Elements of dissemination in cryptococcosis.

As healthcare improves and our ability to support patients with compromised immune systems increases, such patients become more vulnerable to microbes in the environment. These include fungal pathogens such as , the primary cause of fungal meningitis and a top priority pathogen on the World Health Organization fungal pathogen list. Like many other environmental pathogens, must adapt to and thrive in diverse environments in order to cause disease: (i) the environmental niche, (ii) the lungs following inhalation of infectious particles, (iii) the bloodstream and/or lymphatic system during dissemination, and (iv) the central nervous system (CNS), where it causes a deadly cryptococcal meningoencephalitis.

Distinct pathways of adaptive evolution in Cryptococcus neoformans reveal a mutation in adenylyl cyclase with trade-offs for pathogenicity.

Pathogenic fungi populate a wide range of environments and infect a diversity of host species. Despite this substantial biological flexibility, the impact of interactions between fungi and their hosts on the evolution of pathogenicity remains unclear. We studied how repeated interactions between the fungus Cryptococcus neoformans and relevant environmental and mammalian host cells-amoeba and mouse macrophages-shape the evolution of this model fungal pathogen.

A dissemination-prone morphotype enhances extrapulmonary organ entry by Cryptococcus neoformans.

Environmental pathogens move from ecological niches to mammalian hosts, requiring adaptation to dramatically different environments. Microbes that disseminate farther, including the fungal meningitis pathogen Cryptococcus neoformans, require additional adaptation to diverse tissues. We demonstrate that the formation of a small C.

Biology and function of exo-polysaccharides from human fungal pathogens.

Purpose Of Review: Environmental fungi such as and must survive many different and changing environments as they transition from their environmental niches to human lungs and other organs. Fungi alter their cell surfaces and secreted macromolecules to respond to and manipulate their surroundings.

Recent Findings: This review focuses on exo-polysaccharides, chains of sugars that transported out of the cell and spread to the local environment.

How Environmental Fungi Cause a Range of Clinical Outcomes in Susceptible Hosts.

Environmental fungi are globally ubiquitous and human exposure is near universal. However, relatively few fungal species are capable of infecting humans, and among fungi, few exposure events lead to severe systemic infections. Systemic infections have mortality rates of up to 90%, cost the US healthcare system $7.

High-throughput Identification of Synergistic Drug Combinations by the Overlap2 Method.

Although antimicrobial drugs have dramatically increased the lifespan and quality of life in the 20 century, antimicrobial resistance threatens our entire society's ability to treat systemic infections. In the United States alone, antibiotic-resistant infections kill approximately 23,000 people a year and cost around 20 billion USD in additional healthcare. One approach to combat antimicrobial resistance is combination therapy, which is particularly useful in the critical early stage of infection, before the infecting organism and its drug resistance profile have been identified.

Mechanisms of Pulmonary Escape and Dissemination by Cryptococcus neoformans.

is a common environmental saprophyte and human fungal pathogen that primarily causes disease in immunocompromised individuals. Similar to many environmentally acquired human fungal pathogens, initiates infection in the lungs. However, the main driver of mortality is invasive cryptococcosis leading to fungal meningitis.

Regulated Release of Cryptococcal Polysaccharide Drives Virulence and Suppresses Immune Cell Infiltration into the Central Nervous System.

is a common environmental yeast and opportunistic pathogen responsible for 15% of AIDS-related deaths worldwide. Mortality primarily results from meningoencephalitis, which occurs when fungal cells disseminate to the brain from the initial pulmonary infection site. A key virulence trait is the polysaccharide capsule.

Phytotherapy as an alternative to conventional antimicrobials: combating microbial resistance.

In the modern antimicrobial era, the rapid spread of resistance to antibiotics and introduction of new and mutating viruses is a global concern. Combating antimicrobial resistant microbes (AMR) requires coordinated international efforts that incorporate new conventional antibiotic development as well as development of alternative drugs with antimicrobial activity, management of existing antimicrobials, and rapid detection of AMR pathogens. Areas covered: This manuscript discusses some conventional strategies to control microbial resistance.

High-throughput identification and rational design of synergistic small-molecule pairs for combating and bypassing antibiotic resistance.

Antibiotic-resistant infections kill approximately 23,000 people and cost $20,000,000,000 each year in the United States alone despite the widespread use of small-molecule antimicrobial combination therapy. Antibiotic combinations typically have an additive effect: the efficacy of the combination matches the sum of the efficacies of each antibiotic when used alone. Small molecules can also act synergistically when the efficacy of the combination is greater than the additive efficacy.

Unraveling the biology of a fungal meningitis pathogen using chemical genetics.

The fungal meningitis pathogen Cryptococcus neoformans is a central driver of mortality in HIV/AIDS. We report a genome-scale chemical genetic data map for this pathogen that quantifies the impact of 439 small-molecule challenges on 1,448 gene knockouts. We identified chemical phenotypes for 83% of mutants screened and at least one genetic response for each compound.

Cross-kingdom chemical communication drives a heritable, mutually beneficial prion-based transformation of metabolism.

In experimental science, organisms are usually studied in isolation, but in the wild, they compete and cooperate in complex communities. We report a system for cross-kingdom communication by which bacteria heritably transform yeast metabolism. An ancient biological circuit blocks yeast from using other carbon sources in the presence of glucose.

An evolutionarily conserved prion-like element converts wild fungi from metabolic specialists to generalists.

[GAR(+)] is a protein-based element of inheritance that allows yeast (Saccharomyces cerevisiae) to circumvent a hallmark of their biology: extreme metabolic specialization for glucose fermentation. When glucose is present, yeast will not use other carbon sources. [GAR(+)] allows cells to circumvent this "glucose repression.

Estrogen receptor antagonists are anti-cryptococcal agents that directly bind EF hand proteins and synergize with fluconazole in vivo.

Unlabelled: Cryptococcosis is an infectious disease of global significance for which new therapies are needed. Repurposing previously developed drugs for new indications can expedite the translation of new therapies from bench to beside. Here, we characterized the anti-cryptococcal activity and antifungal mechanism of estrogen receptor antagonists related to the breast cancer drugs tamoxifen and toremifene.

Approaching the functional annotation of fungal virulence factors using cross-species genetic interaction profiling.

In many human fungal pathogens, genes required for disease remain largely unannotated, limiting the impact of virulence gene discovery efforts. We tested the utility of a cross-species genetic interaction profiling approach to obtain clues to the molecular function of unannotated pathogenicity factors in the human pathogen Cryptococcus neoformans. This approach involves expression of C.

A major role for capsule-independent phagocytosis-inhibitory mechanisms in mammalian infection by Cryptococcus neoformans.

The antiphagocytic polysaccharide capsule of the human fungal pathogen Cryptococcus neoformans is a major virulence attribute. However, previous studies of the pleiotropic virulence determinant Gat201, a GATA family transcription factor, suggested that capsule-independent antiphagocytic mechanisms exist. We have determined that Gat201 controls the mRNA levels of ∼1100 genes (16% of the genome) and binds the upstream regions of ∼130 genes.

A heritable switch in carbon source utilization driven by an unusual yeast prion.

Several well-characterized fungal proteins act as prions, proteins capable of multiple conformations, each with different activities, at least one of which is self-propagating. Through such self-propagating changes in function, yeast prions act as protein-based elements of phenotypic inheritance. We report a prion that makes cells resistant to the glucose-associated repression of alternative carbon sources, [GAR(+)] (for "resistant to glucose-associated repression," with capital letters indicating dominance and brackets indicating its non-Mendelian character).