Background: Group A Streptococcus (GAS) commonly causes mild, upper respiratory infections. In rarer cases, GAS invades the lower respiratory tract, causing deadly infections like pneumonia. GAS-pneumonia is fatal in more than 35% of cases. There is no vaccine against GAS, and new therapies to mitigate pneumonia are urgently needed. To comprehensively assess host and bacterial dynamics along the human respiratory tract, we developed novel GAS infection models using highly characterised induced pluripotent stem cell (iPSC)-derived airway or alveolar epithelial cells.
Methods: iPSC-derived airway or alveolar epithelial cells were matured at an air-liquid interface, prior to infection with GAS (M1uk or M75 strains). Bacterial attachment and invasion, cytotoxicity, and host and bacterial transcriptomes were profiled over time.
Results: GAS M75 strain displayed significantly better attachment to lung epithelial cells, than the M1uk strain. Strikingly, we observed invasion of GAS (M1uk), and cytotoxicity was enhanced in alveolar epithelial cells, compared with airway epithelial cells. Airway epithelial cells infected with GAS responded by upregulating cytokine and chemokine signalling. In contrast, infected alveolar epithelial cells displayed an exaggerated stress response, including activation of ATR and apoptosis. Direct comparison between infected airway and alveolar epithelial cells demonstrated impaired interferon signalling in the alveolar compartment, suggesting promoting interferon activation in the alveolus may ameliorate the severity of infection.
Conclusion: We have established the first model of GAS infection in physiologically relevant airway and alveolar epithelial cells. Our findings suggest that host responses to infection were influenced by both the lung compartment and the strain of GAS.