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Infection, Genetics and Evolution :... Apr 2021Cryptococcus neoformans is a dimorphic fungus that causes lethal meningoencephalitis mainly in immunocompromised individuals. Different morphotypes enable this... (Review)
Review
Cryptococcus neoformans is a dimorphic fungus that causes lethal meningoencephalitis mainly in immunocompromised individuals. Different morphotypes enable this environmental fungus and opportunistic pathogen to adapt to different natural niches and exhibit different levels of pathogenicity in various hosts. It is well-recognized that C. neoformans undergoes bisexual or unisexual reproduction in vitro to generate genotypic, morphotypic, and phenotypic diversity, which augments its ability for adaptation. However, if and how sexual reproduction and the meiotic machinery exert any direct impact on the infection process is unclear. This review summarizes recent discoveries on the regulation of cryptococcal life cycle and morphogenesis, and how they impact cryptococcal pathogenicity. The potential role of the meiotic machinery on ploidy regulation during cryptococcal infection is also discussed. This review aims to stimulate further investigation on links between fungal morphogenesis, sexual reproduction, and virulence.
Topics: Cryptococcus neoformans; Humans; Morphogenesis; Reproduction; Virulence
PubMed: 33497839
DOI: 10.1016/j.meegid.2021.104731 -
Fungal Genetics and Biology : FG & B May 2015The human fungal pathogen Cryptococcus neoformans is able to rapidly and effectively adapt to varying conditions, favoring its survival in the environment and in the... (Review)
Review
The human fungal pathogen Cryptococcus neoformans is able to rapidly and effectively adapt to varying conditions, favoring its survival in the environment and in the infected host. Many microbial phenotypes have been specifically correlated with virulence in this opportunistic pathogen, such as capsule production, melanin formation, and the secretion of various proteins. Additionally, cellular features such as the cell wall and morphogenesis play important roles in the interaction of this fungus with host immune recognition and response pathways. Survival in the face of host stress also requires maintaining RNA/DNA integrity. Additionally, aging and senescence of the fungal cells determines resistance to host-derived stresses. New mechanisms regulating the expression of these virulence-associated phenotypes have been recently explored. Importantly, human clinical studies are now confirming the roles of specific microbial factors in human infections.
Topics: Cryptococcosis; Cryptococcus neoformans; Host-Pathogen Interactions; Humans; Virulence; Virulence Factors
PubMed: 25256589
DOI: 10.1016/j.fgb.2014.09.004 -
Microbiology (Reading, England) Sep 2020is a lethal fungus disguised in a polysaccharide coat. It can remain dormant in the host for decades prior to reactivation, causing systemic cryptococcosis in humans... (Review)
Review
is a lethal fungus disguised in a polysaccharide coat. It can remain dormant in the host for decades prior to reactivation, causing systemic cryptococcosis in humans and other mammals. deploys a multitude of traits to adapt to and survive within the host, including immunosuppression, an ability to replicate intra- and extra-cellularly in phagocytes, changes in morphology and ploidy, a predilection to infect the CNS, and the capacity to utilize neurotransmitters and unique carbon sources available in the brain. These pathogenic strategies displayed by this fungus might have evolved through its interactions with microbial predators in the environment.
Topics: Adaptation, Physiological; Animals; Cryptococcosis; Cryptococcus neoformans; Genome, Fungal; Humans; Phylogeny; Virulence
PubMed: 32956032
DOI: 10.1099/mic.0.000973 -
Advances in Genetics 2014Sexual reproduction is ubiquitous throughout the eukaryotic kingdom, but the capacity of pathogenic fungi to undergo sexual reproduction has been a matter of intense... (Review)
Review
Sexual reproduction is ubiquitous throughout the eukaryotic kingdom, but the capacity of pathogenic fungi to undergo sexual reproduction has been a matter of intense debate. Pathogenic fungi maintained a complement of conserved meiotic genes but the populations appeared to be clonally derived. This debate was resolved first with the discovery of an extant sexual cycle and then unisexual reproduction. Unisexual reproduction is a distinct form of homothallism that dispenses with the requirement for an opposite mating type. Pathogenic and nonpathogenic fungi previously thought to be asexual are able to undergo robust unisexual reproduction. We review here recent advances in our understanding of the genetic and molecular basis of unisexual reproduction throughout fungi and the impact of unisex on the ecology and genomic evolution of fungal species.
Topics: Cryptococcus neoformans; Fungi; Genes, Mating Type, Fungal; Reproduction, Asexual
PubMed: 24880737
DOI: 10.1016/B978-0-12-800271-1.00005-6 -
Virulence Dec 2019The capsule of is its dominant virulence factor and plays a key role in the biology of this fungus. In this essay, we focus on the capsule as a cellular structure and... (Review)
Review
The capsule of is its dominant virulence factor and plays a key role in the biology of this fungus. In this essay, we focus on the capsule as a cellular structure and note the limitations inherent in the current methodologies available for its study. Given that no single method can provide the structure of the capsule, our notions of what is the cryptococcal capsule must be arrived at by synthesizing information gathered from very different methodological approaches including microscopy, polysaccharide chemistry and physical chemistry of macromolecules. The emerging picture is one of a carefully regulated dynamic structure that is constantly rearranged as a response to environmental stimulation and cellular replication. In the environment, the capsule protects the fungus against desiccation and phagocytic predators. In animal hosts the capsule functions in both offensive and defensive modes, such that it interferes with immune responses while providing the fungal cell with a defensive shield that is both antiphagocytic and capable of absorbing microbicidal oxidative bursts from phagocytic cells. Finally, we delineate a set of unsolved problems in the cryptococcal capsule field that could provide fertile ground for future investigations.
Topics: Cryptococcosis; Cryptococcus neoformans; Fungal Capsules; Humans; Phagocytosis; Polysaccharides; Virulence; Virulence Factors
PubMed: 29436899
DOI: 10.1080/21505594.2018.1431087 -
Current Opinion in Microbiology Dec 2017Upon Cryptococcus neoformans infection of the host lung, the fungus enters a nutrient poor environment and must adapt to a variety of host-specific stress conditions... (Review)
Review
Upon Cryptococcus neoformans infection of the host lung, the fungus enters a nutrient poor environment and must adapt to a variety of host-specific stress conditions (temperature, nutrient limitation, pH, CO). Fungal spores enter this milieu with limited nutritional reserves, germinate, and begin proliferating by budding as yeast. Although relatively little is known about the initial stages of infection, recent work has characterized changes that occur upon germination. This program and subsequent yeast-phase proliferation progress in a dynamic environment as host nutrient immunity responds to the infection via toxic accumulation or sequestration of essential micronutrients and innate immune cells are recruited to the site of infection. Adaptation to the host environment and evasion of the immune response through pathogenicity factor expression allows proliferation and dissemination to multiple sites throughout the body, including, most significantly for human disease, the central nervous system. Here we will discuss recent insights into mechanisms underlying C. neoformans interactions with the host during infection.
Topics: Animals; Cryptococcosis; Cryptococcus neoformans; Fungal Proteins; Gene Expression Regulation, Fungal; Host-Pathogen Interactions; Humans
PubMed: 29154043
DOI: 10.1016/j.mib.2017.10.012 -
Cells Dec 2022The phenotypic plasticity of Cryptococcus neoformans is widely studied and demonstrated in vitro, but its influence on pathogenicity remains unclear. In this study, we...
The phenotypic plasticity of Cryptococcus neoformans is widely studied and demonstrated in vitro, but its influence on pathogenicity remains unclear. In this study, we investigated the dynamics of cryptococcal cell and transcriptional remodeling during pulmonary infection in a murine model. We showed that in Cryptococcus neoformans, cell size reduction (cell body ≤ 3 µm) is important for initial adaptation during infection. This change was associated with reproductive fitness and tissue invasion. Subsequently, the fungus develops mechanisms aimed at resistance to the host’s immune response, which is determinant for virulence. We investigated the transcriptional changes involved in this cellular remodeling and found an upregulation of transcripts related to ribosome biogenesis at the beginning (6 h) of infection and a later (10 days) upregulation of transcripts involved in the inositol pathway, energy production, and the proteasome. Consistent with a role for the proteasome, we found that its inhibition delayed cell remodeling during infection with the H99 strain. Altogether, these results further our understanding of the infection biology of C. neoformans and provide perspectives to support therapeutic and diagnostic targets for cryptococcosis.
Topics: Mice; Animals; Cryptococcus neoformans; Proteasome Endopeptidase Complex; Disease Models, Animal; Cryptococcosis; Virulence
PubMed: 36497155
DOI: 10.3390/cells11233896 -
Eukaryotic Cell Dec 2015Enzymes play key roles in fungal pathogenesis. Manipulation of enzyme expression or activity can significantly alter the infection process, and enzyme expression... (Review)
Review
Enzymes play key roles in fungal pathogenesis. Manipulation of enzyme expression or activity can significantly alter the infection process, and enzyme expression profiles can be a hallmark of disease. Hence, enzymes are worthy targets for better understanding pathogenesis and identifying new options for combatting fungal infections. Advances in genomics, proteomics, transcriptomics, and mass spectrometry have enabled the identification and characterization of new fungal enzymes. This review focuses on recent developments in the virulence-associated enzymes from Cryptococcus neoformans. The enzymatic suite of C. neoformans has evolved for environmental survival, but several of these enzymes play a dual role in colonizing the mammalian host. We also discuss new therapeutic and diagnostic strategies that could be based on the underlying enzymology.
Topics: Animals; Cryptococcus neoformans; Drug Design; Drug Resistance, Fungal; Humans; Melanins; Polysaccharides; Virulence
PubMed: 26453651
DOI: 10.1128/EC.00103-15 -
Clinical Microbiology Reviews Jul 2012The human fungal pathogen Cryptococcus neoformans is characterized by its ability to induce a distinct polysaccharide capsule in response to a number of host-specific... (Review)
Review
The human fungal pathogen Cryptococcus neoformans is characterized by its ability to induce a distinct polysaccharide capsule in response to a number of host-specific environmental stimuli. The induction of capsule is a complex biological process encompassing regulation at multiple steps, including the biosynthesis, transport, and maintenance of the polysaccharide at the cell surface. By precisely regulating the composition of its cell surface and secreted polysaccharides, C. neoformans has developed intricate ways to establish chronic infection and dormancy in the human host. The plasticity of the capsule structure in response to various host conditions also underscores the complex relationship between host and parasite. Much of this precise regulation of capsule is achieved through the transcriptional responses of multiple conserved signaling pathways that have been coopted to regulate this C. neoformans-specific virulence-associated phenotype. This review focuses on specific host stimuli that trigger the activation of the signal transduction cascades and on the downstream transcriptional responses that are required for robust encapsulation around the cell.
Topics: Adaptation, Physiological; Cell Wall; Chitin; Chromatin Assembly and Disassembly; Cryptococcosis; Cryptococcus neoformans; Fungal Proteins; Gene Expression Regulation, Fungal; Genes, Fungal; Host-Parasite Interactions; Humans; Polysaccharides; Signal Transduction; Transcription Factors; Transcription, Genetic
PubMed: 22763631
DOI: 10.1128/CMR.00001-12 -
Molecular Microbiology Nov 2020Fungal infections are a global concern and the evolution of intrinsic resistance to current antifungals presents an alarming problem. For Cryptococcus neoformans, a... (Review)
Review
Fungal infections are a global concern and the evolution of intrinsic resistance to current antifungals presents an alarming problem. For Cryptococcus neoformans, a human fungal pathogen of primarily immunocompromised individuals, resistance toward treatment strategies demands alternative approaches. Given the prevalence of virulence factor production during cryptococcal infection, an emerging and important field of research encompasses the development of novel antivirulence therapies proposed to improve host immune responses and promote fungal clearance. To accomplish this task, information regarding the presence and role of virulence factors, the mechanisms of action within the host, and the ability to influence fungal susceptibility to antifungals is pertinent. Research into mechanisms of antifungal resistance for C. neoformans is limited but extrapolation from successful studies in other fungal species can improve our understanding of mechanisms employed by C. neoformans and suggest targeted strategies to enhance our ability to combat the pathogen. In this Review, we highlight antifungal therapy options against Cryptococcus, explore current knowledge of underlying mechanisms promoting resistance, and present new opportunities for novel and effective strategies to overcome fungal infections and reduce, or possibly even reverse, the effects of resistance evolution.
Topics: Antifungal Agents; Cryptococcosis; Cryptococcus neoformans; Drug Resistance, Fungal; Humans; Virulence; Virulence Factors
PubMed: 32697029
DOI: 10.1111/mmi.14565