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.
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.
Therapeutically targeting airway epithelial repair
Persistent childhood wheezing associates with early-onset asthma and long-term decline in respiratory function. Asthma is a burdensome disease worldwide and often difficult to effectively treat. While conventional therapies target symptoms, they fail to prevent wheeze persistence towards asthma in early childhood. The airway epithelium is the first line of defence in the respiratory system and has been implicated as an orchestrator of paediatric asthma development. Our team and others have reported defective repair responses to ‘injury’ in airway epithelial cultures from children with wheeze. Additionally, we have identified defective airway epithelial repair as a treatable trait by using existing and novel therapeutics – providing a novel opportunity to reduce or prevent long-term asthma disease trajectories. This study aims to characterise defective airway repair and develop and optimise precision-based therapies for children exhibiting defective airway repair endotype. Identifying biomarkers of defective repair, validating drug safety and efficacy, and identifying drug mechanism-of-action on repair are key steps in the development of our new therapeutic approach towards asthma.
Establishing in vitro models for early life nasopharyngeal microbiota profiles.
Pneumonia and asthma are leading causes of death and disability in children worldwide. Research has shown that several potentially harmful bacterial species are present in the microbiome of the upper airways (nasopharynx) of young children, and that these bacteria can be found before disease develops, suggesting that they may drive susceptibility to infection or disease pathogenesis. In contrast, there are health-associated bacterial commensals in the nasopharyngeal microbiome which are preferentially found in children without pneumonia or other respiratory diseases. Very little is known about the biology of these health-associated commensals and how they interact with other members of the microbiome or the host respiratory epithelium. Our research aims to use airway epithelial cells from a paediatric cohort to establish models for commensal colonization and explore precisely which commensal bacteria have health-promoting effects and the underlying mechanisms. Identification of candidate commensal strains will drive our work on the development of live biotherapeutic candidates for prevention of respiratory tract infections in children.
Investigating bacteriophage behaviour and efficacy in the Cystic Fibrosis (CF) lung microenvironment
Antimicrobial resistance (AMR) in Cystic Fibrosis (CF) poses serious long-term health risks. In young children with CF, airways affected by thick mucus fosters chronic bacterial infections. While antibiotics help in early stages, persistent infections alter CF airways and drive AMR. Due to limited development of new antibiotics, alternative treatments like bacteriophage (phage) therapy are being explored. Phages are viruses that can target and kill bacteria. Although studies have focused on how phages interact with bacteria, their relationship with CF airway cells and mucus remains poorly understood. Emerging evidence from gut cell research suggests phages bind to mucus, enhancing bacterial killing. However, CF’s unique environment may influence this effect. This study aims to map the different mucus types produced by CF airway cells using a 3D airway lab-grown model. With this model, researchers will examine how phages interact with airway cells, bacteria, and mucus to determine how the CF environment influences phage attachment and bacterial elimination. Findings will guide future development of phage therapy for CF, helping identify effective delivery methods and optimal formulations.
Investigating the effectiveness of aerosolised phage delivery for the treatment of multi-drug-resistant Pseudomonas aeruginosa airway infections
Chronic infections with antimicrobial-resistant pathogens such as Pseudomonas aeruginosa can greatly reduce the quality of life for those living with chronic respiratory diseases. Bacteriophage (phage) therapy is now being recognised as a potential alternative therapy for antibiotic-resistant infections. Aerosolised phage therapy involves the delivery of phage to the lungs by nebulisation, however nebulisers generate physical stress that can destroy phage and reduce their activity. This damage is not well understood, and there is little knowledge on which phages are better suited for nebulised delivery. This study aims to identify specific characteristics of phage (such as tail length or genome size) that make them more suitable for use with common nebuliser devices available to the public. We also aim to identify compounds that can be added to phage suspensions that can reduce the level of phage damage during nebulisation. By understanding which types of phages are better suited for nebulised delivery, we can use this knowledge to select the most appropriate phage for the job. This will improve the effectiveness of nebulised phage therapy while it is still a novel treatment, promoting its use in the future.
Assessing the danger of heated tobacco products
Heated-tobacco-products (HTPs) are electronic devices that heat processed tobacco, producing an inhalable aerosol containing nicotine, particulate matter and other harmful substances. They are currently sold in over 50 countries and are rapidly increasing in popularity. Big Tobacco are attempting to get approval for sale in Australia. They are manufactured and marketed by "Big Tobacco" companies as "reduced-risk" alternatives to traditional cigarettes, with the goal of attracting new, young customers to tobacco. The reduced-risk sales pitch is based on the fact that they heat tobacco to ~350ºC rather than combusting it at 600-800ºC (as in a conventional cigarette). According to manufacturers, this reduces the number of harmful substances in the inhaled emissions. That said, there is a severe paucity of unbiased hard-data on the potential health effects due to exposure to heated-tobacco-product emissions. Here, we will expose 3-D human lung cells to emissions generated by the three most popular heated-tobacco-products on the market. Outcome measures will include emission physico-chemistry, cellular viability, barrier permeability and production of inflammatory mediators.
Administering Diferuloylmethane-2 Via Aerosol Nebulization to Compromised Epithelium (ADVANCE)
Curcumin is a natural compound derived from turmeric, commonly used as a dietary supplement due to its multiple beneficial effects. While the reformulated oral version (biocurcumin) has shown promise in limiting RSV infection in our earlier studies, the potential for delivering biocurcumin directly to the lungs via aerosol has not yet been explored. Aerosol delivery offers a targeted approach that may enhance effectiveness by acting directly on the airway lining, where RSV infection causes damage. In this study, we will use our expertise in cell culture and animal models to investigate the safety and efficacy of aerosolized biocurcumin as a novel treatment for RSV infection. This work aims to establish a foundation for advancing into clinical safety trials, with the goal of providing a low-cost, accessible treatment option, especially for vulnerable populations in remote, regional areas.