RESUMEN
Immune evasion is critical for fungal virulence. However, how the human opportunistic pathogen Candida glabrata (Cg) accomplishes this is unknown. Here, we present the first genome-wide nucleosome map of the macrophage-internalized Cg consisting of â¼12,000 dynamic and 70,000 total nucleosomes. We demonstrate that CgSnf2 (SWI/SNF chromatin remodeling complex-ATPase subunit)-mediated chromatin reorganization in macrophage-internalized Cg upregulates and downregulates the immunosuppressive seven-gene mannosyltransferase-cluster (CgMT-C) and immunostimulatory cell surface adhesin-encoding EPA1 gene, respectively. Consistently, EPA1 overexpression and CgMT-C deletion elevated IL-1ß (pro-inflammatory cytokine) production and diminished Cg proliferation in macrophages. Further, Cgsnf2Δ had higher Epa1 surface expression, and evoked increased IL-1ß secretion, and was killed in macrophages. Akt-, p38-, NF-κB- or NLRP3 inflammasome-inhibition partially reversed increased IL-1ß secretion in Cgsnf2Δ-infected macrophages. Importantly, macrophages responded to multiple Candida pathogens via NF-κB-dependent IL-1ß production, underscoring NF-κB signaling's role in fungal diseases. Altogether, our findings directly link the nucleosome positioning-based chromatin remodeling to fungal immunomodulatory molecule expression.
RESUMEN
In medical mycology, epigenetic mechanisms are emerging as key regulators of multiple aspects of fungal biology ranging from development, phenotypic and morphological plasticity to antifungal drug resistance. Emerging resistance to the limited therapeutic options for the treatment of invasive fungal infections is a growing concern. Human fungal pathogens develop drug resistance via multiple mechanisms, with recent studies highlighting the role of epigenetic changes involving the acetylation and methylation of histones, remodeling of chromatin and heterochromatin-based gene silencing, in the acquisition of antifungal resistance. A comprehensive understanding of how pathogens acquire drug resistance will aid the development of new antifungal therapies as well as increase the efficacy of current antifungals by blocking common drug-resistance mechanisms. In this article, we describe the epigenetic mechanisms that affect resistance towards widely used systemic antifungal drugs: azoles, echinocandins and polyenes. Additionally, we review the literature on the possible links between DNA mismatch repair, gene silencing and drug-resistance mechanisms.
RESUMEN
Nipah virus (NiV) is an emerging zoonotic pathogen, reported for the recent severe outbreaks of encephalitis and respiratory illness in humans and animals, respectively. Many antiviral drugs have been discovered to inhibit this pathogen, but none of them were that much efficient. To overcome the complications associated with this severe pathogenic virus, we have designed a multi-epitope subunit vaccine using computational immunology strategies. Identification of structural and nonstructural proteins of Nipah virus assisted in the vaccine designing. The selected proteins are known to be involved in the survival of the virus. The antigenic binders (B-cell, HTL, and CTL) from the selected proteins were prognosticated. These antigenic binders will be able to generate the humoral as well as cell-mediated immunity. All the epitopes were united with the help of suitable linkers and with an adjuvant at the N-terminal of the vaccine, for the enhancement of immunogenicity. The physiological characterization, along with antigenicity and allergenicity of the designed vaccine candidates, was estimated. The 3D structure prediction and its validation were performed. The validated vaccine model was then docked and simulated with the TLR-3 receptor to check the stability of the docked complex. This next-generation approach will provide a new vision for the development of a high immunogenic vaccine against the NiV.
