Review

Authors: Eileen K Maziarz, John R Perfect

Cryptococcosis is an invasive mycosis caused by pathogenic encapsulated yeasts in the genus Cryptococcus. Cryptococcus gained prominence as a pathogen capable of widespread disease outbreaks in vulnerable populations. We have gained insight into the pathobiology of Cryptococcus, including the yeast' s capacity to adapt to environmental pressures, exploit new geographic environments, and cause disease in both immunocompromised and apparently immunocompetent hosts. Inexpensive, point-of-care testing makes diagnosis more feasible than ever. The associated worldwide burden and mortality remains unacceptably high. Novel screening strategies and preemptive therapy offer promise at making a sustained and much needed impact on this sugar-coated opportunistic mycosis.

Topics: Antifungal Agents; Cryptococcosis; Cryptococcus; Humans

PubMed: 26897067
DOI: 10.1016/j.idc.2015.10.006

Review

Authors: Youbao Zhao, Xiaorong Lin

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

Review

Authors: Yong-Sun Bahn, Sheng Sun, Joseph Heitman...

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

Review

Authors: Kali R Iyer, Nicole M Revie, Ci Fu...

Cryptococcus spp., in particular Cryptococcus neoformans and Cryptococcus gattii, have an enormous impact on human health worldwide. The global burden of cryptococcal meningitis is almost a quarter of a million cases and 181,000 deaths annually, with mortality rates of 100% if infections remain untreated. Despite these alarming statistics, treatment options for cryptococcosis remain limited, with only three major classes of drugs approved for clinical use. Exacerbating the public health burden is the fact that the only new class of antifungal drugs developed in decades, the echinocandins, displays negligible antifungal activity against Cryptococcus spp., and the efficacy of the remaining therapeutics is hampered by host toxicity and pathogen resistance. Here, we describe the current arsenal of antifungal agents and the treatment strategies employed to manage cryptococcal disease. We further elaborate on the recent advances in our understanding of the intrinsic and adaptive resistance mechanisms that are utilized by Cryptococcus spp. to evade therapeutic treatments. Finally, we review potential therapeutic strategies, including combination therapy, the targeting of virulence traits, impairing stress response pathways and modulating host immunity, to effectively treat infections caused by Cryptococcus spp. Overall, understanding of the mechanisms that regulate anti-cryptococcal drug resistance, coupled with advances in genomics technologies and high-throughput screening methodologies, will catalyse innovation and accelerate antifungal drug discovery.

Topics: Antifungal Agents; Cell Wall; Cryptococcosis; Cryptococcus; Drug Resistance, Fungal; Echinocandins; Fungal Capsules; Fungal Polysaccharides; Virulence Factors

PubMed: 33558691
DOI: 10.1038/s41579-021-00511-0

Review

Authors: Robin C May, Neil R H Stone, Darin L Wiesner...

Cryptococcosis is a globally distributed invasive fungal infection that is caused by species within the genus Cryptococcus which presents substantial therapeutic challenges. Although natural human-to-human transmission has never been observed, recent work has identified multiple virulence mechanisms that enable cryptococci to infect, disseminate within and ultimately kill their human host. In this Review, we describe these recent discoveries that illustrate the intricacy of host-pathogen interactions and reveal new details about the host immune responses that either help to protect against disease or increase host susceptibility. In addition, we discuss how this improved understanding of both the host and the pathogen informs potential new avenues for therapeutic development.

Topics: Antifungal Agents; Cryptococcosis; Cryptococcus; Host-Pathogen Interactions; Humans; Virulence

PubMed: 26685750
DOI: 10.1038/nrmicro.2015.6

Review

Authors: Guilhem Janbon

In Cryptococcus neoformans, nearly all genes are interrupted by small introns. In recent years, genome annotation and genetic analysis have illuminated the major roles these introns play in the biology of this pathogenic yeast. Introns are necessary for gene expression and alternative splicing can regulate gene expression in response to environmental cues. In addition, recent studies have revealed that C. neoformans introns help to prevent transposon dissemination and protect genome integrity. These characteristics of cryptococcal introns are probably not unique to Cryptococcus, and this yeast likely can be considered as a model for intron-related studies in fungi.

Topics: Cryptococcus; DNA, Fungal; Genome, Fungal; Introns; Sequence Analysis, DNA

PubMed: 29513783
DOI: 10.1590/0074-02760170519

Authors: Elaine Cristina Francisco, Auke W de Jong, Ferry Hagen...

Topics: Cryptococcosis; Cryptococcus gattii; Cryptococcus neoformans; Humans

PubMed: 34224075
DOI: 10.1007/s11046-021-00577-7

Review

Authors: Sharon C-A Chen, Wieland Meyer, Tania C Sorrell...

Understanding of the taxonomy and phylogeny of Cryptococcus gattii has been advanced by modern molecular techniques. C. gattii probably diverged from Cryptococcus neoformans between 16 million and 160 million years ago, depending on the dating methods applied, and maintains diversity by recombining in nature. South America is the likely source of the virulent C. gattii VGII molecular types that have emerged in North America. C. gattii shares major virulence determinants with C. neoformans, although genomic and transcriptomic studies revealed that despite similar genomes, the VGIIa and VGIIb subtypes employ very different transcriptional circuits and manifest differences in virulence phenotypes. Preliminary evidence suggests that C. gattii VGII causes severe lung disease and death without dissemination, whereas C. neoformans disseminates readily to the central nervous system (CNS) and causes death from meningoencephalitis. Overall, currently available data indicate that the C. gattii VGI, VGII, and VGIII molecular types more commonly affect nonimmunocompromised hosts, in contrast to VGIV. New, rapid, cheap diagnostic tests and imaging modalities are assisting early diagnosis and enabling better outcomes of cerebral cryptococcosis. Complications of CNS infection include increased intracranial pressure, severe neurological sequelae, and development of immune reconstitution syndrome, although the mortality rate is low. C. gattii VGII isolates may exhibit higher fluconazole MICs than other genotypes. Optimal therapeutic regimens are yet to be determined; in most cases, initial therapy with amphotericin B and 5-flucytosine is recommended.

Topics: Animals; Cryptococcosis; Cryptococcus gattii; Humans

PubMed: 25278580
DOI: 10.1128/CMR.00126-13

Review

Authors: Kevin C Roach, Marianna Feretzaki, Sheng Sun...

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

Authors: R Vilgalys, M Hester

Detailed restriction analyses of many samples often require substantial amounts of time and effort for DNA extraction, restriction digests, Southern blotting, and hybridization. We describe a novel approach that uses the polymerase chain reaction (PCR) for rapid simplified restriction typing and mapping of DNA from many different isolates. DNA fragments up to 2 kilobase pairs in length were efficiently amplified from crude DNA samples of several pathogenic Cryptococcus species, including C. neoformans, C. albidus, C. laurentii, and C. uniguttulatus. Digestion and electrophoresis of the PCR products by using frequent-cutting restriction enzymes produced complex restriction phenotypes (fingerprints) that were often unique for each strain or species. We used the PCR to amplify and analyze restriction pattern variation within three major portions of the ribosomal DNA (rDNA) repeats from these fungi. Detailed mapping of many restriction sites within the rDNA locus was determined by fingerprint analysis of progressively larger PCR fragments sharing a common primer site at one end. As judged by PCR fingerprints, the rDNA of 19 C. neoformans isolates showed no variation for four restriction enzymes that we surveyed. Other Cryptococcus spp. showed varying levels of restriction pattern variation within their rDNAs and were shown to be genetically distinct from C. neoformans. The PCR primers used in this study have also been successfully applied for amplification of rDNAs from other pathogenic and nonpathogenic fungi, including Candida spp., and ought to have wide applicability for clinical detection and other studies.

Topics: Base Sequence; Cryptococcus; DNA, Fungal; DNA, Ribosomal; Molecular Sequence Data; Oligonucleotide Probes; Phylogeny; Polymerase Chain Reaction; Repetitive Sequences, Nucleic Acid; Restriction Mapping

PubMed: 2376561
DOI: 10.1128/jb.172.8.4238-4246.1990