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Silent Fracture: Virus Shattering Cellular Glass
Alpha-1 Antitrypsin Deficiency (
#AATD) is a
#geneticdisorder that can cause
#emphysema and increase susceptibility to early-onset
#lungdisease. Using stem cell–derived models of the human alveolus, we study how AATD alters cellular responses to respiratory pathogens, like
#RespiratorySyncytialVirus (RSV). By uncovering disrupted pathways, we aim to identify new therapeutic strategies to protect the lungs of vulnerable AATD patients from respiratory infections.
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.
To date, we have generated iPSC-derived
#alveolarepithelialcells 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
Credits:
Sahel Amoozadeh, PhD Student, Rhiannon Werder Lab, reNEW Melbourne
@UCPH_Research @UCPH_health @novonordiskfond