Molecular Determinants of Pulmonary Mucormycosis and Aspergillosis

Abstract

Mucormycosis and aspergillosis are invasive fungal infections with very limited treatment options and extremely high mortality rates. During both pulmonary mucormycosis and aspergillosis, inhaled fungal spores must adhere to and invade airway epithelial cells in order to establish infection. The molecular mechanisms governing these interactions in the context of each disease are not completely understood. Mucormycoses are caused by fungi belonging to the Order Mucorales, with ~70% of all cases caused by Rhizopus species. To better understand the molecular mechanisms of fungal invasion during mucormycosis, an unbiased survey of the host transcriptional response to Mucorales infection in in vitro and in vivo murine models of pulmonary mucormycosis using RNA-seq was performed. Network analysis revealed activation of host receptor tyrosine kinase (RTK) signaling pathways and progesterone (PG) signaling pathways. By combining established models of mucormycosis, transcriptomics, cell biology, and pharmacological approaches, we demonstrated that Mucorales activate epidermal growth factor receptor (EGFR), erb-b2 tyrosine kinase 2 (ErbB2), and platelet-derived growth factor receptor (PDGFR) signaling to induce fungal uptake into airway epithelial cells. Furthermore, we demonstrated that inhibition of EGFR signaling with existing FDA-approved cancer drugs significantly increased survival following Rhizopus delemar infection in mice. We also demonstrated that inhibition of progesterone receptor (PGR) signaling decreases R. delemar invasion of airway epithelial cells in vitro. These studies enhance our understanding of how Mucorales invade host cells during the establishment of pulmonary mucormycosis and provide a proof-of concept for repurposing FDA-approved cancer drugs that target RTK function. Aspergillus fumigatus is responsible for 90% of all aspergillosis cases. To better understand how A. fumigatus senses and responds to airway epithelial cells during pulmonary aspergillosis, we used RNA-seq to analyze the transcriptomes of two commonly used clinical A. fumigatus isolates, Af293 and CEA10, during an in vitro infection model of airway epithelial cells. In this analysis, we identified 47 genes that were up-regulated in both strains and enriched for genes involved in iron acquisition, a mechanism required for A. fumigatus virulence in the mammalian host. Knowledge gained from this work could aid in the identification of therapeutic and prevention targets to combat mucormycosis and aspergillosis.