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Modelling Streptococcal Urogenital Tract Infection To Study Mechanisms Of Bacterial Colonization And Persistence
Funder
National Health and Medical Research Council
Funding Amount
$412,085.00
Summary
Colonization of the urogenital tract with bacterial pathogens is one of the most common infections in humans. In Australia millions of people are colonized in their urogenital tracts at any given time, often asymptomatically, and many such individuals require medical intervention for the treatment of consequent infections that result from persistent colonization. Bacterial colonization of the urogenital tract is associated with a variety of disease presentations including urinary tract infection ....Colonization of the urogenital tract with bacterial pathogens is one of the most common infections in humans. In Australia millions of people are colonized in their urogenital tracts at any given time, often asymptomatically, and many such individuals require medical intervention for the treatment of consequent infections that result from persistent colonization. Bacterial colonization of the urogenital tract is associated with a variety of disease presentations including urinary tract infections and neonatal infections resulting from vertical transmission of colonizing bacteria from mothers to newborns. Aside from sexually-transmitted diseases the most prominent bacterial pathogens that colonize the urogenital tract are Group B Streptococcus (GBS) and Escherichia coli. GBS in particular exist in the female urogenital tract as a persistent microbial reservoir in up to 40% of pregnant women and are transmitted to newborns in up to 72% of live births. Colonization of newborns leads to invasive disease including pneumonia, sepsis, and meningitis. While the disease presentations resulting from colonization of the urogenital tract vary the underlying basis that leads to disease is antecedent bacterial persistence in the urogenital tract despite immune system activation. The mechanisms whereby GBS evade immune responses in the urogenital tract to allow their survival are unknown. I will define the immune-evasion mechanisms and virulence traits used by GBS, as a model urogenital pathogen, to successfully colonize the urogenital tract in the face of mounting immune responses. These studies will provide a better understanding of the pathogenesis of urogenital disease in terms of bacterial colonization and immune-evasion strategies. This will shed light onto new approaches for the prevention and treatment of urogenital disease in humans such as improved vaccination, locally acting cytokines, and deliberate colonization with non-invasive strains for the prevention of disease.Read moreRead less
The greatest impact of Plasmodium falciparum malaria infection in Africa is on children and pregnant women. Malaria infected red blood cells stick to receptor molecules on cells lining blood vessels. The parasite produces a family of proteins called PfEMP1, expressed on the cell surface. These PfEMP1 proteins are responsible for the sticking, and are major targets of the host immune response to malaria. We have found two particular receptor molecules, sugars called chondroitin sulphate A (CSA) a ....The greatest impact of Plasmodium falciparum malaria infection in Africa is on children and pregnant women. Malaria infected red blood cells stick to receptor molecules on cells lining blood vessels. The parasite produces a family of proteins called PfEMP1, expressed on the cell surface. These PfEMP1 proteins are responsible for the sticking, and are major targets of the host immune response to malaria. We have found two particular receptor molecules, sugars called chondroitin sulphate A (CSA) and hyaluronic acid (HA), to be particularly important in sticking in the placenta, and have identified a PfEMP1 molecule which sticks to these. We will study the role of antibodies against the parasite, and against the CSA and HA molecules, in protection against malaria. We believe that African women develop these antibodies with increasing pregnancies, protecting themselves and their babies from malaria in later pregnancies, and that men will not have these antibodies. Pregnant women who have HIV-AIDS have greater susceptiblity to malaria. We will compare antibody responses in HIV+ and HIV- women to see if this is because they produce less protective antibodies. The PfEMP1 proteins are the product of var genes. We can compare parasites using the var genes they express to fingerprint them. We will examine the var gene expression by parasites from different patients, and by the parasites circulating in the blood or stuck in the placenta (in pregnant women) or in the brain, lung, gut and other organs (of children who have died of malaria) to see if the fingerprints of var gene expression differ between these different patients, or between different places in the same patient.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
PROTECTING THE PRETERM FETAL BRAIN FROM HYPOXIA AND INFECTION: A HEALTHY START TO LIFE.
Funder
National Health and Medical Research Council
Funding Amount
$495,750.00
Summary
Brain damage during fetal life is a significant cause of later neurological problems such as cerebral palsy. Recent studies have shown that brain injury detected in infants is usually caused by adverse conditions within the uterus prior to labour, but the exact causes are poorly understood. It is also apparent that babies born prematurely are at increased risk of suffering serious brain damage. In recent years it has become evident that infections in the mother may be linked to both premature bi ....Brain damage during fetal life is a significant cause of later neurological problems such as cerebral palsy. Recent studies have shown that brain injury detected in infants is usually caused by adverse conditions within the uterus prior to labour, but the exact causes are poorly understood. It is also apparent that babies born prematurely are at increased risk of suffering serious brain damage. In recent years it has become evident that infections in the mother may be linked to both premature birth and brain damage. It has been proposed that certain chemicals (cytokines), which are released during an infection, can cross the placenta to the fetus causing inflammatory changes that lead to brain damage. We have shown that an inflammatory inducing chemical (bacterial endotoxin) administered to immature fetal sheep induces brain damage similar to that seen in cerebral palsy. This provides an excellent model for testing agents that are known to block the action of cytokines and other markers of inflammation; currently there is no effective strategy for the treatment or prevention of hypoxia and inflammatory induced injury of the brain partly due to our ignorance about how and when the damage is occurring. We will test the effects of two chemicals; N-acetyl cysteine, which is known to block the generation of inflammatory cytokines, and the naturally occurring glycoprotein erythropoietin, which prevents death of neurons (apoptosis). We hope that by blocking these pathways we may be able to prevent brain injury from occurring when the immature fetus is exposed to an infection during gestation. We expect that this project will provide important novel information that helps us to understand how infection in the mother can cause brain injury in the fetus and provide a new approach for strategies to prevent or treat brain injury.Read moreRead less
The Impact Of Maternal Nutrition And Depression On Infant Morbidity, Growth And Development In Vulnerable Populations.
Funder
National Health and Medical Research Council
Funding Amount
$133,351.00
Summary
Malarial infection in pregnant women can lead to serious consequences for the baby including death, low birth weight and bacterial infection. Babies born in the community are more likely to die than babies born in hospital, therefore improving basic medical care for babies at the community level should be an important priority. We aim to evaluate the causes of death and severe illness in newborn infants in Papua New Guinea, and to determine community based strategies to improve these outcomes.
Blood-brain Barrier And White Matter Damage In The Immature Rat Brain Following Systemic Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$353,173.00
Summary
Clinical obstetric and paediatric studies have identified an association between intrauterine infection occurring around two thirds of the way through pregnancy, premature birth and a specific form of damage to the brain of the newborn. This damage mainly affects white matter tracts. These tracts are aggregations of nerve fibres that make the connections between different parts of the brain and may result in cerebral palsy or other neurological disorders. The association between maternal infecti ....Clinical obstetric and paediatric studies have identified an association between intrauterine infection occurring around two thirds of the way through pregnancy, premature birth and a specific form of damage to the brain of the newborn. This damage mainly affects white matter tracts. These tracts are aggregations of nerve fibres that make the connections between different parts of the brain and may result in cerebral palsy or other neurological disorders. The association between maternal infection and brain damage, one form of which is cerebral palsy, is well established from clinical epidemiological studies, but the biological mechanism of this link is unknown. The CIs' group has recently shown that the condition can be reproduced in neonatal rats at a stage of brain development in the rat that is equivalent to the critical time in human brain development when infection may be associated with brain damage. The CIs' group has shown that an induced inflammatory state similar to a bacterial infection, results in damage to blood vessels in the white matter and is associated with changes in white matter, as occurs in affected babies. The purpose of this study is to understand the nature of the damage to white matter blood vessels and the mechanisms by which materials in blood, which in the normal brain do not pass from the blood to the brain across the blood-brain barrier, are able to do so via the inflammation damaged blood vessels. The study also aims to show whether it is components of the blood entering the brain via the damaged blood vessels that are responsible for the damage to white matter in the immature brain. The outcome should lead to development of ways to improve clinical care of women who acquire infections during pregnancy.Read moreRead less
Intrauterine Ureaplasma Infection During Pregnancy: Fetal Effects And Characteristics Of Ureaplasma Pathogenicity.
Funder
National Health and Medical Research Council
Funding Amount
$527,097.00
Summary
Ureaplasmas are microorganisms that are commonly found in the urinary tracts of men and women, without any apparent adverse effects; but their presence in amniotic fluid during pregnancy is associated with preterm birth and other adverse pregnancy outcomes. The effects that ureaplasmas in the amniotic fluid have on the developing baby before birth are likely to result in illness after birth, but the range of potential effects is unknown. We also know very little about how ureaplasmas themselves ....Ureaplasmas are microorganisms that are commonly found in the urinary tracts of men and women, without any apparent adverse effects; but their presence in amniotic fluid during pregnancy is associated with preterm birth and other adverse pregnancy outcomes. The effects that ureaplasmas in the amniotic fluid have on the developing baby before birth are likely to result in illness after birth, but the range of potential effects is unknown. We also know very little about how ureaplasmas themselves manage to infect the fetus and other tissues within the pregnant uterus. Our studies are designed to identify the effects that ureaplasmas in amniotic fluid have on the developing fetus and how common treatments during pregnancy impact on those effects. We will also study ureaplasmas to see what it is about them that allows them to affect the fetus and other uterine tissues. We expect that our studies will lead to better diagnosis and treatment of amniotic ureaplasma infection during pregnancy, and will allow us to better care for babies born after exposure to ureaplasmas before birth.Read moreRead less
Is Infection An Acute Trigger For Preeclampsia? A Case-crossover Study.
Funder
National Health and Medical Research Council
Funding Amount
$207,761.00
Summary
Preeclampsia is a multisystem hypertensive disease affecting up to 10% of pregnancies. It puts both mother and baby at increased risk of major illness and death. The cause is unknown but inflammation appears to play a key role. We will use an innovative design to determine whether recent maternal infection triggers the onset of preeclampsia. If preeclampsia is associated with infection, preventative strategies can be developed.
FluMum: A Prospective Cohort Study Of Mother-infant Pairs Assessing The Effectiveness Of Maternal Influenza Vaccination In Prevention Of Influenza In Early Infancy
Funder
National Health and Medical Research Council
Funding Amount
$2,598,377.00
Summary
Influenza is a serious illness for young babies. Currently there are no vaccines that can be given to babies under 6 months of age to protect them from infection. This study aims to determine whether influenza vaccine given in pregnancy can prevent infection in babies up to 6 months of age.
The Consequences Of Innate Immune Inflammatory Responses During Early Pregnancy And Their Effect On Reproductive Outcomes.
Funder
National Health and Medical Research Council
Funding Amount
$367,788.00
Summary
The mother's immune system can tolerate the growth of an ostensibly foreign fetus during pregnancy, yet remain vigilant to pathogenic challenge. We will investigate whether exposure to viral infections during early pregnancy leads to maternal and fetal inflammation which then impacts adversely on reproductive outcomes including fetal development and life-long health of offspring. Answers to these questions will contribute in designing effective interventions to limit the potential for detrimenta ....The mother's immune system can tolerate the growth of an ostensibly foreign fetus during pregnancy, yet remain vigilant to pathogenic challenge. We will investigate whether exposure to viral infections during early pregnancy leads to maternal and fetal inflammation which then impacts adversely on reproductive outcomes including fetal development and life-long health of offspring. Answers to these questions will contribute in designing effective interventions to limit the potential for detrimental outcomes.Read moreRead less