Virulence Mechanisms In Hypervirulent Epidemic Strains Of Clostridium Difficile.
Funder
National Health and Medical Research Council
Funding Amount
$499,135.00
Summary
The bacterium Clostridium difficile is the major cause of nosocomial diarrhoea in many countries, including Australia. More virulent isolates have emerged since 2000, leading to increased incidence and severity of disease in many countries and resulting in epidemics. This project will make a major contribution to our understanding of how these bacteria cause disease and may help to prevent outbreaks of the hypervirulent strains in Australia by identifying potential new vaccine candidates.
Role Of Protease Activated Receptors Type 2 (PAR2) During Inflammation Of Airways And Intestine
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
Epithelial cells lining the airways and the intestine contain receptors that are activated by proteases, which are protein cleaving enzymes. Activation of the subtype 2 of these receptors (PAR2) has been shown to cause salt and water transport in intestinal cells in culture. Little is known about the effects of PAR2-activation in the native airways and intestinal tissues. These tissues will be studied in the present project. A large increase in PAR2 is found in various diseases which are paralle ....Epithelial cells lining the airways and the intestine contain receptors that are activated by proteases, which are protein cleaving enzymes. Activation of the subtype 2 of these receptors (PAR2) has been shown to cause salt and water transport in intestinal cells in culture. Little is known about the effects of PAR2-activation in the native airways and intestinal tissues. These tissues will be studied in the present project. A large increase in PAR2 is found in various diseases which are paralleled by a strong inflammation. Thus, PAR2 is likely to play a central role in intestinal diseases such as acute infectious diarrhea and chronic inflammatory bowel disease. PAR2 may also participate in the severe diarrhea frequently observed in patients with intestinal tumors. Similarly, inflammatory mediators released during airway infections are likely to act on PAR2, causing inappropriate secretion and a running nose. Most importantly, PAR2 are found in large excess in the airways of asthma patients. Since nothing is known about the impact of these receptors on fluid and electrolyte transport in the airways it appears timely and highly relevant to study the function of PAR2 in the airway epithelium. We will assess PAR2 mediated responses in human nasal biopsies. A more detailed analysis of the intracellular processes will be done in mouse trachea. We will further study the function of PAR2 in the intestinal epithelium. Activation of the ion transport via PAR2 will be examined in the mouse distal colon and in human rectal biopsies. We will utilize techniques such as Ussing chamber and patch clamp recordings to analyze the transport processes. The results should gain new inside into the role of PAR2 during inflammatory diseases of the airways and the intestine such as asthma and chronic inflammatory bowel diseases.Read moreRead less
Shigella Flexneri O Antigen Polysaccharides: Biosynthesis, Function In Virulence, And Interaction With IcsA/VirG
Funder
National Health and Medical Research Council
Funding Amount
$468,055.00
Summary
Shigella flexneri bacteria cause dysentery in millions of humans each year. The bacterium invades and replicates within the cells of the large intestine. Inside cells, S. flexneri is able to use the host cell's actin-based motility machinery to become motile within the cells, and this can be seen as F-actin comet tails extending from one end of the cell. Bacterial cell surface components residing in the outer membrane are important for the bacterium's ability to cause disease. Two of these compo ....Shigella flexneri bacteria cause dysentery in millions of humans each year. The bacterium invades and replicates within the cells of the large intestine. Inside cells, S. flexneri is able to use the host cell's actin-based motility machinery to become motile within the cells, and this can be seen as F-actin comet tails extending from one end of the cell. Bacterial cell surface components residing in the outer membrane are important for the bacterium's ability to cause disease. Two of these components (lipopolysaccharides (LPS) and their polysaccharide chains (O antigens), and IcsA-VirG protein)) are required for initiating actin polymerisation, and mutations affecting synthesis of these components reduce ability to cause disease. In previous studies we have found that O antigen and the synthesis and function of IcsA are interrelated. This project will study how the O antigens are synthesised and their chain length determined by the Wzz protein, and the Wzz structure in relation to its function will also be characterised. The role played by O antigen in intracellular motility will be studied to determine the mechanisms involved. Infection of cells and cell free extracts, antibodies, and an enzyme which specifically degrades the O antigen, will be used to study how O antigen affect the interaction between bacteria with human cell proteins. The relationship between O antigen and IcsA function will be studied using monoclonal antibodies raised to IcsA. The effect of LPS on the outer membrane protease IcsP will be investigated, as will the effect of LPS lipid A mutations on O antigen and virulence. These studies will contribute to a better understanding of the biosynthesis of an ubiquitous bacterial cell surface component (O antigen), its function as a virulence factor in bacterial interactions with host cells. This may lead to novel therapeutic strategies to prevent and control Shigellosis and other bacterial infections.Read moreRead less
Regulation Of Cellular Responses To Neuropeptides.
Funder
National Health and Medical Research Council
Funding Amount
$83,510.00
Summary
Neuropeptides are chemicals released from nerves that are responsible for communication between the nerves, glands, muscles or other nerves. Neuropeptides exert their diverse biological effects by interacting with small structures on the cells they wish to communicate with. These structures bind the neuropeptide and are termed neuropeptide receptors. The responses of tissues to neuropeptides, for example, contraction of muscle, decrease with continued exposure to the neuropeptide. This reduction ....Neuropeptides are chemicals released from nerves that are responsible for communication between the nerves, glands, muscles or other nerves. Neuropeptides exert their diverse biological effects by interacting with small structures on the cells they wish to communicate with. These structures bind the neuropeptide and are termed neuropeptide receptors. The responses of tissues to neuropeptides, for example, contraction of muscle, decrease with continued exposure to the neuropeptide. This reduction in response is termed desensitization is thought to turn off the response to cells following stimulation by neuropeptides. In this study, I will investigate the mechanisms behind the desensitization of VPAC receptors which are a found throughout the body and have many important roles for example, gastrointestinal, pancreatic and reproductive function and control of muscle. VPAC receptors are also highly expressed in certain many cancers such as breast, prostate and colon carcinoma. The wide variety of functions that these receptors perform and the wide distribution in the body suggest that these are very important receptors. To date research into the responses and desensitisation of these receptors has been lacking, and the work that has been done has become confusing as more receptors and neuropeptides which bind them are discovered. The current project aims to carefully study these receptors and to determine their role in health and disease. The understanding the interaction of receptor and neuropeptide can perhaps lead to development of new therapeutic agents.Read moreRead less