Alpha-1 Antitrypsin Deficiency (AATD) is a genetic disorder that can cause emphysema and increase susceptibility to early-onset lung disease. Using stem cell–derived models of the human alveolus, we study how AATD alters cellular responses to respiratory pathogens, like Respiratory Syncytial Virus (RSV). By uncovering disrupted pathways, we aim to identify new therapeutic strategies to protect the lungs of vulnerable AATD patients from respiratory infections.
Impact
Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that predisposes to emphysema. It affects 1 in 5,000 people globally, with ~30,000 affected in Australia and New Zealand. AATD-related chronic obstructive pulmonary disease, particularly emphysema, is the major cause of morbidity and mortality, burdening patients, and health systems. Respiratory infections frequently trigger exacerbations, leading to hospitalisations, and reduced quality of life of patients with AATD. The efficacy of current treatments for AATD is severely limited, especially during respiratory infections, which highlights the lack of human models for infection studies in AATD. Induced pluripotent stem cells (iPSCs) offer a renewable, patient-specific platform for disease modeling, and drug discovery. Our work uses AATD patient–derived iPSC alveolar models to define how pathogens, such as Respiratory Syncitial Virus (RSV), reprogram cellular and molecular pathways, delivering mechanistic insights to accelerate targeted therapies for people with AATD.
reNEW research
To date, we have generated iPSC-derived alveolar epithelial cells and macrophages from AATD patients and matched isogenic controls, and studied their response to infection with various respiratory pathogens including, RSV, influenza A, and Streptococcus pneumoniae. Across complementary cellular and molecular assays, we find that AATD mutations differentially rewire infection responses in both cell types. Looking ahead, we will establish epithelial–macrophage co-cultures to capture cell–cell crosstalk to further investigate infection-driven exacerbations. Moreover, we will evaluate the efficacy of current therapies, such as AAT augmentation therapy, alongside emerging strategies that include autophagy-enhancing drugs
Image description
Immunofluorescence of AATD iPSC-derived alveolar epithelial cells 24 hours post RSV infection. RSV antigen is shown in red, nuclei in blue, and cell borders in green. The red signal indicates widespread viral infection in some cells. On the left, multiple nuclei are enclosed within a single continuous red cytoplasm, reflecting RSV-induced syncytia (cell–cell fusion). This hallmark feature of RSV enables the virus to bud directly from one cell into its neighbors, progressively shattering epithelial junctions and dismantling the integrity of the barrier.
Credits
Sahel Amoozadeh, PhD Student, Werder Lab, reNEW Melbourne.
