Biology subjects

Andes, D.

Publications and source records attributed to Andes, D..

3 recordsLinked to original sources

bioRxiv2025

Candida auris skin colonization is mediated by Als4112 and interactions with host extracellular matrix proteins

Candida auris is an often multidrug-resistant fungal pathogen notorious for persistent skin colonization and transmission in healthcare settings. However, the mechanisms driving its adherence to skin remain poorly understood. Here, we developed in vitro systems to allow for detailed analysis of early skin colonization events and identified critical host and pathogen mediators of attachment. Across multiple strains and clades of C. auris, we identified that Als4112, a conserved adhesin, is required for skin colonization via keratinocyte attachment and direct interactions with host extracellular matrix (ECM) proteins, especially basement membrane proteins such as laminin. In a murine epicutaneous infection and human skin explants, deletion of ALS4112 significantly reduced skin colonization, underscoring its essential role in establishing cutaneous persistence. Als4112 also contributes to systemic infection, highlighting the connection between adherence and pathogenicity in this organism. Finally, coating plastic and catheter surfaces with collagen I or III markedly inhibited C. auris attachment and biofilm formation, offering an approach to curb nosocomial transmission. Our study highlights the critical role of Als4112 in C. auris colonization and virulence in vivo, making it an attractive target for future vaccine development. This study also explores the potential of specific collagen coatings as a novel strategy to prevent C. auris adherence to abiotic surfaces, offering new therapeutic avenues to control the spread of C. auris in healthcare settings.

microbiology↗

bioRxiv2024

Altered oral microbiota of drug-resistant organism carriers exhibit impaired gram-negative pathogen inhibition

The oral microbiome has been understudied as a reservoir for clinical pathogens, including drug-resistant strains. Understanding how alterations in microbiome functioning render this site vulnerable to colonization is essential, as multidrug-resistant organisms (MDRO) carriage is a major risk factor for developing serious infections. To advance our knowledge of oral MDRO carriage and protection against pathogen colonization conferred by native microbiota, we examined microbiomes from individuals colonized by MDROs (n=33) and non-colonized age-matched controls (n=30). Shotgun metagenomic analyses of oral swabs from study participants revealed significant differences in microbial communities with depletion of Streptococcus spp. among those colonized by multidrug-resistant gram-negative bacilli (RGNB), compared to non-carriers. We utilized metagenomic sequencing to characterize the oral resistome and find antimicrobial resistance genes are present in higher abundance among RNGB carriers versus non-carriers. High-throughput co-culture screening revealed oral bacteria isolated from MDRO non-carriers demonstrate greater inhibition of gram-negative pathogens, compared to isolates from carriers. Moreover, biosynthetic gene clusters from streptococci are found in higher abundance from non-carrier microbiomes, compared to RGNB carrier microbiomes. Bioactivity-guided fractionation of extracts from Streptococcus isolate SID2657 demonstrated evidence of strong E. coli and A. baumannii inhibition in a murine model of infection. Together, this provides evidence that oral microbiota shape this dynamic microbial community and may serve as an untapped source for much-needed antimicrobial small-molecules.

microbiology↗

bioRxiv2023

Aspergillus fumigatus transcription factor ZfpA regulates hyphal development and alters susceptibility to antifungals and neutrophil killing during infection

Hyphal growth is essential for host colonization during Aspergillus infection. The transcription factor ZfpA regulates A. fumigatus hyphal development including branching, septation, and cell wall composition. However, how ZfpA affects fungal growth and susceptibility to host immunity during infection has not been investigated. Here, we use the larval zebrafish-Aspergillus infection model and primary human neutrophils to probe how ZfpA affects A. fumigatus pathogenesis and response to antifungal drugs in vivo. ZfpA deletion promotes fungal clearance and attenuates virulence in wild-type hosts and this virulence defect is abrogated in neutrophil-deficient zebrafish. ZfpA deletion also increases susceptibility to human neutrophils ex vivo while overexpression impairs fungal killing. Overexpression of ZfpA confers protection against the antifungal caspofungin by increasing chitin synthesis during hyphal development, while ZfpA deletion reduces cell wall chitin and increases caspofungin susceptibility in neutrophil-deficient zebrafish. These findings suggest a protective role for ZfpA activity in resistance to the innate immune response and antifungal treatment during A. fumigatus infection. Author SummaryAspergillus fumigatus is a common environmental fungus that can infect immunocompromised people and cause a life-threatening disease called invasive aspergillosis. An important step during infection is the development of A. fumigatus filaments known as hyphae. A. fumigatus uses hyphae to acquire nutrients and invade host tissues, leading to tissue damage and disseminated infection. In this study we report that a regulator of gene transcription in A. fumigatus called ZfpA is important for hyphal growth during infection. We find that ZfpA activity protects the fungus from being killed by innate immune cells and decreases the efficacy of antifungal drugs during infection by regulating construction of the cell wall, an important protective layer for fungal pathogens. Our study introduces ZfpA as an important genetic regulator of stress tolerance during infection that protects A. fumigatus from the host immune response and antifungal drugs.

microbiology↗