Project description:Candida auris has been globally recognized as a multidrug-resistant human fungal pathogen that contributes for the worldwide occurrence of nosocomial outbreaks. It has been reported that C. auris was able to avoid neutrophil attack, suggestive of an impaired innate immune response. Whether C. auris evades the innate immune recognition of BMDM (bone marrow derived macrophage) remains poorly understood, and as for well-known Candida species -C. albicans, it can trigger immune response. To determine whether occurs difference between immune response stimulated by C. auris or C. albicans, we performed mRNA-seq of BMDM stimulated by C. auris or C. albicans.
Project description:Candida auris occupies similar niches in various infections as Pseudomonas aeruginosa; however, the details of their interspecies communication remain largely unknown. To gain deeper insights into this bacterial–fungal relationship, phenotypic and transcriptomic analyses were conducted in the presence of the primary P. aeruginosa quorum-sensing molecule, 3-oxo-C12-homoserine lactone (HSL), against C. auris, with the results compared to those of C. albicans. We demonstrated a significant HSL-induced reduction in adhesion of C. auris cells at 100- and 200-μM concentrations. Furthermore, HSL exposure reduced intracellular iron and zinc levels and modulated C. auris metabolism toward beta-oxidation, which may be associated with the observed reduction in in vivo virulence at lower HSL concentrations compared with C. albicans. RNA-sequencing transcriptome analysis revealed 67 and 306 upregulated genes, as well as 111 and 168 downregulated genes, in response to 100 and 200 μM HSL, respectively. We identified 45 overlapping upregulated and 25 overlapping downregulated genes between the two HSL concentrations. Our findings indicate that HSL-induced effects are not specific to C. albicans; additionally, several characteristics are present in C. auris but not in C. albicans following HSL exposure. Similar to other Candida-derived C12 compounds (e.g., farnesol), HSL reduces several C. auris survival strategies, which may significantly influence the nature of P. aeruginosa–C. auris co-habitation.
Project description:Candida auris is amongst the most important emerging fungal pathogens, yet mechanistic insights in its immune recognition and control are lacking. Here, we integrate transcriptional and functional immune cell profiling to uncover innate anti-C. auris defense mechanisms. C. auris induces a specific transcriptome in human mononuclear cells, a stronger cytokine response compared to C. albicans, but a lower macrophage lysis capacity. C. auris-induced innate immune activation is mediated through recognition of C-type lectin receptors, mainly elicited by structurally unique C. auris mannoproteins. In in-vivo experimental models of disseminated candidiasis, C. auris was less virulent than C. albicans. Collectively, these results demonstrate that C. auris is a strong inducer of innate host defense and identify possible targets for adjuvant immunotherapy.
Project description:Candida auris (C. auris) is an emerging fungal pathogen with a remarkable ability to persist on human skin, but how structural skin cells respond to colonization is unclear. We used ex vivo human skin models, primary keratinocytes and fibroblasts to characterize epithelial and stromal responses to C. auris compared with Candida albicans (C. albicans). C. auris formed biofilms and induced a wound-model-dependent pattern of cytokine secretion dominated by IL-1β and IL-6, yet caused minimal epithelial damage and modest reductions in leukocyte viability. RNA sequencing revealed complementary but cell-type-specific responses. Keratinocytes and fibroblasts both amplified a pro-inflammatory IL-6/CXCL8 response, while keratinocytes additionally upregulated antimicrobial genes such as RNASE7, TSLP, DEFB103A, and the neutrophil-recruiting chemokines CXCL2 and CXCL3. Fibroblasts further induced CCL28, supporting T-cell recruitment, alongside transcriptional programs associated with tissue remodeling. Recombinant RNase 7 and short form TSLP directly inhibited C. auris growth in vitro in a dose-dependent manner. Together, these findings identify keratinocytes as epithelial sentinels that integrate inflammatory and antimicrobial defenses against skin-tropic C. auris and suggest that fibroblast-driven cytokine amplification and especially antimicrobial peptides from within the skin barrier may provide therapeutic targets to limit C. auris skin colonization.
Project description:Candidozyma auris, previously known as Candida auris, is a recently found pathogenic yeast that causes systemic infections, showing a high mortality rate. Moreover, this species is highly resistant to the commonly used antifungal drugs and some of the strains are multiresistant. This fungus is also able to cause outbreaks in hospital settings. All of this has cause an alarm in the health care system. Therefore, finding alternative treatments for C. auris is critical. In this sense, our research group developed a monoclonal antibody (Ca37) against Candida albicans alcohol dehydrogenase enzyme (Adh) that successfully reduced the growth of the fungus in vitro and also showed a protective effect in vivo. Due to the high homology between both fungal alcohol dehydrogenases, we wanted to test the effect of Ca37 over C. auris. In order to do this, first we assessed if the monoclonal antibody also recognized C. auris Adh by sequencing the spots detected by two dimensional western blot when using the monoclonal antibody as first antibody. Two spots were detected in this western blot. The sequencing showed a mixture of proteins, but in both cases, Adh was one of the identified proteins.
Project description:Candida auris is a recently found pathogenic yeast that causes systemic infections, showing a high mortality rate. The delay on making a correct diagnosis of C. auris is a current problem in the healthcare system setting. As immunoproteomics studies are important to identify immunoreactive proteins for new diagnostic strategies, in this study immunocompetent murine systemic infections caused by non-aggregative and aggregative phenotypes of C. auris, and by Candida albicans and Candida haemulonii were carried out, and the obtained sera were used to study their immunoreactivity against C. auris proteins. The aim was to identify the most immunoreactive antigens of this yeast. Thirteen spots were recognized by sera from mice infected with both C. auris phenotypes and analyzed by mass spectrometry. They corresponded to enolase, phosphoglycerate kinase, glyceraldehyde 3-phosphate dehydrogenase and phosphoglycerate mutase. These four proteins seem to be also recognized by sera obtained from human patients with disseminated C. auris infection, but not by sera obtained from mice infected with other fungi such as C. albicans or Aspergillus fumigatus. In conclusion, this study showed that the identified proteins could be potential candidates to be studied as new diagnostic or even therapeutic targets for C. auris.
Project description:we performed mitochondrial proteomic analysis on multiple Candida species (C. albicans, C. glabrata, C. krusei and Candida auris) and analyzed the differentially expressed mitochondrial proteins (DEMPs) between azole-sensitive and azole-resistant Candida species.
Project description:Candida auris is an emerging multidrug-resistant fungus that has sparked public health alarm. However, the mechanisms supporting its persistence in skin, a major risk factor for deadly outbreaks, remain unclear. Here, we compared skin colonization by C. auris with that of the related pathobiont C. albicans, illuminating fungal–immune interactions. C. auris exhibited enhanced skin persistence, tropism to hair follicles, and direct binding to hair. Whereas C. albicans triggered a type 3/17-skewed sterilizing antifungal immune response, C. auris triggered a type 1 IFNg-driven response directed toward hair follicles. IFNg unexpectedly enhanced C. auris colonization through direct signaling to keratinocytes, impairing barrier integrity and repressing antifungal defense programs. Genetic and biochemical approaches demonstrated that, in response to skin-associated cues, C. auris upregulates the exposure of cell wall chitin, which is sufficient to trigger type 1 immunity and benefit the pathobiont.
Project description:Candida auris is an emerging multidrug-resistant fungus that has sparked public health alarm. However, the mechanisms supporting its persistence in skin, a major risk factor for deadly outbreaks, remain unclear. Here, we compared skin colonization by C. auris with that of the related pathobiont C. albicans, illuminating fungal–immune interactions. C. auris exhibited enhanced skin persistence, tropism to hair follicles, and direct binding to hair. Whereas C. albicans triggered a type 3/17-skewed sterilizing antifungal immune response, C. auris triggered a type 1 IFNg-driven response directed toward hair follicles. IFNg unexpectedly enhanced C. auris colonization through direct signaling to keratinocytes, impairing barrier integrity and repressing antifungal defense programs. Genetic and biochemical approaches demonstrated that, in response to skin-associated cues, C. auris upregulates the exposure of cell wall chitin, which is sufficient to trigger type 1 immunity and benefit the pathobiont.
Project description:Candida auris is an emerging multidrug-resistant fungus that has sparked public health alarm. However, the mechanisms supporting its persistence in skin, a major risk factor for deadly outbreaks, remain unclear. Here, we compared skin colonization by C. auris with that of the related pathobiont C. albicans, illuminating fungal–immune interactions. C. auris exhibited enhanced skin persistence, tropism to hair follicles, and direct binding to hair. Whereas C. albicans triggered a type 3/17-skewed sterilizing antifungal immune response, C. auris triggered a type 1 IFNg-driven response directed toward hair follicles. IFNg unexpectedly enhanced C. auris colonization through direct signaling to keratinocytes, impairing barrier integrity and repressing antifungal defense programs. Genetic and biochemical approaches demonstrated that, in response to skin-associated cues, C. auris upregulates the exposure of cell wall chitin, which is sufficient to trigger type 1 immunity and benefit the pathobiont.