Morphotype-specific susceptibility to Neosartorya (Aspergillus) fischeri antifungal protein 2 is associated with an anabolic transcriptional signature in Candida

Merber, Richárd and Laczi, Krisztián and Bende, Gábor and Kazinczi, Erika and Farkas, Attila and Maróti, Gergely and Sinka, Rita and Galgóczy, László (2026) Morphotype-specific susceptibility to Neosartorya (Aspergillus) fischeri antifungal protein 2 is associated with an anabolic transcriptional signature in Candida. MICROBIOLOGY SPECTRUM. ISSN 2165-0497

Preview

Text merber-et-al-2026-morphotype-specific-susceptibility-to-neosartorya-aspergillus-fischeri-antifungal-protein-2-is.pdf - Published Version Available under License Creative Commons Attribution. Download (3MB) | Preview

Abstract

The emergence of drug-resistant Candida species has created a demand for global antifungal strategies that extend beyond classical growth inhibition to target unknown vulnerabilities of fungal pathogens. In this study, we demonstrated that the Neosartorya (Aspergillus) fischeri antifungal protein NFAP2 selectively targets early morphogenetic states of Candida albicans and Candidozyma auris, revealing a transient window of susceptibility during filament and pseudohypha formation. Integrated transcriptomic and in vivo analyses indicate that these developmental states may represent context-dependent entry points for NFAP2 activity. In C. albicans, transcriptomic and network analyses indicate the presence of an anabolic, translation-associated gene expression signature, accompanied by suppression of stress-protective pathways, which is associated with increased susceptibility of emerging hyphae to NFAP2 but does not establish a direct causal mechanism. In C. auris, increased susceptibility of pseudohyphal cells occurred without overt transcriptional remodeling, consistent with the characteristically muted gene expression responses of this species, suggesting that NFAP2 sensitivity is governed primarily by biophysical and post-transcriptional mechanisms rather than transcriptional reprogramming. Importantly, morphotype-specific vulnerabilities observed in vitro were reflected in distinct in vivo outcomes in Galleria mellonella, as NFAP2 was well tolerated and provided a moderate, transient survival benefit in pseudohyphal C. auris infections, but not in filamentous C. albicans, where a worsened outcome was observed, consistent with species- and morphotype-dependent activity. Taken together, these results suggest that early morphogenetic states of Candida are stress-sensitive phenotypes associated with increased susceptibility to NFAP2. This work provides a proof-of-concept framework for future investigation of morphotype-associated antifungal vulnerability to peptide-based antifungal strategies.IMPORTANCEDrug-resistant Candida species represent an escalating global health threat; however, most antifungal strategies continue to target fungal growth rather than intrinsic biological vulnerabilities. In this study, we identified early morphogenetic transitions as a shared window of increased susceptibility in both Candida albicans and the highly drug-resistant pathogen Candidozyma (formerly Candida) auris. By integrating transcriptomic profiling with in vivo infection models, we found that NFAP2 exhibits antifungal activity that is influenced by these transient developmental states in a context-dependent manner while remaining well tolerated by the host. We further demonstrated that morphotype-specific stress responses are associated with the divergent sensitivities of C. albicans and C. auris to NFAP2. These results support the concept that fungal morphogenesis may represent a therapeutically actionable process and provide a framework for designing antifungal strategies that target developmental states rather than growth. This strategy may open new opportunities for improving protein- and peptide-based therapies, as well as combination therapies against difficult-to-treat fungal pathogens.

Actions (login required)

Edit Item