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Co-immunoprecipitation Assay Using Endogenous Nuclear Proteins from Cells Cultured Under Hypoxic Conditions
Published on: August 2, 2018
Multiple roles for hypoxia inducible factor 1-alpha in airway epithelial cells during mucormycosis
Povilas Kavaliauskas1, Yiyou Gu2, Naushaba Hasin3,4
1Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Abstract:
During pulmonary mucormycosis, inhaled sporangiospores adhere to, germinate, and invade airway epithelial cells to establish infection. We provide evidence that HIF1α plays dual roles in airway epithelial cells during Mucorales infection. We observed an increase in HIF1α protein accumulation and increased expression of many known HIF1α-responsive genes during in vitro infection, indicating that HIF1α signaling is activated by Mucorales infection. Inhibition of HIF1α signaling led to a substantial decrease in the ability of R. delemar to invade cultured airway epithelial cells. Transcriptome analysis revealed that R. delemar infection induces the expression of many pro-inflammatory genes whose expression was significantly reduced by HIF1α inhibition. Importantly, pharmacological inhibition of HIF1α increased survival in a mouse model of pulmonary mucormycosis without reducing fungal burden. These results suggest that HIF1α plays two opposing roles during mucormycosis: one that facilitates the ability of Mucorales to invade the host cells and one that facilitates the ability of the host to mount an innate immune response.
Insights
Hypoxia-inducible factor 1-alpha (HIF1α) has dual roles in pulmonary mucormycosis. It aids fungal invasion but also promotes the host immune response, suggesting therapeutic targeting.
Area of Science:
- Infectious Diseases
- Cell Biology
- Immunology
Background:
- Pulmonary mucormycosis is a severe fungal infection initiated by inhaled spores.
- Airway epithelial cells are the primary site of initial fungal adherence, germination, and invasion.
- The role of hypoxia-inducible factor 1-alpha (HIF1α) in this process is not fully understood.
Purpose of the Study:
- To investigate the role of HIF1α in airway epithelial cells during Mucorales infection.
- To elucidate the dual functions of HIF1α in host-pathogen interactions during pulmonary mucormycosis.
Main Methods:
- In vitro infection models using airway epithelial cells and Rhizopus delemar.
- Analysis of HIF1α protein accumulation and gene expression.
- Transcriptome analysis to identify differentially expressed genes.
- Pharmacological inhibition of HIF1α in a mouse model of pulmonary mucormycosis.
Main Results:
- Mucorales infection activates HIF1α signaling in airway epithelial cells.
- HIF1α inhibition significantly reduced fungal invasion of epithelial cells.
- HIF1α inhibition decreased the expression of pro-inflammatory genes induced by infection.
- Pharmacological inhibition of HIF1α improved survival in a mouse model without reducing fungal load.
Conclusions:
- HIF1α plays opposing roles in pulmonary mucormycosis: facilitating fungal invasion and promoting host innate immunity.
- Targeting HIF1α may offer a therapeutic strategy for pulmonary mucormycosis by modulating host response.
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