Starkey - Immunology and Regenerative Medicine

Key Terms

Mucosal cytokines, innate lymphoid cells, postnatal lung development, chronic lung disease, urinary tract infection, kidney stone disease

Research

The Immunology and Regenerative Medicine Laboratory studies the immune mechanisms of organ development, repair and regeneration with a focus on the respiratory and urinary tracts. Our team is particularly interested the early-life infectious origins of chronic diseases and the role of tissue resident immune cells and mucosal cytokines. We employ a range of cutting-edge experimental models and tools to answer fundamental immunological questions for translational outcomes in human diseases.

Research projects available

Understanding how group 2 innate lymphoid cells in early life regulate postnatal lung development and susceptibility to chronic respiratory diseases

The neonatal lung is constantly exposed to countless environmental challenges, including respiratory pathogens. The lung has evolved a local immune system that protects it against these challenges. However, these protective immune responses may also have unwanted deleterious effects on lung structure and function. This is particularly important in early life when the lung is still developing. This project aims to define novel immunological processes that are involved in postnatal lung development and their roles in underpinning the development of chronic respiratory diseases. For this we will elucidate the role of a subset of innate immune cells, group 2 innate lymphoid cells (ILC2s), in promoting normal lung development through the regulation of bronchioalveolar stem cells (BASCs). We have discovered processes that regulate ILC2s in the neonatal lung and that respiratory infections in early life impair ILC2 homeostasis. These changes are associated with a loss of BASCs and impaired lung structure and function. The critical next steps are to gain a detailed understanding of the contribution of ILC2s in early life to these processes and in driving susceptibility to chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). Importantly, over 6 million Australians have a chronic respiratory disease, which collectively is the third leading cause of death, costing over $3 billion p.a. However, how these diseases are initiated is poorly understood and this has seriously hampered the development of effective treatments. Thus, increasing our understanding of the immunological processes that regulate postnatal lung development may eventually lead to novel strategies for the prevention and treatment of chronic respiratory diseases.

Repurposing of immunotherapies for severe urinary tract infection and associated renal complications

Urinary tract infections are a common cause of bacterial infection, especially in females. These infections are often chronic and can cause long-term damage to the urinary tract, especially when they occur in children. In some cases, the bacteria can ascend to the kidney and cause kidney scarring, a key precursor to the development of chronic kidney disease, which predisposes to systemic health complications including cardiovascular disease and diabetes. The most common cause of urinary tract infection is uropathogenic Escherichia coli, which accounts for >80% of infections. Importantly, this pathogen is becoming increasingly resistant to existing antibiotic therapies. Therefore, there is an unmet need for alternative strategies to treat these infections and prevent deleterious sequela in susceptible individuals. Our approach involves targeting the host immune system rather than the bacteria, which we propose will reduce the burden of the bacterial infection and limit the severity of the associated renal complications. Our idea is to target the immune cytokine interleukin-22 (IL-22), which is known to protect against bacterial infections at other mucosal sites and to regenerate damaged tissue in other organs. However, its function during urinary tract infection is unknown. We have established a complete toolbox of genetically modified mice, in vivo models, techniques, human patients and analysis platforms to enable us to determine the role of IL-22 in urinary tract infection and associated renal complications. We aim to use these established tools to provide crucial evidence for the re-purposing of emerging immunotherapies that target IL-22 that have been developed for other diseases. This is likely to provide a much-needed alternative therapy to antibiotics to combat the bacterial resistance in urinary tract infections, promote tissue repair to limit the severity of renal complications and reduce the likelihood of progression to chronic kidney disease.

Harnessing the immune system for organ repair in kidney stone diseases

Kidney stones are a common urinary tract problem that disproportionally affects men. Stones can cause obstructions in the urinary system and are a significant risk factor for development of chronic kidney disease later in life. Current treatments for stones focus on removal of the stones, often with multiple invasive procedures. There is a lack in understanding of the reasons why stones reoccur and the reasons why individuals with stones are at increased risk of developing chronic disease. Therefore, there is a clear need for novel approaches to prevent stone recurrence and their deleterious consequences. Our immune system is known to be pivotal in controlling the severity of inflammation and in regulating the repair of our organ systems after insults such as stone formation or infection. However, as our understanding of the immune system grows and becomes more complex, new cells are identified that may hold the key to understanding the “switch” that controls whether an insult is appropriately dealt with or not, and whether the affected organ system is appropriately repaired. Incomplete repair may lead reoccurring stones and chronic disease. This project aims to improve our understanding of how our immune system protects against stone recurrence and its role in preventing long-term consequences such as impaired kidney function.

Publications

Grants

  • NHMRC project grant (2019-2021) Understanding how group 2 innate lymphoid cells in early life regulate postnatal lung development and susceptibility to chronic respiratory diseases
  • Thoracic Society of Australia and New Zealand Lungs for Life grant (2020) Understanding how group 2 innate lymphoid cells in early life regulate postnatal lung development and susceptibility to chronic respiratory diseases
  • Klosterfrau research grant (2020) Early-life origins of chronic lung diseases