Global Regulation Of Toxin Production In Clostridium Perfringens
Funder
National Health and Medical Research Council
Funding Amount
$389,860.00
Summary
This project involves an investigation of how the bacteria that cause an often fatal wound infection control the production of the toxic proteins that are essential elements of the disease process. In all pathogenic bacteria there are specific genes that encode the virulence factors that are involved in the disease. The expression of these genes is generally controlled by the products of other genes known as regulatory genes. The function of these regulatory networks is generally responsive to e ....This project involves an investigation of how the bacteria that cause an often fatal wound infection control the production of the toxic proteins that are essential elements of the disease process. In all pathogenic bacteria there are specific genes that encode the virulence factors that are involved in the disease. The expression of these genes is generally controlled by the products of other genes known as regulatory genes. The function of these regulatory networks is generally responsive to environmental stimuli. This project involves the detailed functional analysis of a regulatory network that was first identified in this laboratory and which controls the expression of extracellular toxins that have been implicated in gas gangrene. The overall objectives of the project are to develop a detailed understanding of the mechanisms involved in this regulatory process. Specifically, the project aims to determine the functional components of the regulatory proteins that interact with the environmental signal or which bind to the genes encoding the bacterial toxins, to determine the nature of the target sites to which the regulatory proteins bind, and to examine the hypothesis that there is another regulatory gene that is involved in this process. The project will make a major contribution to our knowledge of the complex interactions that occur between an invading bacterium and the host tissues. If we are to fully comprehend how bacteria cause disease then it is critical that we understand how bacteria control the production of the toxic products that are an integral part of the disease process.Read moreRead less
Structural Studies Of Bacterial Pore-forming Protein Toxins
Funder
National Health and Medical Research Council
Funding Amount
$509,017.00
Summary
In this project the three-dimensional structures of proteins that form pores in membrane cell walls will be determined. These proteins are bacterial toxins and knowledge of their structure may prove useful in the design of new antibiotics. This project will focus on a class of toxins called the cholesterol-dependent cytolysins which are released by Gram positive bacteria such as Clostridia and Streptococcus and which cause a variety of nasty infectious diseases such as gas gangrene, pneumonia an ....In this project the three-dimensional structures of proteins that form pores in membrane cell walls will be determined. These proteins are bacterial toxins and knowledge of their structure may prove useful in the design of new antibiotics. This project will focus on a class of toxins called the cholesterol-dependent cytolysins which are released by Gram positive bacteria such as Clostridia and Streptococcus and which cause a variety of nasty infectious diseases such as gas gangrene, pneumonia and meningitis. The three-dimensional structures will be elucidated using X-ray crystallography. Protein crystallography is the study of three-dimensional shapes of proteins at near atomic resolution. In this method proteins are made to form crystals. X-ray beams are then shone on the crystals causing the X-rays to scatter in a pattern which is characteristic of the protein's three-dimensional shape. Knowledge of the structure of proteins is necessary for the complete understanding of their biological activity and is also very useful for the rational design of new drugs that may alter their activity.Read moreRead less
Structural Studies Of Bacterial Pore-forming Protein Toxins
Funder
National Health and Medical Research Council
Funding Amount
$267,750.00
Summary
The general aim of this work is to investigate the three-dimensional structures of important target proteins using X-ray crystallography. Protein crystallography is the study of the three-dimensional shapes of proteins at near atomic resolution. In this method proteins are made to form crystals. X-ray beams are then shone on the crystals causing the X-rays to scatter in a pattern which is characteristic of the protein's three-dimensional shape. Knowledge of the structure of proteins is necessary ....The general aim of this work is to investigate the three-dimensional structures of important target proteins using X-ray crystallography. Protein crystallography is the study of the three-dimensional shapes of proteins at near atomic resolution. In this method proteins are made to form crystals. X-ray beams are then shone on the crystals causing the X-rays to scatter in a pattern which is characteristic of the protein's three-dimensional shape. Knowledge of the structure of proteins is necessary for the complete understanding of their biological activity and is also very useful for the rational design of new drugs that may alter their activity. Approximately, one third of the body's proteins are attached to membranes. However, relatively little is known about the three-dimensional structures of this important class of proteins. In this project the structures of proteins that form pores in membrane cell walls are being determined. Thses proteins are bacterial toxins and knowledge of their structure may prove useful in the design of new antibiotics.Read moreRead less
The aim of this project is to provide a better understanding of the mechanisms underlying the development of gas gangrene, an often fatal disease of particular significance to elderly and diabetic patients, who are particularly susceptible following injury, or surgery, or in some cases when suffering from colon cancer. Although research has been carried out on this disease for many years prompt surgical removal of the infected tissue, often including amputation of a limb, is still commonly used ....The aim of this project is to provide a better understanding of the mechanisms underlying the development of gas gangrene, an often fatal disease of particular significance to elderly and diabetic patients, who are particularly susceptible following injury, or surgery, or in some cases when suffering from colon cancer. Although research has been carried out on this disease for many years prompt surgical removal of the infected tissue, often including amputation of a limb, is still commonly used to ensure the patient's survival. This project involves the study of the two bacteria that are the major causes of the disease. We aim to find out how the bacteria mediate the disease, in particular to determine which toxic factors produced by the bacteria are involved. The normal host response to a bacterial infection is a rapid influx of white blood cells to the infected tissue, which is part of the normal inflammatory response. These cells engulf and degrade the bacteria, clearing the infection. However, a major characteristic of gas gangrene pathology is that very few white blood cells infiltrate the infected tissue. We aim to determine why the host fails to mount an inflammatory response to this bacterial infection. We will achieve this objective by developing a better understanding of the role of the bacterial toxins in the development of this morbid disease. It is hoped the results from this study will enable the development of more effective therapeutic and prophylactic treatments for this disease and also provide a foundation for studies into the modulation of the host response by other bacterial species.Read moreRead less
Host-pathogen Interactions In Clostridial Myonecrosis
Funder
National Health and Medical Research Council
Funding Amount
$577,573.00
Summary
We will analyse the interaction between the bacteria that cause gas gangrene, and the infected host, from both a host and pathogen perspective. We will examine how the host’s response to infection can be modulated to decrease the severity of disease and we will identify the biochemical processes that are essential for bacterial growth in the host, a necessary prerequisite for disease. Outcomes will be a better understanding of the mechanisms of disease causation and improved disease control.
Two-component Regulatory Systems Involved In Toxin Production In Clostridium Perfringens
Funder
National Health and Medical Research Council
Funding Amount
$78,500.00
Summary
The bacterium studied in this project causes gas gangrene, a severe and often fatal infection of traumatic or surgical wounds. The project involves the detailed analysis of the process by which this bacterium controls the production of the toxic proteins that are required for disease to occur. The emphasis is to determine the mechanism by which this regulatory process is mediated. Research in this laboratory has identified two genes whose protein products are the key links in this regulatory net ....The bacterium studied in this project causes gas gangrene, a severe and often fatal infection of traumatic or surgical wounds. The project involves the detailed analysis of the process by which this bacterium controls the production of the toxic proteins that are required for disease to occur. The emphasis is to determine the mechanism by which this regulatory process is mediated. Research in this laboratory has identified two genes whose protein products are the key links in this regulatory network. The objectives of the project will be to determine which part of the regulatory protein interacts with the target toxin gene, to start to determine the structure of the regulatory protein so that the precise biochemical mechanism of action can be ascertained, to determine the components of the DNA target that are essential for binding activity, and to identify other genes that are involved in the regulation of both the toxin genes and other genes that may be implicated in the disease process. These studies will be facilitated by the availability of the complete genome sequence of this pathogenic bacterium. The project will make a major contribution to our knowledge of how bacteria that cause disease are able to control the production of the toxins that are critical to the disease process. If we are to learn how to more effectively control and treat bacterial infections then it is very important that we understand the complex regulatory networks that tell bacteria when to produce its disease-causing products.Read moreRead less
Role Of Regulatory Genes In The Control Of Toxin Production In Clostridium Perfringens
Funder
National Health and Medical Research Council
Funding Amount
$495,710.00
Summary
This project investigates how the bacteria responsible for gas gangrene, an often fatal wound infection, control or regulate the expression of genes that encode toxins and other virulence factors. The overall objective is to develop a detailed understanding of the function and biological role of each element in these regulatory systems, thereby making a major contribution to our knowledge of how bacteria control the production of toxic products that are essential for the disease process.