Implications Of Bacterial Load For Vaccine Efficacy And Antibiotic Treatment Outcomes In High-risk Populations
Funder
National Health and Medical Research Council
Funding Amount
$345,000.00
Summary
Otitis media (middle ear disease) is a common childhood infection, and a major concern in remote Aboriginal communities of the Northern Territory. For these children, otitis media commences within the first few weeks of life and progresses to perforation of the ear drum in 60% of children by 12 months of age. Few children in remote Aboriginal communities have normal ear status or normal hearing and many have conductive hearing loss, affecting language development and education. Otitis media in t ....Otitis media (middle ear disease) is a common childhood infection, and a major concern in remote Aboriginal communities of the Northern Territory. For these children, otitis media commences within the first few weeks of life and progresses to perforation of the ear drum in 60% of children by 12 months of age. Few children in remote Aboriginal communities have normal ear status or normal hearing and many have conductive hearing loss, affecting language development and education. Otitis media in these children results from infection with the bacteria Streptococcus pneumoniae, Haemophilus influenzae and-or Moraxella catarrhalis. Therefore the types of interventions we are using to combat the high prevalence of ear disease are antibiotic therapy, Streptococcus pneumoniae vaccination, and hygiene interventions. However we fear that the high load of bacteria carried by these children compromises the treatment and prevention strategies. The current proposal will test this hypothesis, and if found to be true, there will be implications for the management of otitis media. For example, dose, frequency and choice of antibiotic treatment, and vaccine schedule changes including an early dose or a booster dose.Read moreRead less
Multiple Cytomegalovirus Infections: Biological And Evolutionary Significance.
Funder
National Health and Medical Research Council
Funding Amount
$555,776.00
Summary
This project involves the study of cytomegalovirus (CMV) a common viral infection of humans which normally cause little disease. However in individuals whose immune system is suppressed (such as AIDS patients or transplant recipients), or in infection of pregnant women, CMV can cause serious or life-threatening disease in the patient or foetus. An interesting feature of CMV diseases in such patients is that enhanced viral growth and more severe disease is frequently associated with the presence ....This project involves the study of cytomegalovirus (CMV) a common viral infection of humans which normally cause little disease. However in individuals whose immune system is suppressed (such as AIDS patients or transplant recipients), or in infection of pregnant women, CMV can cause serious or life-threatening disease in the patient or foetus. An interesting feature of CMV diseases in such patients is that enhanced viral growth and more severe disease is frequently associated with the presence of multiple strains of CMV in the patient. We suggest that mixed CMV infections provide a survival advantage to the virus, with different strains within the mixed infection assisting the growth of other strains. This would result in increased virus growth overall, and enhanced disease. To study the mechanisms by which multiple infections with different CMV strains may affect both the virus and the host, experiments will be performed using an animal model of CMV, murine cytomegalovirus (MCMV). We will examine the effect of the presence of multiple strains of virus on virus growth and distribution within the infected host. We will also determine if functional MCMV strains are capable of assisting non-functional strains to survive within the host. These studies are relevant to the design of a CMV vaccine, and will be valuable in revealing the ways in which viruses can co-operate within an infection.Read moreRead less
DNA methylation is a mechanism used by many organisms, including humans, to keep certain regions of DNA inactive, i.e. in a state where they will not be read. Errors in this process may result in inappropriate inactivation of a gene, termed epimutation; this may occur even when no DNA sequence changes (i.e. mutations) are present. Some individuals are born with high levels of an epimutation that predisposes them to developing multiple cancers. Little is known about whether low levels of epimutat ....DNA methylation is a mechanism used by many organisms, including humans, to keep certain regions of DNA inactive, i.e. in a state where they will not be read. Errors in this process may result in inappropriate inactivation of a gene, termed epimutation; this may occur even when no DNA sequence changes (i.e. mutations) are present. Some individuals are born with high levels of an epimutation that predisposes them to developing multiple cancers. Little is known about whether low levels of epimutations (only a portion of the body's cells affected) are important in development of sporadic (common) cancer. The aim of this project is to determine the levels of epimutations in the normal tissues of healthy individuals, and compare these with the levels in normal tissues of people who have had certain types of cancers. In doing this we hope to find out if low level epimutations contribute to the risk of developing sporadic cancer.Read moreRead less
Resistant forms of childhood acute lymphoblastic leukaemia (ALL) constitute a leading cause of cancer-related deaths in children. Despite tremendous improvements in therapy, 25-30% of patients still experience a relapse and many of them occur in patients stratified as low risk. Further treatment is often toxic, frequently unsuccessful and carries the risk of significant long-term morbidity. For the design of more appropriate therapy, information on the biology of relapsed ALL is urgently require ....Resistant forms of childhood acute lymphoblastic leukaemia (ALL) constitute a leading cause of cancer-related deaths in children. Despite tremendous improvements in therapy, 25-30% of patients still experience a relapse and many of them occur in patients stratified as low risk. Further treatment is often toxic, frequently unsuccessful and carries the risk of significant long-term morbidity. For the design of more appropriate therapy, information on the biology of relapsed ALL is urgently required. The sequencing of the human genome and advanced screening technology (microarrays) allow the detailed analysis of expression patterns in large numbers of specimens. We propose to study the genetic features of this disease by investigating 28 childhood ALL patients from whom we have stored specimens received at two time points, one at diagnosis and one at relapse. The hypothesis of this study is that relapsed leukaemias display genetic features which are correlated to their resistance to therapy. The specific questions we will be asking are: (1) Which genes are expressed at high levels in leukaemia specimens at the time of relapse while not expressed (or expressed at lower levels) at the time of diagnosis and vice versa? (2) What is the function of differentially expressed genes? (3) Is the pattern of gene expression correlated with resistance to the particular drug therapy used? (4) Is the leukaemia clone at relapse related or unrelated to the clone present at diagnosis, as determined by receptor rearrangement? The expression levels of identified discriminator genes will be confirmed by real-time quantitative polymerase chain reaction (PCR). The quality of this set of specimens makes them particularly suited to achieve the stated goals, providing a unique opportunity to investigate drug resistance in childhood ALL. The data generated will provide the basis for the examination of genes suitable as new therapeutic targets.Read moreRead less
Mechanisms Underlying APOBEC3G Restriction Of HIV-1
Funder
National Health and Medical Research Council
Funding Amount
$540,075.00
Summary
In the fight against worldwide HIV-AIDS, understanding natural cell defenses to the HIV virus may identify new virus targets and strategies to block HIV in humans. Here, we will use state-of-the-art, high resolution, fluorescent microscopy to understand how the recently identified cell protein, APOBEC3G, blocks the HIV life cycle in human cells. We anticipate that APOBEC3G will stop HIV from invading the nucleus of human cells to defend against HIV, a strategy we can apply to new therapies.
A Stable Protein:DNA Complex For Development Of Ultrasensitive Diagnostics In Multiplex Format
Funder
National Health and Medical Research Council
Funding Amount
$521,961.00
Summary
A new technology platform will be developed to carry out diagnostic tests in a multiplex format with increased sensitivity and precision. We recently discovered a very strong interaction between a protein and a particular fragment of DNA. This interaction can be tuned to enable its use for the simultaneous detection of different disease markers in a single assay. This will improve the time and space needed to perform diagnostic tests in laboratories.