Characterization Of Neutralizing Antibody Responses In HCV Infected Individuals.
Funder
National Health and Medical Research Council
Funding Amount
$478,076.00
Summary
Hepatitis C virus is a major human pathogen infecting 200 million people world-wide. Currently, there is no vaccine to prevent infection and treatment regimes are only partially effective. IInitial HCV infection is frequently asymptomatic and 30% of people spontaneously clear the virus. The remaining 70% of people develop a life-long chronic infection that causes progressive liver disease, cirrhosis and in some cases liver cancer. The reason why some people are able to clear virus has been attri ....Hepatitis C virus is a major human pathogen infecting 200 million people world-wide. Currently, there is no vaccine to prevent infection and treatment regimes are only partially effective. IInitial HCV infection is frequently asymptomatic and 30% of people spontaneously clear the virus. The remaining 70% of people develop a life-long chronic infection that causes progressive liver disease, cirrhosis and in some cases liver cancer. The reason why some people are able to clear virus has been attributed to the development of a strong cellular immune response and antibody is belived to play a monir role in achieving viral clearance. However, measurememnt of antibody responses in HCV infected pateints is routinely performed using conventional diagnostic tests that do not measure antibody that can help neutralize and clear virus. We have developed an assay that accurately measures the level of NAb in patient sera. We have found that chronically infected patients have broadly reactive neutralizing antibodies but that patients who clear virus, naturally or through treatment do not have broadly reactive neutralizing antibodies. Possibly explaining this phenomenon is that early during infection, antibody is frequently specific only to the infecting virus therefore to detect neutralizing antibodies, homologous viral sequences must be examined. In addition, we have found evidence that HCV can evade neutralzing antibodies through masking of sites to which antibodies bind. We propose to explore whether acutely infected patients develop NAb to autologous viral sequences, and how do these viral sequences and the antibody titre change throughout the course of infection and treatment. We also plan to determine the mechanism of neutralization resistance through the use of mutagenesis of resistant HCV glycoproteins. These studies are aimed at gaining a thorough understanding of the true role of antibody in HCV infection and its influence on viral evolution.Read moreRead less
Origins And Relationships Of Shigella And Enteroinvasive Escherichia Coli
Funder
National Health and Medical Research Council
Funding Amount
$377,310.00
Summary
Shigella is a well known highly infectious human pathogen with as few as 10 cells allowing effective spread by infected food or water, and also by person to person contact. Shigellosis is a particularly significant disease for children due to lack of pre-existing immunity and greater chance of transfer by fecal-oral route. One group of E. coli called Enteroinvasive E. coli (EIEC) resembles Shigella in many aspects from disease symptoms to biochemical properties. EIEC is a major cause of diarrhoe ....Shigella is a well known highly infectious human pathogen with as few as 10 cells allowing effective spread by infected food or water, and also by person to person contact. Shigellosis is a particularly significant disease for children due to lack of pre-existing immunity and greater chance of transfer by fecal-oral route. One group of E. coli called Enteroinvasive E. coli (EIEC) resembles Shigella in many aspects from disease symptoms to biochemical properties. EIEC is a major cause of diarrhoea in less developed countries and has also caused large outbreaks in developed countries. It is now clear that Shigella and E. coli are really one species. EIEC and Shigella strains are variants of E. coli with humans as the only host. However separation of the two in all records and most studies means that there is no integrated understanding of the forms. We aim to study the relationships of Shigella and EIEC and expect significant insights into the origins of Shigella-EIEC. This will facilitate diagnosis and understanding of the disease(s) and lead to a far better classification . EIEC-Shigella strains have arisen from other E. coli independently. This has happened seven times in the derivation of Shigella and we expect more such events with EIEC. An interesting phenomenon during this process is that strains tend to lose metabolic functions. In this study we will look at what, why and how functions are lost. O antigens are important in evading the host immune system. Shigella strains obtained many O antigens, the majority apparently from other species. This is quite likely the key to its success. We will look at how Shigella obtained new O antigens. This project will be significant in the understanding of Shigell-EIEC, a very significant human pathogen, and in general for understanding emergence of new pathogens.Read moreRead less
The broad aim of this project is to understand how the eye receives visual signals and sends them to the brain. Our experimental goal is to study the structure of neural connections in a poorly understood division of the visual system, called the koniocellular pathway. The cells of the koniocellular pathway make up close to 10 percent of all projections from the eye to the brain, but their functions are almost completely unknown. The fovea is a specialised region of the retina (the nerve cells w ....The broad aim of this project is to understand how the eye receives visual signals and sends them to the brain. Our experimental goal is to study the structure of neural connections in a poorly understood division of the visual system, called the koniocellular pathway. The cells of the koniocellular pathway make up close to 10 percent of all projections from the eye to the brain, but their functions are almost completely unknown. The fovea is a specialised region of the retina (the nerve cells which line the back of the eye). It is characterised by a very high density of cone photoreceptors, and is essential for high-acuity vision. This makes the fovea the most important part of the primate retina, but the high density of nerve cells there is thought to be the reason why the fovea is especially vulnerable to disease and age-related degeneration. Our aim is to analyse, using high-resolution microscopic techniques, the connections of koniocellular-pathway cells within the retina. We specifically aim to discover whether the koniocellular pathway contributes to foveal vision. Recent work from our and other laboratories has shown that many koniocellular-pathway cells receive functional connections from short-wavelength sensitive (blue) cone photoreceptors. Thus, our study will provide new insights into the connectivity of blue-cone pathways in the fovea. Although these experiments address basic scientific questions, they can lead to improved clinical practice. Understanding the wiring diagram of the retina can inform clinical studies of conditions such as glaucoma, and helps to give a rational basis for development of treatments. For example, dysfunction in blue-cone pathways is an early sign of glaucoma, so understanding the connections of blue-cone pathways in the fovea can lead to improved methods for early detection of this leading cause of blindness.Read moreRead less
Using Contextual Effects To Test Theories Of Coding In Visual Cortex
Funder
National Health and Medical Research Council
Funding Amount
$200,500.00
Summary
The visual cortex is the main structure in the brain that processes the visual scene. Cells in the cortex respond selectively to features of the scene such as the orientation of objects, the direction they move and their brightness relative to the background. Cortical cells are arranged in a topographic map of visual space, so that nearby cells respond to light from nearby parts of the image. Recent advances have shown that cells talk to each other so a stimulus in one part of the visual field c ....The visual cortex is the main structure in the brain that processes the visual scene. Cells in the cortex respond selectively to features of the scene such as the orientation of objects, the direction they move and their brightness relative to the background. Cortical cells are arranged in a topographic map of visual space, so that nearby cells respond to light from nearby parts of the image. Recent advances have shown that cells talk to each other so a stimulus in one part of the visual field can influence the responses of cells looking at other regions. This communication between cells is important in guiding the brain to focus on areas of the visual scene that are most important, a process known as attention. An example would be that a mouse moving through the periphery of someone's vision would attract their attention away from objects elsewhere in the scene. This project is designed to study the way that cells in the visual cortex cooperate to guide attention. Attention is important because it reduces the need to process all the detail in the visual scene with the same level of accuracy, leaving more resources free to process what is important. Attention deficits are a problem for people with dyslexia, so understanding the physiological basis of attention is an important goal. As well as attention, the visual system has a range of other mechanisms to select important information from the visual scene. For example, visual adaptation tends to improve the ability to code changes in the visual scene at the expense of reducing the sensitivity of the system overall. This project will investigate the relationship between attentional and adaptive mechanisms in the visual cortex. We expect to establish the precise physiological mechanisms that drive adaptive and attentional mechanisms in the mammalian brain.Read moreRead less
Multidimensional Coding Of Visual Information In The Retina
Funder
National Health and Medical Research Council
Funding Amount
$359,431.00
Summary
Although both the retina and visual cortex are part of the central nervous system, the coding of visual information in the two laminar structures differs markedly in that all three dimensions of the cortical sheet are used to code multiple response axes but only one dimension of the retinal sheet. This project examines how visual response properties are mapped through the depth of the retina and this will provide a comparatively simple paradigm of complex information processing in the brain.
The GABAergic System In Eye Growth Control And Myopia
Funder
National Health and Medical Research Council
Funding Amount
$318,142.00
Summary
Shortsightedness (myopia) is the most common visual disorder. High myopia is associated with an increased risk of eye diseases. Current treatments do not stop myopia developing or decrease the associated risk of eye disease. The continued worsening of myopia is very concerning. A safe effective treatment that can either prevent myopia or stop its progression to extreme levels is needed. We have data showing that GABA ergic drugs modify myopia. This proposal will determine the mechanisms.