Cryptococcus neoformans is the major causative agent of fungal meningoencephalitis in both immunocompromised and immunocompetent individuals. During infection, this fungus is observed in the yeast ...form and is only occasionally seen as the pseudohyphal or hyphal form (filamentous forms). Early studies suggested that phase transition of
C. neoformans from a multi-cellular filamentous form to the unicellular yeast form might be essential for the survival of this fungus in mammalian hosts. However, how different
Cryptococcus morphotypes exhibit different levels of pathogenicity in hosts are unclear. This review discusses the possible roles of each form inside and outside of mammalian hosts and summarizes recent insights on the life cycle and morphogenesis of this fungus and their impact on the pathogenicity. Application of recently developed advanced tools for
C. neoformans research may assist in understanding the genetic and molecular mechanisms of morphology-associated virulence in this important fungal pathogen. Research on the association between fungal dimorphism and pathogenicity has been traditionally limited to a few related ascomyceteous fungal pathogens. This review is to stimulate discussion and expansion of this type of investigation to a larger group of evolutionary divergent fungi capable of causing systemic fungal infections in humans. Hopefully, a common theme for the convergent evolution of virulence-associated morphology will emerge with future studies.
Cryptococcus neoformans is a major cause of fungal meningoencephalitis in immunocompromised patients. Despite recent advances in the genetics and molecular biology of C. neoformans, and improved ...techniques for molecular epidemiology, aspects of the ecology, population structure, and mode of reproduction of this environmental pathogen remain to be established. Application of recent insights into the life cycle of C. neoformans and its different ways of engaging in sexual reproduction under laboratory conditions has just begun to affect research on the ecology and epidemiology of this human pathogenic fungus. The melding of these disparate disciplines should yield rich dividends in our understanding of the evolution of microbial pathogens, providing insights relevant to diagnosis, treatment, and prevention.
Hypoxia-inducible factor-1 (HIF-1) is a master driver of glucose metabolism in cancer cells. Here, we demonstrate that a HIF-1α anti-sense lncRNA, HIFAL, is essential for maintaining and enhancing ...HIF-1α-mediated transactivation and glycolysis. Mechanistically, HIFAL recruits prolyl hydroxylase 3 (PHD3) to pyruvate kinase 2 (PKM2) to induce its prolyl hydroxylation and introduces the PKM2/PHD3 complex into the nucleus via binding with heterogeneous nuclear ribonucleoprotein F (hnRNPF) to enhance HIF-1α transactivation. Reciprocally, HIF-1α induces HIFAL transcription, which forms a positive feed-forward loop to maintain the transactivation activity of HIF-1α. Clinically, high HIFAL expression is associated with aggressive breast cancer phenotype and poor patient outcome. Furthermore, HIFAL overexpression promotes tumor growth in vivo, while targeting both HIFAL and HIF-1α significantly reduces their effect on cancer growth. Overall, our results indicate a critical regulatory role of HIFAL in HIF-1α-driven transactivation and glycolysis, identifying HIFAL as a therapeutic target for cancer treatment.
To aerobic organisms, low oxygen tension (hypoxia) presents a physiological challenge. To cope with such a challenge, metabolic pathways such as those used in energy production have to be adjusted. ...Many of such metabolic changes are orchestrated by the conserved hypoxia-inducible factors (HIFs) in higher eukaryotes. However, there are no HIF homologs in fungi or protists, and not much is known about conductors that direct hypoxic adaptation in lower eukaryotes. Here, we discovered that the transcription factor Pas2 controls the transcript levels of metabolic genes and consequently rewires metabolism for hypoxia adaptation in the human fungal pathogen
Through genetic, proteomic, and biochemical analyses, we demonstrated that Pas2 directly interacts with another transcription factor, Rds2, in regulating cryptococcal hypoxic adaptation. The Pas2/Rds2 complex represents the key transcription regulator of metabolic flexibility. Its regulation of metabolism rewiring between respiration and fermentation is critical to our understanding of the cryptococcal response to low levels of oxygen.
is the main causative agent of fungal meningitis that is responsible for about 15% of all HIV-related deaths. Although an obligate aerobic fungus,
is well adapted to hypoxia conditions that the fungus could encounter in the host or the environment. The sterol regulatory element binding protein (SREBP) is well known for its role in cryptococcal adaptation to hypoxia through its regulation of ergosterol and lipid biosynthesis. The regulation of metabolic reprogramming under hypoxia, however, is largely unknown. Here, we discovered one key regulator, Pas2, that mediates the metabolic response to hypoxia together with another transcription factor, Rds2, in
The findings help define the molecular mechanisms underpinning hypoxia adaptation in this and other lower eukaryotes.
The existence of morphotype-associated pathogenicity is also observed in some zygomycetes 10 and in dermatophytes 11. ...it appears that pathogens of different major phyla in the fungal kingdom have ...adopted dimorphism as a common pathogenic strategy. ...the znf2δ mutant is more virulent than the wild type, even though both strains are in the yeast form during infection 8, 9. Success by these fungi to colonize the host, establish infections, and disseminate systemically is a combination of the downregulation of filament- or spore-specific molecules and upregulation of the yeast-specific ones. ...investigation of cell-surface molecules specific to each morphological form will provide a new opportunity to comprehend host-fungus interactions.
Cryptococcus neoformans is a ubiquitous human fungal pathogen. This pathogen can undergo morphotype transition between the yeast and the filamentous form and such morphological transition has been ...implicated in virulence for decades. Morphotype transition is typically observed during mating, which is governed by pheromone signaling. Paradoxically, components specific to the pheromone signaling pathways play no or minimal direct roles in virulence. Thus, the link between morphotype transition and virulence and the underlying molecular mechanism remain elusive. Here, we demonstrate that filamentation can occur independent of pheromone signaling and mating, and both mating-dependent and mating-independent morphotype transition require the transcription factor Znf2. High expression of Znf2 is necessary and sufficient to initiate and maintain sex-independent filamentous growth under host-relevant conditions in vitro and during infection. Importantly, ZNF2 overexpression abolishes fungal virulence in murine models of cryptococcosis. Thus, Znf2 bridges the sex-independent morphotype transition and fungal pathogenicity. The impacts of Znf2 on morphological switch and pathogenicity are at least partly mediated through its effects on cell adhesion property. Cfl1, a Znf2 downstream factor, regulates morphogenesis, cell adhesion, biofilm formation, and virulence. Cfl1 is the first adhesin discovered in the phylum Basidiomycota of the Kingdom Fungi. Together with previous findings in other eukaryotic pathogens, our findings support a convergent evolution of plasticity in morphology and its impact on cell adhesion as a critical adaptive trait for pathogenesis.
Resistance development to one chemotherapeutic reagent leads frequently to acquired tolerance to other compounds, limiting the therapeutic options for cancer treatment. Herein, we find that ...overexpression of Rac1 is associated with multi-drug resistance to the neoadjuvant chemotherapy (NAC). Mechanistically, Rac1 activates aldolase A and ERK signaling which up-regulates glycolysis and especially the non-oxidative pentose phosphate pathway (PPP). This leads to increased nucleotides metabolism which protects breast cancer cells from chemotherapeutic-induced DNA damage. To translate this finding, we develop endosomal pH-responsive nanoparticles (NPs) which deliver Rac1-targeting siRNA together with cisplatin and effectively reverses NAC-chemoresistance in PDXs from NAC-resistant breast cancer patients. Altogether, our findings demonstrate that targeting Rac1 is a potential strategy to overcome acquired chemoresistance in breast cancer.
Ordered mesoporous silica materials based on nickel and other elements have been extensively studied because controlling the size of metal nanoparticles is an effective method to tune the superficial ...physicochemical process. Neodymium (Nd)-promoted mesoporous silica xNdMS (x: molar ratio of Nd/Si = 0.01, 0.02, 0.04, 0.06) were prepared through a sol–gel strategy. Nickel-based catalysts with high dispersion by using xNdMS as supports were investigated for methane reforming with carbon dioxide and/or oxygen to produce syngas. xNdMS supports and nickel catalysts were examined by combining textural, structural, local and surface information. The characterization results showed that Nd was successfully incorporated into the mesoporous framework of MS and Nd was beneficial to improve the metal dispersion. All Nd-promoted Ni/MS catalysts were effective for the methane reforming reaction. Ni/0.04NdMS catalyst exhibited the highest initial catalytic activity during 12 h time on stream, which was attributed to its high metal dispersion, more basic sites and the strengthened nickel-support interaction. The readily deactivation and poorest catalytic activity of Ni/MS catalyst were due to the serious oxidation of metallic nickel under reaction medium.
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•Nd-containing mesoporous silica support xNdMS were prepared by sol–gel method.•Positive effect of Nd on structural properties of Ni/xNdMS was investigated.•Ni/xNdMS catalysts exhibited high catalytic performance in OCRM and DRM reactions.•The oxidation state and the nickel particle size affected the activity.
causes cryptococcal meningoencephalitis, a disease that kills more than 180,000 people annually. Contributing to its success as a fungal pathogen is its cell wall surrounded by a capsule. When the ...cryptococcal cell wall is compromised, exposed pathogen-associated molecular pattern molecules (PAMPs) could trigger host recognition and initiate attack against this fungus. Thus, cell wall composition and structure are tightly regulated. The cryptococcal cell wall is unusual in that chitosan, the acetylated form of chitin, is predominant over chitin and is essential for virulence. Recently, it was shown that acidic pH weakens the cell wall and increases exposure of PAMPs partly due to decreased chitosan levels. However, the molecular mechanism responsible for the cell wall remodeling in acidic pH is unknown. In this study, by screening for genes involved in cryptococcal tolerance to high levels of CO
, we serendipitously discovered that the aspartyl peptidase May1 contributes to cryptococcal sensitivity to high levels of CO
due to acidification of unbuffered media. Overexpression of
increases the cryptococcal cell size and elevates PAMP exposure, causing a hyper-inflammatory response in the host while
deletion does the opposite. We discovered that May1 weakens the cell wall and reduces the chitosan level, partly due to its involvement in the degradation of Chs3, the sole chitin synthase that supplies chitin to be converted to chitosan. Consistently, overexpression of
largely rescues the phenotype of
in acidic media. Collectively, we demonstrate that May1 remodels the cryptococcal cell wall in acidic pH by reducing chitosan levels through its influence on Chs3.
The fungal cell wall is a dynamic structure, monitoring and responding to internal and external stimuli. It provides a formidable armor to the fungus. However, in a weakened state, the cell wall also triggers host immune attack when PAMPs, including glucan, chitin, and mannoproteins, are exposed. In this work, we found that the aspartyl peptidase May1 impairs the cell wall of
and increases the exposure of PAMPs in the acidic environment by reducing the chitosan level. Under acidic conditions, May1 is involved in the degradation of the chitin synthase Chs3, which supplies chitin to be deacetylated to chitosan. Consistently, the severe deficiency of chitosan in acidic pH can be rescued by overexpressing
. These findings improve our understanding of cell wall remodeling and reveal a potential target to compromise the cell wall integrity in this important fungal pathogen.
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