Biology subjects

Rangel-Grimaldo, M.

Publications and source records attributed to Rangel-Grimaldo, M..

4 recordsLinked to original sources

bioRxiv2026

Opportunistic pathogenicity in fungi can transcend species boundaries

Multiple fungal lineages have independently evolved the ability to opportunistically infect humans, imposing a major burden on public health. Opportunistic pathogenicity requires the confluence of pre-existing fungal traits that facilitate host colonization (e.g., the ability to grow at 37{degrees}C) and host immune filters that permit the survival of some colonizers (e.g., inborn errors of immunity). Numerous studies have shown that fungal pathogens can exhibit extensive strain-to-strain variation in the ability to cause disease. Moreover, it is also well established that non-pathogenic fungi can occasionally cause severe infections. Together, these observations raise the question: What differentiates opportunistic fungal pathogens from non-pathogens? To address this empirically, we compared phenotypic, metabolomic, and genomic variation between Aspergillus fumigatus, an organism responsible for more than 300,000 infections per year, and Aspergillus fischeri, a close relative that is not considered clinically relevant. By examining 26 phenotypic traits across 16 representative strains of A. fumigatus and 16 of A. fischeri, we found that infection-relevant traits measured under in vitro monoculture conditions showed species-specific distributions, whereas traits measured under in vitro coculture with murine macrophages overlapped. Strikingly, strains of the two species also overlapped in their virulence profiles in an immunocompromised murine model of pulmonary aspergillosis; three strains of A. fischeri exhibited lethality rates of >50% while two A. fumigatus strains were among the least virulent of all 32 strains tested. Consistent with this overlap, we could not associate virulence variation with the presence of specific genomic elements, phenotypic traits, or secondary metabolites. Our results raise the hypothesis that opportunistic pathogenicity can extend beyond the boundaries of individual species. We propose a conceptual model in which the opportunistic pathogenic potential of any fungal strain is the product of complex interactions among numerous genomic, ecological, and host immunity factors.

evolutionary biology↗

bioRxiv2025

An integrative genomic and chemical similarity approach linking fungal secondary metabolites and biosynthetic gene clusters

Fungi are well known to biosynthesize structurally complex secondary metabolites (SMs) with diverse bioactivities. These fungal SMs are frequently produced by biosynthetic gene clusters (BGCs). Linking SMs to their BGCs is key to understanding their chemical and biological functions. Reasoning that structural similarity of SMs arises from similarities in the genes involved in their biosynthesis, we developed an integrative approach that leverages known BGC-SM pairs to predict global links across SMs and BGCs in fungi. As proof of concept, we systematically interrogated metabolomes and genomes of 16 strains of the filamentous fungus Aspergillus fischeri, detecting a total of 60 metabolites. Of those, we were able to assign 22 to known BGC-SM pairs and propose specific hypotheses for the remaining 38 metabolites. These results suggest that coupling genomic similarity and chemical structure-based similarity is a straightforward and high-throughput approach for linking fungal SMs to their BGCs.

microbiology↗

bioRxiv2024

Strain heterogeneity in a non-pathogenic fungus highlights factors contributing to virulence

Fungal pathogens exhibit extensive strain heterogeneity, including variation in virulence. Whether closely related non-pathogenic species also exhibit strain heterogeneity remains unknown. Here, we comprehensively characterized the pathogenic potentials (i.e., the ability to cause morbidity and mortality) of 16 diverse strains of Aspergillus fischeri, a non-pathogenic close relative of the major pathogen Aspergillus fumigatus. In vitro immune response assays and in vivo virulence assays using a mouse model of pulmonary aspergillosis showed that A. fischeri strains varied widely in their pathogenic potential. Furthermore, pangenome analyses suggest that A. fischeri genomic and phenotypic diversity is even greater. Genomic, transcriptomic, and metabolomic profiling identified several pathways and secondary metabolites associated with variation in virulence. Notably, strain virulence was associated with the simultaneous presence of the secondary metabolites hexadehydroastechrome and gliotoxin. We submit that examining the pathogenic potentials of non-pathogenic close relatives is key for understanding the origins of fungal pathogenicity.

evolutionary biology↗

bioRxiv2022

Genomic and phenotypic trait variation of the opportunistic human pathogen Aspergillus flavus and its non-pathogenic close relatives

Fungal diseases affect millions of humans annually, yet fungal pathogens remain understudied. The mold Aspergillus flavus is a causative agent of both aspergillosis and fungal keratitis infections, but species closely related to A. flavus are not considered clinically relevant. To study the evolution of A. flavus pathogenicity, we examined genomic and phenotypic traits of two strains of A. flavus and three closely related non- pathogenic species: Aspergillus arachidicola (two strains), Aspergillus parasiticus (two strains), and Aspergillus nomiae (one strain). We identified over 3,000 orthologous proteins unique to A. flavus, including seven biosynthetic gene clusters present in A. flavus strains and absent in the three non-pathogenic species. We chose to characterize secondary metabolite production for all seven strains under two clinically relevant conditions, temperature and salt concentration. Temperature impacted metabolite production in all species. Conversely, we found a lack of impact of salinity on secondary metabolite production. Strains of the same species produced different metabolites. Growth under stress conditions revealed additional heterogeneity within species. Using the invertebrate model of fungal disease Galleria mellonella, we found virulence of strains of the same species varied widely, and A. flavus strains were not more virulent than strains of the non-pathogenic species. In a murine model of fungal keratitis, we observed significantly lower disease severity and corneal thickness for A. arachidicola compared to other species at 48 hrs, but not at 72 hrs. Our work identifies key phenotypic, chemical, and genomic similarities and differences between the opportunistic human pathogen A. flavus and its non-pathogenic relatives.

evolutionary biology↗