Identifying and Preventing the Epithelial Triggers of Neutrophilic Inflammation in Cystic Fibrosis
Cystic Fibrosis (CF) is an inherited disease affecting mainly the lungs and digestive systems in over 3,000 Australians. Babies are diagnosed via newborn screening, and advances to date have helped them develop normally during these early stages of life. Many different types of lung infections still occur at this age that cause permanent lung damage and it is this damage that causes most deaths in people with CF. Past studies have shown that infection with common cold virus (rhinovirus) causes more hospitalisation in children with CF and is linked to decreases in the way the lung functions. We have also shown that a specific protein is produced when the lungs get infected early in life and that when more is produced more damage in the lung is seen. In this study we want to understand how this happens and to identify medicines that stop this damage from happening.
Innate Responses of the Epithelium to Respiratory Virus Infection. Pathogen-Host Interactions – A Systems Biology Approach
Asthma is a life-long illness affecting the lungs and poses a significant burden on public health within the Australian community. Cells lining the lungs provide a physical barrier to the external environment and are constantly exposed to pathogens and allergens. Our research has found that in children with asthma, this protective barrier is different from children without asthma; it is leakier making it easy for pathogens to enter the cells. We also observed that the cells cannot fully repair after injury due to an absence of specific proteins. Other studies have also found that infection with pathogens such as viruses early in life is linked to worsening asthma symptoms and hospitalisation. Therefore, there is a relationship between the leaky barrier and how cells react to virus infection in asthma. This project aims to assess the effects of multiple and consecutive viral infections between abnormal responses of the cells and to identify new treatments to improve the way cells behave.
Establishing a Biologically Relevant Model of Biofilms Disease of the Ears and Airways
Bacteria are known to form layers within themselves so that they have protection in a hostile/unfavourable environment. This study looks at how these bacteria settle, spread and interact with cells in the human airway; as well as how bacterial layers react when an infection caused by a virus occurs in the human airway. We have generated bacterial layers in the laboratory and visualised how human airway cells react when they are invaded by them. We compared these with airway cells first infected with viruses before the bacteria are allowed to colonise the airway cells. We found that when airway cells are colonised by bacterial layers, viruses are prevented from infecting these cells. Furthermore, airway cells infected with viruses initially allow for a bacterial layer to be more established. We believe this happens because the viruses have destroyed part of the airway defences, allowing for the bacteria to establish.
Epithelial Drivers of Neutrophil Plasticity in Early Cystic Fibrosis Lung Disease
This project has developed a powerful laboratory model to study the interaction between lung cells and the immune system during different types of lung infection. We are finding that the bacteria (bug) Pseudomonas aeruginosa can create an environment that makes blood immune cells behave differently. We are now exploring whether there are other bugs that cause lung infection that also have this effect. This will allow us to unravel new ways to assist the immune system in fighting lung infections in children with cystic fibrosis, who experience infections more frequently and severely than their peers.
Understanding Airway Epithelial Cell Repair From Children Born Preterm
Our body relies on airway cells to maintain a protective barrier between the air we breathe in and out of our lungs, to keep us healthy and free from bugs. It is therefore important that airway cells repair quickly following an injury. Our study has assessed the ability of nasal cells from preterm infants to repair. We have found that airway cells from term infants completely repair, however cells from preterm infants do not. This defect may be further impaired after exposure to antenatal steroids. We do not yet know why cells from preterm infants repair slower than in those born at term. Our study is also looking to see if there are differences in the way genes are expressed in term and preterm cells, to see if this explains the slower repair.
Exploring the Effects of Electronic Cigarette Aerosol Exposure on Diseased and Healthy Airway Epithelial Cells
Electronic cigarettes (“e-cigarettes”) heat and atomize a liquid solution (“e-juice”) producing an aerosol which is inhaled. They are a relatively new technology and their use is widespread and increasing rapidly, especially in adolescents. There are many gaps in knowledge related to how e-cigarette use may impact health. The limited data that exist suggest that they are likely to have a negative impact on health in non-smokers (which typically includes one of the key demographics of e-cigarette users – adolescents). Such health effects may be more severe in situations of pre-existing respiratory disease. Importantly, data suggest that the type of e-cigarette (in terms of e-juice and “vaping” settings) can significantly influence health outcomes. In this study we are using our expertise in in vitro exposure models to investigate the effects of exposure to various aerosols generated by a 4th generation sub-ohm e-cigarette.
CF Epithelial Cell Migration and Rescue of Tissue Repair
Some studies have demonstrated the airway cells from cystic fibrosis (CF) patients may not be able to repair following injury as efficiently as non-CF tissue, and this appears to be due to the basic CFTR mutation, as new corrective therapies can partially improve repair by CF lung cells. Research from another project investigating poor repair by asthmatic airway cells developed a method to track the direction and speed of individual airway cells during time of repair. Using this tool, we have also been able to identify a drug compound that can be repurposed to improve the repair of airway cells from all individuals. We are now studying in depth how CF airway cells conduct tissue repair and whether the compound discovered by our group to assist repair in asthmatic airway tissue could benefit CF lungs. This could provide clinicians with an important new therapy to delay or minimise lung damage.
Developing a Novel Therapeutic Pipeline For Antibiotic Resistant Infections in Children
Common infections can sometimes be difficult to treat as some bacteria do not respond to the antibiotic drugs used to treat the infections. Developing new medicines is challenging. Bacteriophages are viruses that infect bacteria. Scientists think that these bacteriophages could be a new treatment for bacterial infections because they kill only the bacteria causing the infection. They have been used in several countries as a form of treatment in many types of diseases and without major side effects. To date, it is not a form of treatment in Australia. Cystic fibrosis (CF) is an inherited genetic disease that causes the lungs to be filled with sticky fluid. People with CF are more likely to get lung infections with two types of bacteria called Pseudomonas aeruginosa and Staphylococcus aureus, resulting in lung damage that cannot be fixed. We believe that developing a new and safe treatment is important for those with CF who often get this bacterial infection. This can then stop lung damage from occurring and help improve the quality and length of their lives. There are no studies that have used bacteriophages to treat bacterial lung infections. The purpose of this study is to find out whether bacteriophages are safe to use in the lung and can be used to fight Pseudomonas aeruginosa and Staphylococcus aureus infection. The outcomes of the study will help us continue research and one day be able to offer this new form medicine to those with CF.
Assessment of SARS-Cov2 Receptor Genes Expression in Airway Epithelial Cells and Evaluation of Innate Immune Responses to SARS-Cov2 Infection
The current global pandemic coronavirus disease 2019 (COVID 2019) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). Some of the people that were positive for this virus reported no clinical symptoms, whilst others have mild upper respiratory tract illness or even severe viral pneumonia with the resulting respiratory failure and death. The lungs appear to be the main target for SARS-CoV2 which cause them to stop working properly and cascading to other types of organ failure and death. With the data collected thus far, there is an emerging pattern that certain groups of individuals or ages are more susceptible to the effects SARS-CoV2 infection. However, little is known about what makes these ‘at risk’ groups more vulnerable. Therefore, this study aims to use airway epithelial cells from both paediatric and adult cohorts to determine the expression profiles of SARS-CoV2 receptors and to investigate the cellular responses to infection. By profiling the gene expression and detailed understanding of the cellular responses to infection we hope to identify potential therapies which are currently still unavailable.
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