Understanding the Roles of Hypoxia-Inducible Factor 1 Alpha in Early Host Responses Against Pneumococcal Pneumonia
Date
2023-09-11
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Abstract
Pneumococcal pneumonia, caused by the bacteria Streptococcus pneumoniae (SP), is the leading infectious cause of death in young children worldwide. Current 2D human and small animal models used to study SP infections do not account for complex organ microenvironments or species-specific immune pathways, respectively. To address this, we created a human vascularized lung on a chip (LoC) containing a ventilated epithelial lined air-liquid interface surrounded by human lung fibroblasts and a functional microvascular network. Single cell RNA sequencing of LoC treated with SP for 6 hours demonstrated early hypoxia inducible factor 1- alpha (HIF-1α) target gene activation. Therefore, we hypothesized that HIF-1α-dependent immune responses play an important role in pneumococcal pneumonia. LoC showed increased CD15+ neutrophil recruitment from perfused whole blood in microvessels to tissue and airway during SP infection, partially mediated by HIF-1α. CXCL family chemokines and IL-17C gene expression, and protein release of the latter, increased 6 hours post-infection in LoC; however, we did not observe vascular or airway dysfunction and microvascular damage until 24 hours post-infection. SP-induced HIF-1α activation may be driven by rapidly activated upstream signaling pathways and may require metabolically active bacteria. Altogether, we have characterized a number of functional roles of HIF-1α during early stages of SP infection and showed the utility of LoC as a pre-clinical human model that can identify key inflammatory and cell-cell interactions during pneumococcal pneumonia.
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Keywords
Pneumonia, HIF-1a, Neutrophil recruitment, Lung-on-a-chip
Citation
Kang, H. (2023). Understanding the roles of hypoxia-inducible factor 1 alpha in early host responses against pneumococcal pneumonia (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.