Destruction of the pulmonary epithelium is a major feature of lung diseases caused by the mould pathogen Aspergillus fumigatus. Although it is widely postulated that tissue invasion is governed by fungal proteases, A. fumigatus mutants lacking individual or multiple enzymes remain fully invasive, suggesting a concomitant requirement for other pathogenic activities during host invasion. In this study we discovered, and exploited, a novel, tissue non-invasive, phenotype in A. fumigatus mutants lacking the pH-responsive transcription factor PacC. Our study revealed a novel mode of epithelial entry, occurring in a cell wall-dependent manner prior to protease production, and via the Dectin-1 β-glucan receptor. ΔpacC mutants are defective in both contact-mediated epithelial entry and protease expression, and significantly attenuated for pathogenicity in leukopenic mice. We combined murine infection modelling, in vivo transcriptomics, and in vitro infections of human alveolar epithelia, to delineate two major, and sequentially acting, PacC-dependent processes impacting epithelial integrity in vitro and tissue invasion in the whole animal. We demonstrate that A. fumigatus spores and germlings are internalised by epithelial cells in a contact-, actin-, cell wall- and Dectin-1 dependent manner and ΔpacC mutants, which aberrantly remodel the cell wall during germinative growth, are unable to gain entry into epithelial cells, both in vitro and in vivo. We further show that PacC acts as a global transcriptional regulator of secreted molecules during growth in the leukopenic mammalian lung, and profile the full cohort of secreted gene products expressed during invasive infection. Our study reveals a combinatorial mode of tissue entry dependent upon sequential, and mechanistically distinct, perturbations of the pulmonary epithelium and demonstrates, for the first time a protective role for Dectin-1 blockade in epithelial defences. Infecting ΔpacC mutants are hypersensitive to cell wall-active antifungal agents highlighting the value of PacC signalling as a target for antifungal therapy.

Isodimorphic random copolyesters are intriguing polymeric materials that can crystallize in their entire composition range, despite the random distribution of comonomer units along their chains. This behavior stems from the relatively similar chemical repeating units of the parent homopolymers. In this feature article, we review our recent works on isodimorphic aliphatic copolyesters, and extract general trends in the framework of the literature. Isodimorphic behavior is a complex phenomenon driven by comonomer partition within the crystalline unit cells formed. These copolyesters crystallize in the entire composition range displaying a pseudo-eutectic behavior when their melting points are plotted as a function of composition. Two crystalline phases, which resembled the crystalline structures of the parent homopolymers, are formed, depending on the considered composition range. The unit cell dimensions of the parent homopolymers change, as a consequence of the inclusion of co-units. At the pseudo eutectic point or pseudo-eutectic region, two crystalline phases can co-exist and their formation strongly depends on thermal history. In this case, double crystalline random copolyesters with two melting points and mixed double-crystalline spherulites can be obtained. The exact composition of the pseudo-eutectic point, the level of comonomer inclusion and the crystallinity degrees cannot be easily predicted by the copolyester chemical structure and composition. These are important issues for further future studies, as well as the quantitative determination of comonomer inclusion in the generated crystalline phases. The extraordinary variation of thermal properties, morphology and crystallinity that isodimorphic random copolyesters display as a function of composition, allows to conveniently tailor their biodegradation, permeability to gases and mechanical properties.

Tuning the thermal properties and morphology of isodimorphic poly[(butylene succinate)-ran-(ɛ-caprolactone)] copolyesters by changing composition, molecular weight and thermal history