Molecular Parasitology

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Lab Head: Professor Don McManus

The Molecular Parasitology Laboratory researches parasitic worms of humans, particularly schistosome bloodflukes, which are responsible for the potentially debilitating disease schistosomiasis or Bilharziasis, and dog tapeworms (Echinococcus), which are the cause of hydatid disease.

Schistosomiasis

This laboratory is undertaking extensive human field studies in Hunan Province (Dongting Lake region) and Jiangxi Province (Poyang Lake) in China. This has included longitudinal and cohort surveys of subjects from endemic areas, treatment and follow-up, measurement of reinfection rates, water contact studies, assessment of pathology by ultrasound and specific liver fibrosis markers. We are also continuing large immuno-epidemiological surveys including antibody isotype analysis, T cell proliferation assays and cytokine responses to S. japonicum vaccine candidates following our identification of putative susceptible/resistant schistosomiasis individuals by epidemiological criteria. We have identified close associations between HLA class II antigens and resistance/susceptibility to hepatosplenic disease caused by schistosomiasis and are embarking on a new project aimed at determining whether there are additional genetic components associated with human susceptibility to advanced schistosomiasis. A new 5-year, NIH-supported project will investigate the hypothesis that bovine, especially buffalo, infections are responsible for the persistence of human schistosomiasis transmission in much of southern China. The project will also involve 5-year population-based incidence studies of infection and infection intensity of schistosome infections in humans and livestock animals. Mathematical modelling will be integral to the project so as to predict the effect of the closure of the Three Gorges Dam on schistosome transmission. Don McManus, Li Yuesheng and Gail Williams are involved in the project.

Echinococcosis
Other studies are characterising nuclear and mitochondrial genomes and investigating molecular variation both in the genomes and in key molecules that may be the targets of new anti-schistosome and anti-Echinococcus vaccines. A major finding of our mitochondrial genomics studies was the distinctiveness of the complete mt DNA sequences of the horse-dog and sheep-dog strains of Echinococcus granulosus which indicates that each should be regarded as distinct at the specific level.

Vaccines
We focus on dyneins, secreted enzymes and surface molecules, including receptors that are also likely novel targets for drugs and vaccines. The Molecular Parasitology laboratory is currently searching for vaccines against Schistosoma mansoni (endemic to Africa, the Eastern-Mediterranean, the Caribbean and South America) and Schistosoma japonicum, the Asian or Oriental schistosome (endemic mainly in China and The Philippines). We are also working on aspects of the schistosome genome and the worm surface, which may impact on vaccine and drug development.

Diagnostic tools
We aim to develop new methods of diagnosis in patients infected with hydatid disease and have cloned and expressed a novel E. granulosus antigen that shows appropriate specificity and sensitivity for a commercial test.

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Background information

Schistosomiasis
Schistosomiasis is caused by adult bloodflukes (trematode worms) depositing eggs in blood vessels surrounding the bladder or gut of the infected host. A serious parasitic disease that infects over 200 million people, schistosomiasis occurs mainly in rural agricultural and peri-urban areas of the developing world. Twenty million suffer severe consequences from the disease and 120 million are symptomatic with symptoms ranging from fever, headache, and lethargy, to severe sequelae including ascites, hepatosplenomegaly, and often death. Indeed, it has been estimated that 500,000 deaths occur annually due to schistosomiasis, which is testimony to its public health significance. The development of effective vaccines against schistosomiasis is a public health priority.

Schistosomiasis vaccine development
We have cloned and characterised an extensive number of cDNAs encoding Schistosoma japonicum vaccine candidates including a 14 kDa fatty acid binding protein, paramyosin, glutathione S- transferase 26, glutathione S-transferase 28, 22.6 kDa tegumental antigen, 23 kDa transmembrane protein, aspartic protease, calponin, calreticulin, dynein light chain, calpain, triose-phosphate isomerase (TPI) and heat shock proteins. In addition to understanding the molecular characteristics of many of these proteins, we have undertaken studies on their function and localisation. Further, the majority have been expressed in bacteria and/or baculovirus and have been tested for vaccine efficacy in mice and large domestic animals notably pigs and bovines in China. As a result of this large scale work, we have identified three vaccine targets, paramyosin, GST-26 and TPI which we are pursuing further. Paramyosin and GST-26 have provided very encouraging levels of protection in mice and bovines, notably water buffaloes. Paramyosin is currently being produced under GMP conditions at the Hong Kong Institute of Biotechnology (HKIB) for planned extensive use in China and possibly The Philippines. We plan to commence a new vaccine trial in buffaloes in China with paramyosin and in mice comparing QIMR and HKIB produced materials. New adjuvant formulations will also be tested. In addition, a large trial in bovines is planned in China to compare the combined protective efficacy of paramyosin and GST-26. New studies investigating the effectives of DNA vaccines will commence. Another new project will commence which involves signal peptide selection for identification of genes encoding secreted proteins and receptors, novel targets for schistosome vaccines.

Life cycle of Schistosoma japonicum

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Field ecology of schistosomiasis
We have undertaken extensive human field studies with our large team of Chinese collaborators in Hunan Province (Dongting Lake region) and Jiangxi Province (Poyang Lake). This has included longitudinal and cohort surveys of subjects from endemic areas, treatment and follow-up, measurement of reinfection rates, water contact studies, assessment of pathology by ultrasound and specific liver fibrosis markers. In addition, we have undertaken large immunoepidemiological surveys including antibody isotype analysis, T cell proliferation assays and cytokine responses to S. japonicum vaccine candidates following our identification of putative susceptible/resistant schistosomiasis individuals by epidemiological criteria. We propose to follow up these patients in the coming year. We have also identified close associations between HLA class II antigens and resistance/susceptibility to hepatosplenic disease caused by schistosomiasis.

The epidemiological and immunoepidemiological studies will continue in China. Extensive new epidemiological and laboratory data will evolve as a result of the work in Poyang Lake. The full impact of bovines on human schistosomiasis transmission should be evaluated as a result of this unique study and we believe this will represent a major advance and maintain the impetus of vaccine development and its use in control targeting bovine hosts. Furthermore, we are anticipating the development of new schistosomiasis field projects in Agusan Del Sur, Mindanao, which will link with the current ongoing malaria program and in Leyte and Samar. We will also be field-testing new potential diagnostic molecules we and our collaborators have produced to aid in serodiagnosis of schistosomiasis.

Parasite population diversity and genetics
We have undertaken a widescale survey of Schistosoma japonicum genotypes in China. In particular we have targeted the mitochondrial genome as a source of genetic markers and have now totally sequenced and obtained the gene order of a range of different flatworm species including all three human schistosomes, Schistosoma mekongi, Fasciola and Taenia. These are the first flatworm mitochondrial genomes to have been completed. We are also heavily involved in the schistosome genome project supported by The World Health Organisation; we have been instrumental in obtaining an extensive number of new schistosome genes using the expressed sequence tag (EST) approach and have identified a number of unique transposable elements. We have recently commenced studies using a fundamentally new approach (signal sequence trap) to identify surface and receptor molecules, which may provide new targets for vaccine development.

The wealth of mitochondrial DNA data we have generated will be used in phylogenetic analysis and molecular epidemiology studies. We will be in a position to track the evolution and migration of schistosomes from Africa across Asia into China, Thailand and The Philippines and determine whether the South American schistosomes were introduced from Africa by the Slave trade. We will also be able to determine the extent of genetic variability in discrete schistosome populations; such knowledge is important practically as it may impact on the future use of anti-schistosome vaccines. The other genetic work on schistosomes (transposable elements, EST analysis) will be maintained. Potential students can get involved with any of these exciting projects.

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The schistosome surface
The surface of larval and adult schistosomes, the tegument, is in intimate contact with the host immune system. The parasite exhibits a remarkable ability to avoid immune destruction while being constantly bathed in host antibodies and immune effector cells. While this evasion strategy is multi-faceted, one of the most intriguing mechanisms used by the parasite is the adsorption of host glycoprotein ligands such as MHC class I, complement and IgG onto the tegument to mask recognition by the host. In collaboration with Dr Alex Loukas (Molecular Helminthology laboratory) we are presently searching for the schistosome surface receptors of these host molecules using the following techniques:
1. affinity purification using biotinylated parasite surface extracts and ligands conjugated to sepharose;
2. construction of schistosome cDNA libraries in mammalian expression vectors to allow eukaryotic processing and cell surface expression of receptors - once achieved the libraries will be screened with labelled human ligands and recombinant clones identified using FACS and other techniques;
3. signal sequence trap where cDNAs encoding schistosome surface and secreted proteins are selectively identified by the ability of their signal peptides to direct surface expression of a reporter construct in mammalian cells.

Hydatid Disease Research
Hydatid disease, caused by dog tapeworms of the genus Echinococcus, is a major cosmopolitan disease of widespread importance and is a continuing problem in Australia. We are involved in studies which aim to produce new methods of diagnosis in infected patients and in investigating the extent of genetic variation in Echinococcus. We have recently completed extensive molecular epidemiological surveys of hydatid genotypes in Argentina, Nepal and China and plan to sequence the Echinococcus mitochondrial genome for a source of new genetic markers. We are also using the EST and Signal Sequence Trap approaches to identify new Echinococcus genes with relevance for immunodiagnosis and as markers of stage-specific differentiation. We will expand on a new project we have recently commenced aimed at using differential display to identify stage-specific expressed molecules which are of potential vaccine and/or diagnostic relevance. We are testing efficicacy of a novel compound derived from traditional medicines of China against cystic echinococcosis. We are also developing a vaccine effective against the adult stage of Echinococcus in the dog definitive host.

We encourage potential students to participate in a range of projects associated with our work on hydatid disease.

Below left: Professor Don McManus with Magda Ellis, a student from the Molecular Parasitology Laboratory who received the John Sprent Prize in Adelaide in July 2008. Presented by the Australian Society for Parasitology once every three years for an outstanding thesis in the field of parasitology. Below right: Members of the Molecular Parasitology Laboratory.

Staff

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Funding

We gratefully acknowledge support from the following organisations and funding bodies:

• UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases
• The National Health and Medical Research Council of Australia
• The Australian Research Council
• The National Institutes of Health (NIH), U.S.A.
• The National Institute of Allergy and Infectious Diseases (NIAID) (Tropical Medicine Research Center (TMRC) Grant)
• ACITH
• IDP/AUSAID China/Australia Institutional Links Program
• Wellcome Trust
• Dana Foundation
• The Sandler Foundation
• The University of Queensland
• The Ramaciotti Foundation

Funding Highlight:

In August 2003 Professor Don McManus received an International Collaborative Research Grants Scheme Award from The Hon. Senator Kay Patterson, Federal Minister for Health and Ageing, at Parliament House, Canberra (picture left). The International Collaborative Research Grants (ICRG) Scheme is a partnership between the UK-based Wellcome Trust, Australia's National Health and Medical Research Council (NHMRC) and the Health Research Council (HRC) of New Zealand. The Scheme is designed to foster collaborative research between the developing countries of the region and both Australia and New Zealand. Countries of the region include countries in South and South East Asia and the islands of the Pacific.
The grants scheme has been established to improve health in developing countries by:

• Funding research into major health issues of developing countries, and
• Developing research capacity in both developing countries of the region and in Australia and New Zealand.

The grants scheme aims to provide support for teams of researchers drawn from different countries, to pursue collaborative research projects in health issues of importance to the people of the region.

Professor McManus' project, one of only 11 successful projects, is entitled: Pathways to improved, sustainable morbidity control and prevention of schistosomiasis in the People's Republic of China. The 5 year program grant award is for AUD $2.5 million.

Collaborators

• Dr Feng Zheng and Professor Guo Jiagang, WHO Collaborating Centre for Malaria,Schistosomiasis and Filariasis, Institute of Parasitic Diseases, Chinese Centre for Disease Control and Prevention, Shanghai, PR China.
• Dr Charles Bix Shoemaker, AgResearch Ltd, Wallaceville Animal Research Centre, Upper Hutt, New Zealand.
  
• Professor Honggen Chen, Jiangxi Provincial Institute of Parasitic Diseases, Nanchang, Jiangxi, PR China.
  
• Professor Alain Dessein, INSERM U399, Faculte de Medecine, Marseille, France.
  
• Dr Weiqing Pan, Department of Etiologic Biology, Second Military Medical University, Shanghai, PR China.
  
• Professor Paul Brindley, Dept Tropical Medicine, Tulane University, New Orleans, Louisiana, USA.
  
• Professor Marcel Tanner, Director, Swiss Tropical Institute, Basel, Switzerland.
  
• Professor Philip Craig, Biology Dept, Salford University, Salford, United Kingdom.
  
• Dr Thanh Hoa Le, Hanoi Institute of Biotechnology, Hanoi, Vietnam.
  
• Dr David Blair, Biology Dept, James Cook University, Townsville, Australia.
  
• Professor Remi Olveda, Research Institute for Tropical Medicine, Manila, Philippines.

Student Projects

Research projects are available within the Molecular Parasitology Laboratory for BSc Honours, MMedSci and PhD students interested in working in the schistosomiasis, hydatid and nematode biology areas.

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Recent Publications

Selected journal articles from the last three years

Balen, J. Zhao, Z-Y., Williams, G.M., McManus, D.P., Raso, J., Utzinger, J., Zhou, J. and Li, Y.S. (2007). Prevalence, intensity and associated morbidity of Schistosoma japonicum infection in the Dongting Lake region, China. Bulletin of the World Health Organisation 85; 519-526. (Corresponding author).

Bartley, P.B., Ramm, G.A, Jones, M.K., Ruddell, R.G., Li, Y.S. and McManus, D.P. (2006). A contributory role for hepatic stellate cells in the dynamics of Schistosoma japonicum egg-induced fibrosis. International Journal for Parasitology 36: 993-1001. (Article featured on issue cover).

Bergquist, R., Utzinger, J. & McManus, D.P. Trick or treat: the role of a vaccine in integrated schistosomiasis control. PLoS Neglected Diseases (in press). (Accepted 13th March, 2008).

Chai, M., McManus, D.P., Moertel, L., Tran, M., Loukas, A., Jones, M.K. and Gobert, G.N. (2006). Transcriptome profiling of lung schistosomula, in vitro cultured schistosomula and adult Schistosoma japonicum. Cellular and Molecular Life Sciences 63: 919-929.

Craig, P.S. McManus, D.P., Lightowlers, M.W., Chabalogoity, J.A., Garcia, H.H., Gavidia, C.M., Gilman, R.H., Gonzalez, A.E., Lorca, M., Naquira, C., Nieto, A., and Schantz, P.M. (2007). Prevention and control of cystic echinococcosis. Lancet Infectious Diseases 7: 385-394.

Ellis, M., Li, Y.S., Rong, Z., Chen, H. and McManus, D.P. (2006). Familial aggregation of human infection with Schistosoma japonicum in the Poyang Lake region, China. International Journal for Parasitology 36: 71-77.

Ellis, M.K., Li, Y.S., Hou, X., Chen H. & McManus, D.P. TNFR-II and sICAM-1 are associated with acute disease and hepatic inflammation in schistosomiasis japonica. (2008). International Journal for Parasitology 38: 717-723.

Ellis, M.K., Raso, G., Li, Y.S., Rong, Z., Chen, H. and McManus, D.P. (2007). Familial aggregation of human susceptibility to co- and multiple helminth infections in a population from the Poyang Lake region, China. International Journal for Parasitology 37:1153-1161.

Ellis, M.K., Zhen Zhen Zhao, Z.Z., Chen, H-G., Montgomery, G.W., Li, T.S. & McManus, D.P. (2007). Analysis of the 5q31-33 locus shows an association between SNP variants in the IL-5 gene and symptomatic infection with the human bloodfluke, Schistosoma japonicum. Journal of Immunology 179: 8366-8371.

Glanfield, A., McManus, D.P., Anderson G.J. and Jones, M.K. (2007). Pumping iron: a potential target for novel therapeutics against schistosomes. Trends in Parasitology 23:583-588.

Gobert, G.N., Moertel, L., Nelson, C., McInnis, R.L., Jones, M.K., Hu, W. and McManus, D.P. (2006). Transcriptomics tool for the human blood flukes Schistosoma using microarray gene expression profiling. Experimental Parasitology 114: 160-172.

Gray, D., Williams, G. Li, Y.S., Chen, H., Li, R., Forsyth, S., Barnett, A., Guo, J., Feng, Z. and McManus, D.P. (2007). A cluster-randomized bovine intervention trial against Schistosoma japonicum in the Peoples Republic of China: design and baseline results. American Journal of Tropical Medicine and Hygiene 77: 866-874.

Jones, M.K., McManus, D.P., Sivadorai, P., Glanfield, A., Moertel, L., Belli, S.I., Gobert, G.N. (2007). Tracking the fate of iron in early development of human blood flukes. The International Journal of Biochemistry & Cell Biology 39:1646-1658.

Jones, M.K., Randall, L., McManus, D.P. and Engwerda, C. (2004). Laser microdissection microscopy in parasitology: microscopes meet thermocyclers. Trends in Parasitology 20: 502-506.

Jones, M.K., Zhang, L., Gobert, G.N., Sunderland, P. and McManus, D.P. (2004). The cytoskeleton and cytoskeletal components of schistosomes. Bioessays 26:752-765. (Article featured on issue cover).

Le, T.H., De, N.V, Blair, D. Sithitharworn, P. and McManus, D.P. (2006). Clonorchis sinensis and Opisthorchis viverrini: development of a mitochondrial DNA-based multiplex PCR for their identification and discrimination. Experimental Parasitology 112:109-114.

Li, Y.S., Raso, G., Zhao, Y., He, H.K., Ellis M. and McManus, D.P. (2007). Predicted impact of large water management projects on schistosomiasis transmission and control in the Dongting Lake Region, China. Emerging Infectious Diseases 13: 973-979.

Liu, F., Lu, J., Hu, W., Wang, S-Y., Cui, S-J., Chi,, M., Yan, Q., Wang, X-R., Song, H-D., Xu, X-N., Wang, J-J., Zhang, X-L., Zhang, X., Wang, Z-Q., Xue, C-L., Brindley, P.J., McManus D.P., Yang, P-Y., Feng Z., Chen, Z. and Han, Z-G. (2006). New perspectives on host parasite interplay by comparative transcriptomic and proteomic analyses of the human blood fluke Schistosoma japonicum. PLOS Pathogens Apr 14;2(4).

McManus, D.P. & Loukas A. (2008). The current status of vaccines for schistosomiasis. Clinical Microbiology Reviews 21: 225-242.

McManus, D.P. and Dalton, J.P. (2006). Vaccines against the zoonotic trematodes Schistosoma japonicum, Fasciola hepatica and Fasciola gigantica. Parasitology 133: Suppl: S43-61. (Article featured on issue cover).

McManus, D.P. Taenia in the gastrointestinal tract. (2008). New England Journal of Medicine 358: 311.

McManus, D.P., Gray, D.J., Williams, G. M. & Li, Y.S. (2008). Responses: Multi-host transmission dynamics of Schistosoma japonicum: the China perspective. PLoS Medicine Vol. 5, No. 1,

McManus, D.P., Hu, W., Brindley, P.J., Feng, Z. and Han, Z-G. (2004). Schistosome transcriptome analysis at the cutting edge. Trends in Parasitology 20: 301-304.

Moertel, L., McManus, D.P., Piva, T.J., Young, L., McInnis, R.L and Gobert, G.N. (2006). Oligonucleotide microarray analysis of strain- and gender- associated gene expression in the human blood fluke, Schistosoma japonicum. Molecular and Cellular Probes 20: 280-289.

Raso, G., Vounatsou, P., McManus, D.P. & Utzinger, J. (2007). Bayesian risk maps for Schistosoma mansoni and hookworm mono-infections in a setting where both parasites co-exist. Geospatial Health 2: 85-96.

Raso, G., Vounatsou, P., McManus, D.P., N'Goran, E.K. and Utzinger, J. (2007). A Bayesian approach to estimate the age-specific prevalence of Schistosoma mansoni and implications for schistosomiasis control. International Journal for Parasitology 37: 1491-1500

Rosenzvit, M.C., Zhang , W., Motazedian H., Smyth, D., Pearson, M., Loukas, A., Jones, M.K. and McManus, D.P. (2006). Identification of membrane-bound and secreted proteins from Echinococcus granulosus by signal sequence trap. International Journal for Parasitology 36:123-130.

Ross, A.G., Vickers, D., Olds, R.G., Shah, S.M. and McManus, D.P. (2007). Katayama syndrome. Lancet Infectious Diseases 7: 218-224.

Smyth, D.J., Glanfield, A., McManus, D.P., Hacker, E., Blair, D., Anderson G. and Malcolm K. Jones (2006). Two isoforms of a divalent metal transporter (DMT1) in Schistosoma mansoni suggest a surface-associated pathway for iron absorption in schistosomes. Journal of Biological Chemistry 281: 2242-2248.

Tran, M.H., Pearson, M.S., Bethony, J.M., Smyth, D.J., Jones, M.K., Duke, M., Don, T.A, McManus, D.P., Correa-Oliveira, R., and Loukas, A. (2006). Tetraspanins on the surface of Schistosoma mansoni are protective antigens against schistosomiasis. Nature Medicine (Article featured on issue cover) 12: 835 - 840.

Yang, Y.R, Rosenzvit, M.C., Zhang L.H., Zhang, L.H. and McManus, D.P. (2005). Molecular study of Echinococcus from west-central China. Parasitology 131:547-555.

Yang, Y.R., Craig, P.S., Ito,A., Vuitton, D.A., Giraudoux, P., Sun, T., Williams, G.M., Huang,Z., Li, Z., Wang, Y., Teng, J., Y. Li, Huang,L., Wen,H., Jones, M.K. and McManus, D.P. (2007). A correlative study of ultrasound with serology in an area in China co-endemic for human alveolar and cystic echinococcosis. Tropical Medicine and International Health 12: 637-646.

Yang, Y.R., Ellis, M., Sun, T., Li, Z., Li, X., Vuitton, D.R. Bartholomot, B., Giradoux, P., Craig, P.S., Boufana, B., Wang, Y., Feng, X., Wen, H., Ito, A. and McManus, D.P. (2006). Unique family clustering of human echinococcosis cases in a Chinese community. American Journal of Tropical Medicine and Hygiene 74: 487-494.

Zhang, W. and McManus, D.P. (2006). Recent advances in the immunology and diagnosis of echinococcosis. FEMS Immunology and Medical Microbiology 47: 24-41.

Zhang, W.B., Jones, W.B., Li, J. and McManus, D.P. (2005). Echinococcus granulosus: preculture of protoscoleces in vitro significantly increases development and viability of secondary hydatid cysts in mice. Experimental Parasitology 110:88-90.

Zhang, W.B., Zhang, Z.Z., Shi, B.X., Li, J., You, H., Tulson, G., Dang, X.S., Song, Y.C., Yimiti, T., Wang, J.C., Jones, M.K. and McManus, D.P. (2006). Vaccination of dogs against Echinococcus granulosus, the cause of cystic hydatid disease in humans. Journal of Infectious Diseases 194: 966-974.

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