Irere, H. | bioRxiv Science

bioRxiv2026

Cryptococcus gattii responds to mycobacterial exposure through coordinated remodelling of population dynamics and cell surface architecture, enhancing pulmonary persistence in a co-infection model

Cryptococcus neoformans and Cryptococcus gattii are major causes of fungal pneumonia and meningitis, frequently co-occurring with Mycobacterium tuberculosis in endemic regions, where co-infection is associated with increased mortality. Yet, how Cryptococcus adapts to mycobacterial co-presence within the lung remains poorly understood. Here, we show that mycobacterial cues trigger a conserved adaptive programme in C. gattii, mirroring responses previously observed in C. neoformans. Increasing exposure to mycobacteria drives cell and capsule enlargement and promotes titan cell formation, accompanied by dose-dependent remodelling of chitin and chitosan. Importantly, in vivo exposure to heat-killed mycobacteria increases C. gattii pulmonary burden, linking structural remodelling to enhanced persistence. These findings identify mycobacterial co-presence as a driver of fungal phenotypic plasticity and reveal pathogen-pathogen interactions as critical regulators of disease outcome, highlighting a previously unrecognised axis of co-infection relevant to C. gattii pathogenesis and therapeutic strategy.

microbiology↗

bioRxiv2026

A murine model to study chronic airway fungal colonisation that recapitulates human disease

Aspergillus fumigatus is a ubiquitous environmental mould and a leading cause of chronic fungal-associated respiratory disease, yet the mechanisms by which persistent airway colonisation drives immune adaptation and lung pathology remain poorly understood. Progress in this area has been limited by the lack of in vivo models that recapitulate stable, non-invasive fungal persistence without immunosuppression. Here, we developed and optimised a murine model of chronic airway colonisation using agar bead-embedded A. fumigatus conidia delivered intratracheally. Embedding did not impair fungal germination or hyphal growth, and the agar matrix was immunologically inert, supporting its use as a neutral scaffold. This approach established stable fungal persistence in the airways for at least three weeks in immunocompetent mice without inducing invasive disease or systemic morbidity. Colonisation elicited a transient, airway-restricted innate immune response characterised by early neutrophil and monocyte recruitment and increased CXCL1, MIP-1, MIP-1{beta}, and TNF production, which resolved over time. Histopathological analysis revealed a progressive sequence of disease-relevant features, including initial immune containment, followed by mucus hypersecretion, and airway remodelling. At the adaptive level, persistent colonisation induced a dynamic T cell response that transitioned from an early polyfunctional profile to a sustained Th17-dominant phenotype. Importantly, application of this model in CFTR-deficient mice uncovered enhanced collagen deposition and fibrotic remodelling without altered fungal burden, demonstrating its utility in modelling disease-relevant outcomes in susceptible hosts. Together, this study establishes a robust and physiologically relevant platform for investigating host-fungal interactions during chronic airway colonisation. This model provides new opportunities to dissect mechanisms of immune adaptation, fungal persistence, and tissue remodelling, and to identify therapeutic strategies targeting chronic Aspergillus-associated lung disease.

immunology↗