Abstract
Incidences of invasive pulmonary aspergillosis, an infection caused predominantly by Aspergillus fumigatus, have increased due to the growing number of immunocompromised individuals. While A. fumigatus is reliant upon deficiencies in the host to facilitate invasive disease, the distinct mechanisms that govern the host-pathogen interaction remain enigmatic, particularly in the context of distinct immune modulating therapies. To gain insights into these mechanisms, RNA-Seq technology was utilized to sequence RNA derived from lungs of 2 clinically relevant, but immunologically distinct murine models of IPA on days 2 and 3 post inoculation when infection is established and active disease present. Our findings identify notable differences in host gene expression between the chemotherapeutic and steroid models at the interface of immunity and metabolism. RT-qPCR verified model specific and nonspecific expression of 23 immune-associated genes. Deep sequencing facilitated identification of highly expressed fungal genes. We utilized sequence similarity and gene expression to categorize the A. fumigatus putative in vivo secretome. RT-qPCR suggests model specific gene expression for nine putative fungal secreted proteins. Our analysis identifies contrasting responses by the host and fungus from day 2 to 3 between the two models. These differences may help tailor the identification, development, and deployment of host- and/or fungal-targeted therapeutics.
Highlights
98% of mapped reads aligned to mouse genes, while (50,000 to 1.1 M) paired end reads mapped to A. fumigatus strain A1163 genes per sample replicate
The form of immune suppression sets the foundation for the progression of invasive pulmonary aspergillosis
Prolonged glucocorticoid treatment reduces inflammation through trans-activation, trans-repression, and direct protein-protein interactions with the glucocorticoid receptor. These molecular phenomena result in an anti-inflammatory effect, curtailed immune signaling, decrease function of neutrophils, lymphocytes, monocytes, and macrophages
Summary
Transcriptomics has facilitated the identification of global gene expression changes associated with the pH-responsive transcription factor PacC during chemotherapeutic mouse model of IPA28. We provide a global overview of our dual organism transcriptomics study aimed at identifying differences and similarities in host and fungal gene expression between steroid treatment and chemotherapeutic mouse models of IPA. We identify conserved and contrasting expression of the putative A. fumigatus secretome between the chemotherapeutic and steroid mouse models of IPA These differences and similarities in host and fungal gene expression provide a system-wide overview of the interaction of A. fumigatus and the host. Determination of global gene expression profiles during chemotherapeutic and steroid models of IPA provides an important framework for the system-wide identification of potential novel host and fungal therapeutic targets that can be explored mechanistically in future studies for biological significance
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