an efficacious vaccine against murine schistosomiasis. Moreover, Sm-TSP-2 is uniquely recognised by IgG1 and IgG3 from putatively resistant individuals resident in S. mansoniendemic areas in Brazil. In the present study, we expressed Sm-TSP-2 at high yield and in soluble form in E. coli without the need for a solubility enhancing fusion partner. We also expressed in E. coli a chimera called Sm-TSP-2/5B, which consisted of Sm-TSP-2 fused to …

Characterising The Mucosal And Systemic Immune Responses To Experimental Human Hookworm Infection., Soraya Gaze, Henry J. Mcsorley, James Daveson, Di Jones, Jeffrey M. Bethony, Luciana M. Oliveira, Richard Speare, James S. Mccarthy, Christian R. Engwerda, John Croese, Alex Loukas

Microbiology, Immunology, and Tropical Medicine Faculty Publications

The mucosal cytokine response of healthy humans to parasitic helminths has never been reported. We investigated the systemic and mucosal cytokine responses to hookworm infection in experimentally infected, previously hookworm naive individuals from non-endemic areas. We collected both peripheral blood and duodenal biopsies to assess the systemic immune response, as well as the response at the site of adult worm establishment. Our results show that experimental hookworm infection leads to a strong systemic and mucosal Th2 (IL-4, IL-5, IL-9 and IL-13) and regulatory (IL-10 and TGF-β) response, with some evidence of a Th1 (IFN-γ and IL-2) response. Despite upregulation after …

Redefining Chronic Toxoplasmosis: A T Cell Exhaustion Perspective, Rajarshi Bhadra, Imtiaz A. Khan

Microbiology, Immunology, and Tropical Medicine Faculty Publications

No abstract provided.

Cell-Free Circulating Mirna Biomarkers In Cancer., Meng-Hsuan Mo, Liang Chen, Yebo Fu, Wendy Wang, Sidney W. Fu

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Considerable attention and an enormous amount of resources have been dedicated to cancer biomarker discovery and validation. However, there are still a limited number of useful biomarkers available for clinical use. An ideal biomarker should be easily assayed with minimally invasive medical procedures but possess high sensitivity and specificity. Commonly used circulating biomarkers are proteins in serum, most of which require labor-intensive analysis hindered by low sensitivity in early tumor detection. Since the deregulation of microRNA (miRNA) is associated with cancer development and progression, profiling of circulating miRNAs has been used in a number of studies to identify novel minimally …