https://www.cell.com/immunity/pdf/S1074-7613(11)00190-7.pdf

Toll-like Receptors and Their Crosstalk with Other Innate Receptors in Infection and Immunity

Isogenic strain construction and gene mapping in Candida albicans.

Immunity to pathogens critically requires pattern-recognition receptors (PRRs) to trigger intracellular signaling cascades that initiate and direct innate and adaptive immune responses. For fungal infections, these responses are primarily mediated by members of the C-type lectin receptor family. In this Review, we highlight recent advances in the understanding of the roles and mechanisms of these multifunctional receptors, explore how these PRRs orchestrate antifungal immunity and briefly discuss progress in the use of these receptors as targets for antifungal and other vaccines.

/pdf/c-type-lectin-receptors-orchestrate-antifungal-immunity-iq2d5uycjz.pdf

C-type lectin receptors orchestrate antifungal immunity

Myeloid C-type Lectin Receptors in Pathogen Recognition and Host Defense

https://www.cell.com/molecular-cell/pdf/S1097-2765(13)00901-5.pdf

Early Steps in Autophagy Depend on Direct Phosphorylation of Atg9 by the Atg1 Kinase.

Human fungal pathogens like Candida albicans respond to host immune surveillance by rapidly adapting their transcriptional programs. Chromatin assembly factors are involved in the regulation of stress genes by modulating the histone density at these loci. Here, we report a novel role for the chromatin assembly-associated histone acetyltransferase complex NuB4 in regulating oxidative stress resistance, antifungal drug tolerance and virulence in C. albicans. Strikingly, depletion of the NuB4 catalytic subunit, the histone acetyltransferase Hat1, markedly increases resistance to oxidative stress and tolerance to azole antifungals. Hydrogen peroxide resistance in cells lacking Hat1 results from higher induction rates of oxidative stress gene expression, accompanied by reduced histone density as well as subsequent increased RNA polymerase recruitment. Furthermore, hat1Δ/Δ cells, despite showing growth defects in vitro, display reduced susceptibility to reactive oxygen-mediated killing by innate immune cells. Thus, clearance from infected mice is delayed although cells lacking Hat1 are severely compromised in killing the host. Interestingly, increased oxidative stress resistance and azole tolerance are phenocopied by the loss of histone chaperone complexes CAF-1 and HIR, respectively, suggesting a central role for NuB4 in the delivery of histones destined for chromatin assembly via distinct pathways. Remarkably, the oxidative stress phenotype of hat1Δ/Δ cells is a species-specific trait only found in C. albicans and members of the CTG clade. The reduced azole susceptibility appears to be conserved in a wider range of fungi. Thus, our work demonstrates how highly conserved chromatin assembly pathways can acquire new functions in pathogenic fungi during coevolution with the host.

/pdf/the-candida-albicans-histone-acetyltransferase-hat1-3nx234tvj5.pdf

The Candida albicans Histone Acetyltransferase Hat1 Regulates Stress Resistance and Virulence via Distinct Chromatin Assembly Pathways.

Conventional Dendritic Cells Mount a Type I IFN Response against Candida spp. Requiring Novel Phagosomal TLR7-Mediated IFN-Beta Signaling

We developed a protein-proximity assay in yeast based on fusing a histone lysine methyltransferase onto a bait and its substrate onto a prey. Upon binding, the prey is stably methylated and detected by methylation-specific antibodies. We applied this approach to detect varying interaction affinities among proteins in a mitogen-activated protein kinase pathway and to detect short-lived interactions between protein phosphatase 2A and its substrates that have so far escaped direct detection.

/pdf/m-track-detecting-short-lived-protein-protein-interactions-2auqt3i1f5.pdf

M-Track: detecting short-lived protein-protein interactions in vivo

Echinocandin drugs such as caspofungin (CASP), micafungin, and anidulafungin inhibit fungal cell wall biogenesis by blocking Fks1-mediated β-glucan deposition into the cell surface. Candins have become suitable drugs to treat life-threatening diseases caused by several fungal species, including Candida albicans, that are pathogenic for humans. Here, we present the discovery of a novel CASP-induced flocculation phenotype of C. albicans, which formed large cell aggregates in the presence of CASP. High concentrations of sugars such as mannose or glucose inhibit CASP-induced flocculation and improve survival of C. albicans cells exposed to CASP. Notably, exposure of C. albicans cells to CASP triggers Efg1-dependent expression of the adhesin ALS1 and induces invasive growth on agar plates. Indeed, cells lacking either Efg1 or Als1 show strongly diminished CASP-induced flocculation, and the absence of Efg1 leads to marked CASP hypersensitivity. On the other hand, CASP-induced invasive growth is enhanced in cells lacking Efg1. Hence, CASP stress drives an Efg1-dependent response, indicating that this multifunctional transcriptional regulator, which is otherwise involved in filamentation, white-to-opaque switching, and virulence, also modulates cell wall remodeling upon CASP challenge. Taken together, our data suggest that CASP-induced cell wall damage activates Efg1 in parallel with the known cell integrity stress signaling pathway to coordinate cell wall remodeling.

https://journals.asm.org/doi/pdf/10.1128/EC.05187-11

Ingrid E. Frohner

Papers

The Candida albicans Histone Acetyltransferase Hat1 Regulates Stress Resistance and Virulence via Distinct Chromatin Assembly Pathways.

Conventional Dendritic Cells Mount a Type I IFN Response against Candida spp. Requiring Novel Phagosomal TLR7-Mediated IFN-Beta Signaling

M-Track: detecting short-lived protein-protein interactions in vivo

Efg1 Controls Caspofungin-Induced Cell Aggregation of Candida albicans through the Adhesin Als1

Weak Organic Acids Trigger Conformational Changes of the Yeast Transcription Factor War1 in Vivo to Elicit Stress Adaptation