Multiple roles for hypoxia inducible factor 1-alpha in airway epithelial cells during mucormycosis

Povilas Kavaliauskas, Yiyou Gu, Naushaba Hasin, Karen T. Graf, Abdullah Alqarihi, Amol C. Shetty, Carrie McCracken, Thomas J. Walsh, Ashraf S. Ibrahim and Vincent M. Bruno ()
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Povilas Kavaliauskas: University of Maryland School of Medicine
Yiyou Gu: Harbor-UCLA Medical Center
Naushaba Hasin: University of Maryland School of Medicine
Karen T. Graf: University of Maryland School of Medicine
Abdullah Alqarihi: Harbor-UCLA Medical Center
Amol C. Shetty: University of Maryland School of Medicine
Carrie McCracken: University of Maryland School of Medicine
Thomas J. Walsh: University of Maryland School of Medicine
Ashraf S. Ibrahim: Harbor-UCLA Medical Center
Vincent M. Bruno: University of Maryland School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49637-8

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