Abstract
ABSTRACTThe echinocandins are a class of antifungal agents that target β-1,3-d-glucan (BG) biosynthesis. In the ascigerous Pneumocystis species, treatment with these drugs depletes the ascus life cycle stage, which contains BG, but large numbers of forms which do not express BG remain in the infected lungs. In the present study, the gene expression profiles of Pneumocystis murina were compared between infected, untreated mice and mice treated with anidulafungin for 2 weeks to understand the metabolism of the persisting forms. Almost 80 genes were significantly up- or downregulated. Like other fungi exposed to echinocandins, genes associated with sexual replication, cell wall integrity, cell cycle arrest, and stress comprised the strongest upregulated signals in P. murina from the treated mice. The upregulation of the P. murina β-1,3-d-glucan endohydrolase and endo-1,3-glucanase was notable and may explain the disappearance of the existing asci in the lungs of treated mice since both enzymes can degrade BG. The biochemical measurement of BG in the lungs of treated mice and fluorescence microscopy with an anti-BG antibody supported the loss of BG. Downregulated signals included genes involved in cell replication, genome stability, and ribosomal biogenesis and function and the Pneumocystis-specific genes encoding the major surface glycoproteins (Msg). These studies suggest that P. murina attempted to undergo sexual replication in response to a stressed environment and was halted in any type of proliferative cycle, likely due to a lack of BG. Asci appear to be a required part of the life cycle stage of Pneumocystis, and BG may be needed to facilitate progression through the life cycle via sexual replication.
Highlights
The echinocandins are a class of antifungal agents that target -1,3-Dglucan (BG) biosynthesis
The therapeutic potential of the commercially available agents caspofungin, anidulafungin, and micafungin for Pneumocystis pneumonia (PCP) is reduced due to lack of activity of these -1,3-D-glucan (BG) synthase inhibitors on the trophic and other non-BG-expressing forms of its life cycle, which we showed to remain in large numbers after 3 weeks of treatment with up to 10
Transcriptome sequencing (RNA-seq) and network modeling in Aspergillus fumigatus after exposure to caspofungin revealed that genes involved in carbohydrate metabolism, such as those coding for the -glucosidases and exo- and endo--1,3(4)-D-glucanases were differentially expressed, as they were in a previous study of Aspergillus niger [6, 85]
Summary
The echinocandins are a class of antifungal agents that target -1,3-Dglucan (BG) biosynthesis. Gene signatures reported for fungi exposed to echinocandins were found in the treated P. murina cells and included those for cell wall integrity, cell cycle perturbation, and notably, for sexual reproduction This is the first study to report the effects of an echinocandin on global gene expression of a Pneumocystis species. The strong upregulation of genes related to sexual reproduction, cell wall integrity, and stress and the significant downregulation of ribosome function indicate that the fungi sensed their inhospitable environment and attempted, unsuccessfully, to initiate sexual reproduction These findings support the requirement of a sexual cycle and formation of asci, for progression through the full life cycle of Pneumocystis
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