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Host/Pathogen Interactions

Regulation of the Intestinal Immune Response to Toxoplasma gondii

Toxoplasma gondii is a parasite that infects around 30% of the world’s people. It causes serious disease including encephalitis, abortion, stillbirth, congenital defects to hearing and sight, and mental retardation and disorders. As is the case for many infections, its first point of interaction with our immune system is the intestine. Inflammation of the intestine results from failed regulation of this interaction. Our hypothesis is that the P2X7 receptor plays a critical role in regulating the intestinal inflammatory response to Toxoplasma. We predict that the P2X7 receptor affects intestinal inflammation by influencing: (1) the level of infection with Toxoplasma;

(2) the quality and quantity of the immune response to Toxoplasma; and/or

(3) the population structure of intestinal bacteria which, in turn, may affect the inflammatory response to infection with Toxoplasma.

Researchers: Nick Smith, Kate Miller

Program: Host/Pathogen Interactions

Sexual Stage Development of Toxoplasma gondii: The Path to a Transmission-Blocking Vaccine

Oocysts
Oocysts. Image by Nick Smith
Toxoplasma gondii is a common parasite; it infects 30% of the world's people and can cause serious disease. All human infections can be traced back to the shedding of infectious, egg-like structure – oocysts – in cat faeces. Our research will identify proteins that play key roles in how Toxoplasma survives and reproduces in the cat and how it produces oocysts. We will localise proteins that are critical for these processes and create gene-knockout Toxoplasma strains that lack the ability to complete their lifecycle in the cat. We will ultimately produce a vaccine that, when given to cats, will halt the reproduction and transmission of this parasite.

Researchers: Nick Smith, Robert Walker (and collaborators, Adrian Hehl and Peter Deplazes, University of Zurich, and Mike Grigg, National Institutes of Health, USA)

Program: Host/Pathogen Interactions

Vaccine Development for Human Helminth Infections

Schistomosomes 3 male
3 male Schistosomes. Image by Mic Smout
We are using cutting-edge approaches to the discovery of antigens for inclusion in subunit vaccines for human helminthiases.  In collaboration with Prof Phil Felgner at University of California Irvine, we have produced the first protein microarrays for any multi-cellular pathogen (hookworms and schistosomes) and are probing these arrays with sera from resistant and susceptible humans and animals. Antigens of interest are then tested in animal models for vaccine efficacy and prioritised for human clinical trials in collaboration with US colleagues at Sabin Vaccine Institute, Baylor College of Medicine and George Washington University. We also seek to understand the functions of vaccine antigens within the parasite by addressing phenotypic changes induced by gene silencing approaches.

Researchers: Mark Pearson, Annette Dougall, Javier Sotillo, Darren Pickering, Cinzia Cantacessi, Leon Tribolet

Program: Host/Pathogen Interactions

Molecular Mechanisms of Liver Fluke-Induced Carcinogenesis

Echinostoma
Echinostoma adult. Image by Javier Sotillo
We are interested in the molecular mechanisms by which the liver fluke, Opisthorchis viverrini, causes cholangiocarcinoma in many infected individuals in SE Asia. Our particular focus is on the excretory/secretory components of the parasite and the changes that these induces in cholangiocytes. We have identified a number of proteins that induce proliferation and pre-cancerous changes in host cells, notably a homologue of the human growth factor, granulin.

ResearchersMichael Smout, Javier Sotillo, Cinzia Cantacessi, Sujittra Chaiyadet

Program: Host/Pathogen interactions

Proteomics Analysis of Nippostrongylus braziliensis

Hookworm lava and eggs
Hookworm lava and eggs. Image by Mic Smout
Hookworm infections are one of the most represented neglected tropical diseases in developing countries. Nippostrongylus braziliensis is often used as a model to study host-parasite relationships in hookworm infections as it can infect mice and its life cycle can be maintained in the laboratory. The study of the proteins involved in this relationship can serve to elucidate how parasites penetrate, migrate and survive in the host and can provide the basis for further investigation to determine the factors leading to the establishment of an infection.

ResearchersAlex Loukas, Darren Pickering, Cinzia Cantacessi, Javier Sotillo

Program: Host/Pathogen interactions

Identification of Tegumental Proteins from Schistosoma mansoni Schistosomula

Schistosomula
Schistosomula. Image by Javier Sotillo
Schistosomiasis is a parasitic disease afflicting over 200 million people worldwide. Although the importance of this disease and the efforts that have been put to eradicate it, little is known about the interactions between the infective stage (schistosomula) and the host. The proteins present on the surface of schistosomula may be of importance to understand how these larvae penetrate and migrate through the skin of the host and could help in the identification of new potential targets against these parasites.

Researchers: Alex Loukas, Cinzia Cantacessi, Javier Sotillo

Program: Host/Pathogen Interactions

Identification of Novel Strategies to Mediate Immunity Against Intracellular Pathogens

Infections with intracellular bacterial or protozoan pathogens are a major cause of death, particularly in immunocompromised individuals. Their intracellular lifestyle and immune evasion has made it difficult to develop vaccines and immunomodulatory treatment strategies.

Cytosolic pattern recognition receptors (PRR) sense pathogen and host derived danger signals inside cells. This project investigates how PRR-mediated cytosolic pathogen recognition can be exploited to develop novel strategies to control infections with intracellular pathogens, including in situations where full function of the immune system has been compromised. Our research compares and contrasts the important bacterial pathogen Mycobacterium tuberculosis and the important protozoan parasite Toxoplasma gondii.

Researchers:

Researchers: Andreas Kupz, Nick Smith (and collaborator, Stefan Kaufmann, Max Planck Institute for Infection Biology, Berlin, Germany)

Program: Host/Pathogen Interactions

Development of RNA Interference as a Tool to Assess Gene Function in Hookworms

Ancylostoma caninum
Mouth parts of dog hookworm. Image by Ivana Ferreira
RNA interference has been successfully demonstrated in the sheep parasitic nematode, Haemonchus contortus by targeting accessible genes such as those expressed in the gut, excretory cell and amphids.  To date RNA interference has not been described in hookworm.  Given the similarities of H. contortus to hookworm, we have begun similar trials targeting accessible and/or abundant genes found in adults and infective L3 of Necator americanus and Ancylostoma caninum.  Successful application of this technique to hookworm biology will allow researchers to assess gene function and lethality in the search for new drug and vaccine candidates for hookworm disease.

Researchers: Annette Dougall, Darren Pickering, Atik Susianto, Mark Pearson, Alex Loukas

Program: Host/Pathogen Interactions

Bacterial Infections and Diabetes

Burkholderia
Burkholderia. Image by Jeff Warner

Bacterial infections and type 2 diabetes are major health problems worldwide. Our core research aims are to determine the function of macrophages, dendritic cells and T lymphocytes and their interaction and cross-talk in infections caused by Burkholderia pseudomallei and Mycobacterium tuberculosis in diabetics. Human ex vivo experiments and rodent models are being used to determine the interaction between bacterial and host factors that contribute to acute, chronic and latent infections. Immunomodulatory agents as adjunct therapies for bacterial sepsis are being investigated as part of the translational arm of this programme.

Researchers: Brenda Govan, Natkunam Ketheesan, Jodie Morris, Robert Norton, Cathy Rush

Program: Host/Pathogen Interactions

Development of a Preventative Strategy for Rheumatic Fever and Rheumatic Heart Disease

A1E84
Image by Natkunam Ketheesan
Streptococcal infections are known to trigger an autoimmune sequelae leading to rheumatic fever and rheumatic heart disease (RF/RHD). We have characterised the only credible model for RF/RHD, the Rat Autoimmune Valvulitis (RAV) model, which we use to determine several facets of the autoimmune process. Our core research aims are to determine the early immune changes that occur on valvular endothelium and myocardium and to determine the function of T and B cells that lead to and continue to enhance the destruction of host tissue. This chronic process leads to RF/RHD followed by permanent cardiac damage and heart failure. The translational arm of the programme is focussed on determining whether peptides from group A streptococcal M protein can be used to induce tolerance in the RAV model to suppress self-reactive lymphocytes and alter cytokine responses. We are also involved in research projects aimed at developing diagnostic tools based on antibody reactivity to myosin S2 peptides and in testing novel vaccine candidates for safety using the RAV model.

Researchers: Brenda Govan, Natkunam Ketheesan, Jodie Morris, Robert Norton, Cathy Rush

Program: Host/Pathogen Interactions

Regulation of Innate Immunity to Helminths

Parasitic worm infections are a massive global health problem. Our research will increase our understanding of how our immune system controls infection with intestinal worms. Specifically, we want to know how the cells that line the intestinal tract respond to parasites to release factors that can cause elimination of the worm from the body by the immune system. Understanding how these cells promote anti-parasite immunity may help in the development of a vaccine for parasitic worms.

Researchers: Paul Giacomin, Alex Loukas

Program: Host/Pathogen interactions

Utilising Transgenesis to Investigate the Role of Insulin Signaling in Helminth Infections

Significant strides in descriptive genomics have been made in the past decade for both the schistosomes and parasitic nematodes. The growing body of descriptive genomic data for parasitic helminths forms a sound basis for the application of reverse genetic methods such as targeted gene ablation gene silencing or transgenesis to the study of gene function. The overall goal of this project is to identify which parts of the insulin signaling pathway are critical for signaling transduction to occur and whether or not this pathway is crucial in the development and survival of these parasites externally and within the host.

Researchers: Najju Ranjit, Alex Loukas (and collaborator, James Lok, University of Pennsylvania)

Program: Host/Pathogen Interactions

Virulence Mechanisms of the Frog-Killing Fungus, Batrachochytrium dendrobatidis

Green-eyed treefrog
Litoria serrata (Green-eyed treefrog) Queensland rainforest, declined due to chytridiomycosis. Photo: Lee Skerratt
The greatest loss of vertebrate biodiversity from disease is due to the fatal amphibian chytrid fungus Batrachochytrium dendrobatidis (Bd), which has caused over 90 species extinctions in the past 30 years. While Bd is highly pathogenic, the mechanisms of virulence and infection are not known. We are using genetic, proteomic, metabolomic and microbiological tools to understand how the fungus kills frogs. Specifically, this project focuses on isolating and characterising Bd virulence factors, including proteins and metabolites that cause amphibian immunosuppression and epidermal damage. Understanding Bd virulence has implications for pathogen control, protecting biodiversity and the discovery of novel drug targets.

Researchers: Alex RobertsLee BergerLee Skerratt, Rebecca Webb

Program: Host/Pathogen Interactions