Investigating The Host Determinants Of Viral Clearance Versus Collateral Pathology In Chronic Infection
Funder
National Health and Medical Research Council
Funding Amount
$1,250,756.00
Summary
Hepatitis B virus has infected over 2 billion people. Some people control the virus but it remains incurable and there is a lifelong risk of liver cancer. Understanding how host cells interact with the virus, the mechanisms the cells use in an attempt to eliminate the virus and the mechanisms the virus uses to sabotage these responses, will provide insights that could lead to therapies. Potential therapies could be applicable to other infections like HIV-1 and tuberculosis.
Dissemination And Virulence Properties Of The She Pathogenicity Island Of Shigella Flexneri.
Funder
National Health and Medical Research Council
Funding Amount
$110,625.00
Summary
Bacterial species belonging to the genus Shigella are responsible for intestinal diseases ranging from mild diarrhoea to life threatening bacillary dysentery. Such diseases kill over a million people, mainly infants in developing countries, every year and lead to serious morbidity and mortality even in industrialised countries with well developed health care systems. In many cases the virulence of Shigella species is augmented by large fragments of DNA, called pathogenicity islands, that carry g ....Bacterial species belonging to the genus Shigella are responsible for intestinal diseases ranging from mild diarrhoea to life threatening bacillary dysentery. Such diseases kill over a million people, mainly infants in developing countries, every year and lead to serious morbidity and mortality even in industrialised countries with well developed health care systems. In many cases the virulence of Shigella species is augmented by large fragments of DNA, called pathogenicity islands, that carry genes which contribute to the development of disease (pathogenesis) in humans. Pathogenicity islands are important genetic elements which appear to spread independantly throughout bacterial populations and therefore contribute to the emergence of new virulence traits in bacteria. Recently, we identified two related pathogenicity islands carried by both Shigella flexneri and other species of the genus Shigella. The two pathogenicity islands belong to a unique class of genetic elements found in Shigella species and virulent strains of the intestinal bacterium E. coli. Our current study is aimed at (1) understanding the mechanisms by which one of these islands, the she pathogenicity island, spreads from one bacterial strain to another to introduce disease-producing or virulence genes to new bacteria and (2) to study how the sigA virulence gene, carried on the she pathogenicity island, contributes to disease development in humans. We know that sigA encodes a protein toxin which contributes to the loss of fluid from the intestines of rabbits that have been experimentally infected with Shigella flexneri. We propose to study the structure and function of the SigA protein to determine how it interacts with tissues to produce a pathological state. Such studies will enhance our understanding of the process of disease development and contribute to the investigation and assessment of new strategies for therapeutic intervention.Read moreRead less
Improved biosecurity through the engineering of microbial ecosystems. This project aims to provide data and understanding that will help develop predictive models for changes in the distribution of drug-resistant bacteria, and surveillance and response programs for key biosecurity threats. Microorganisms, including commensals and pathogens, can live in complex communities in a range of environments including animal hosts. It is now known that these communities (known as microbiomes) can exert a ....Improved biosecurity through the engineering of microbial ecosystems. This project aims to provide data and understanding that will help develop predictive models for changes in the distribution of drug-resistant bacteria, and surveillance and response programs for key biosecurity threats. Microorganisms, including commensals and pathogens, can live in complex communities in a range of environments including animal hosts. It is now known that these communities (known as microbiomes) can exert a profound effect on animal health. This project seeks to understand where antimicrobial resistance genes reside in pig gut microbiotia and how they move between members of this complex microbial community, and to provide information on how probiotics may be used to reduce dependence on antibiotics.Read moreRead less
Rapid functional and taxonomic skin microbe characterisation. Rapid functional and taxonomic skin microbe characterisation. This project aims to develop methods to detect and characterise bioactive molecules released by skin microbes, and a novel microspectroscopy method for rapid taxonomic identification. This project will acquire independent spectra and develop classification algorithms, and participate in strategic planning for applications and product development. The expected outcomes from ....Rapid functional and taxonomic skin microbe characterisation. Rapid functional and taxonomic skin microbe characterisation. This project aims to develop methods to detect and characterise bioactive molecules released by skin microbes, and a novel microspectroscopy method for rapid taxonomic identification. This project will acquire independent spectra and develop classification algorithms, and participate in strategic planning for applications and product development. The expected outcomes from this project are research tools for skin microbiome modulation of immunity, and proof-of-concept data for future commercial product development. Potential commercial applications include microbial characterisation for biosecurity, agriculture, environmental and soil biology.Read moreRead less
Unravelling small RNA regulatory networks to target and control bacteria. Small RNA (sRNA) molecules are critical regulators of bacterial gene expression. These molecules control important phenotypes in the Gram-negative veterinary pathogen Pasteurella multocida. This project aims to identify the range of P. multocida sRNAs and to show how expression of these molecules changes under various growth conditions. Specifically, this project endeavours: to identify the mRNA targets of the sRNAs; to id ....Unravelling small RNA regulatory networks to target and control bacteria. Small RNA (sRNA) molecules are critical regulators of bacterial gene expression. These molecules control important phenotypes in the Gram-negative veterinary pathogen Pasteurella multocida. This project aims to identify the range of P. multocida sRNAs and to show how expression of these molecules changes under various growth conditions. Specifically, this project endeavours: to identify the mRNA targets of the sRNAs; to identify the mechanisms of sRNA-mRNA interaction; to build systems-biology models that describe the sRNA regulatory circuits; to design inhibitors capable of disrupting critical sRNA-mRNA interactions; and to use the new inhibitors to modulate specific phenotypes. The ability to precisely manipulate sRNA regulatory circuits could allow fine control of bacterial phenotypes and could be widely applicable.Read moreRead less
Molecular pumps and metabolism: regulatory interactions that control metal uptake and metabolism in bacteria. ABC (ATP-Binding Cassette) transporters are ubiquitous pumps that transport small molecules into and out of cells. This project investigates the novel roles of small-molecule-binding domains in the protein machine that drives the transporters for molybdenum and iron. They are predicted to interact with regulatory proteins and integrate transport with metabolism. It will provide insights ....Molecular pumps and metabolism: regulatory interactions that control metal uptake and metabolism in bacteria. ABC (ATP-Binding Cassette) transporters are ubiquitous pumps that transport small molecules into and out of cells. This project investigates the novel roles of small-molecule-binding domains in the protein machine that drives the transporters for molybdenum and iron. They are predicted to interact with regulatory proteins and integrate transport with metabolism. It will provide insights into metal trafficking and characterize gene regulatory networks that are important for bacterial pathogenicity and biological nitrogen fixation.Read moreRead less
A comprehensive analysis of the outer membrane, surface exposed and secreted proteome of Pasteurella multocida. Pasteurella multocida is the causative agent of a range of animal diseases. The molecular mechanisms of P. multocida pathogenesis are poorly understood and the current vaccines generally ineffective. We will identify all P. multocida outer membrane, surface exposed and secreted proteins expressed during natural infection, or under conditions which mimic natural infection, by a global p ....A comprehensive analysis of the outer membrane, surface exposed and secreted proteome of Pasteurella multocida. Pasteurella multocida is the causative agent of a range of animal diseases. The molecular mechanisms of P. multocida pathogenesis are poorly understood and the current vaccines generally ineffective. We will identify all P. multocida outer membrane, surface exposed and secreted proteins expressed during natural infection, or under conditions which mimic natural infection, by a global proteomics approach. We believe that secreted proteins and those found on the outer surface of the bacterial cell are likely to be crucial virulence determinants. The expected outcomes are the identification of a number of candidate vaccine antigens and an enhanced understanding of Pasteurella pathogenesis.Read moreRead less
Discovery of Novel Bacteriophage with the Capacity to Modulate Gut Bacteria. This project aims to experimentally validate the largest ever collection of bacterial viruses (bacteriophages) within the gut microbiome. This project expects to generate new knowledge in the area of bacteriophage biology and genomics by using the innovative approaches of wet-lab and bioinformatic genome analyses. Expect outcomes of this project include the discovery of novel phages using bioinformatics, wet-lab validat ....Discovery of Novel Bacteriophage with the Capacity to Modulate Gut Bacteria. This project aims to experimentally validate the largest ever collection of bacterial viruses (bacteriophages) within the gut microbiome. This project expects to generate new knowledge in the area of bacteriophage biology and genomics by using the innovative approaches of wet-lab and bioinformatic genome analyses. Expect outcomes of this project include the discovery of novel phages using bioinformatics, wet-lab validation of their activity and characterisation of their potential to contribute new bacterial host metabolism. This should provide benefits, such as advancement to our understanding of bacteriophages, improved bioinformatic software, and a characterised collection of commercially valuable bacterial strains and phages.Read moreRead less
The role of virulence factors of Clostridium difficile in food animals. Disease caused by the bacterium Clostridium difficile are a significant food production animal and public health problem in many countries. Specific animal and human public health resources have been allocated in many countries in efforts to mitigate the growing epidemics. The study proposed in this application presents a significant opportunity to learn about the virulence factors of animal strains of this bacterium about w ....The role of virulence factors of Clostridium difficile in food animals. Disease caused by the bacterium Clostridium difficile are a significant food production animal and public health problem in many countries. Specific animal and human public health resources have been allocated in many countries in efforts to mitigate the growing epidemics. The study proposed in this application presents a significant opportunity to learn about the virulence factors of animal strains of this bacterium about which very little is known. This project will lead to rationally designed preventative and treatment strategies that apply to both animals and humans, thereby impeding epidemics caused by C. difficile in Australia.Read moreRead less
Exploring the role of the domestic dog and wild rodents as peri-domestic reservoirs of Rickettsia felis. This project aims to explore the role of domestic dogs and wild rats as maintenance hosts for flea-borne spotted fever. Cases of this disease, transmitted to humans by the common dog and cat flea are being increasingly recognised throughout the world. The findings of this study will add significant importance to flea control in pets.