Dena L. Toffaletti

Journal Article mBio · October 16, 2024 UNLABELLED: Cryptococcal meningitis causes an estimated 112,000 global deaths per annum. Genomic and phenotypic features of the infecting strain of Cryptococcus spp. have been associated with outcomes from cryptococcal meningitis. Additionally, population- ... Full text Link to item Cite

Structures of trehalose-6-phosphate synthase, Tps1, from the fungal pathogen Cryptococcus neoformans: A target for antifungals.

Journal Article Proc Natl Acad Sci U S A · August 6, 2024 Invasive fungal diseases are a major threat to human health, resulting in more than 1.5 million annual deaths worldwide. The arsenal of antifungal therapeutics remains limited and is in dire need of drugs that target additional biosynthetic pathways that a ... Full text Link to item Cite

Efficacy of Liposomal Nystatin in a Rabbit Model of Cryptococcal Meningitis.

Journal Article J Fungi (Basel) · July 26, 2024 Cryptococcal meningitis (CM) causes significant global morbidity and mortality. Current therapeutic strategies rely on deoxycholated or liposomal forms of the polyene amphotericin B. Nystatin is also a polyene with broad-spectrum antimicrobial activity. Tr ... Full text Link to item Cite

A ketogenic diet enhances fluconazole efficacy in murine models of systemic fungal infection.

Journal Article mBio · May 8, 2024 Invasive fungal infections are a significant public health concern, with mortality rates ranging from 20% to 85% despite current treatments. Therefore, we examined whether a ketogenic diet could serve as a successful treatment intervention in murine models ... Full text Link to item Cite

Biolistic Transformation of Cryptococcus neoformans.

Journal Article Methods Mol Biol · 2024 Biolistic transformation of Cryptococcus neoformans is used as a molecular tool to genetically alter or delete targeted genes. The DNA is introduced into the yeast on DNA-coated gold beads by a helium shock wave produced using a biolistic particle system. ... Full text Link to item Cite

Cryptococcus neoformans trehalose-6-phosphate synthase (tps1) promotes organ-specific virulence and fungal protection against multiple lines of host defenses.

Journal Article Front Cell Infect Microbiol · 2024 Trehalose-6-phosphate synthase (TPS1) was identified as a virulence factor for Cryptococcus neoformans and a promising therapeutic target. This study reveals previously unknown roles of TPS1 in evasion of host defenses during pulmonary and disseminated pha ... Full text Link to item Cite

Genetic diversity and microevolution in clinical Cryptococcus isolates from Cameroon.

Journal Article Med Mycol · December 1, 2023 Cryptococcal meningitis is the second most common cause of death in people living with HIV/AIDS, yet we have a limited understanding of how cryptococcal isolates change over the course of infection. Cryptococcal infections are environmentally acquired, and ... Full text Link to item Cite

Pharmacodynamics of ATI-2307 in a rabbit model of cryptococcal meningoencephalitis.

Journal Article Antimicrob Agents Chemother · October 18, 2023 Cryptococcal meningoencephalitis (CM) is a devastating fungal disease with high morbidity and mortality. The current regimen that is standard-of-care involves a combination of three different drugs administered for up to one year. There is a critical need ... Full text Link to item Cite

Susceptibility to Cryptococcus neoformans Infection with Bruton's Tyrosine Kinase Inhibition.

Journal Article Infect Immun · August 16, 2023 Patients receiving the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib have an increased likelihood of fungal infections. The objectives of this study were to determine if Cryptococcus neoformans infection severity was isolate dependent with BTK inhibit ... Full text Link to item Cite

Efficacy of APX2039 in a Rabbit Model of Cryptococcal Meningitis.

Journal Article mBio · December 20, 2022 Cryptococcal Meningitis (CM) is uniformly fatal if not treated, and treatment options are limited. We previously reported on the activity of APX2096, the prodrug of the novel Gwt1 inhibitor APX2039, in a mouse model of CM. Here, we investigated the efficac ... Full text Link to item Cite

Genomic Variation across a Clinical Cryptococcus Population Linked to Disease Outcome.

Journal Article mBio · December 20, 2022 Cryptococcus neoformans is the causative agent of cryptococcosis, a disease with poor patient outcomes that accounts for approximately 180,000 deaths each year. Patient outcomes may be impacted by the underlying genetics of the infecting isolate; however, ... Full text Link to item Cite

Transcriptional Profiles Elucidate Differential Host Responses to Infection with Cryptococcus neoformans and Cryptococcus gattii.

Journal Article J Fungi (Basel) · April 22, 2022 Many aspects of the host response to invasive cryptococcal infections remain poorly understood. In order to explore the pathobiology of infection with common clinical strains, we infected BALB/cJ mice with Cryptococcus neoformans, Cryptococcus gattii, or s ... Full text Link to item Cite

Inositol Metabolism Regulates Capsule Structure and Virulence in the Human Pathogen Cryptococcus neoformans.

Journal Article mBio · December 21, 2021 The environmental yeast Cryptococcus neoformans is the most common cause of deadly fungal meningitis in primarily immunocompromised populations. A number of factors contribute to cryptococcal pathogenesis. Among them, inositol utilization has been shown to ... Full text Link to item Cite

Gene Expression of Diverse Cryptococcus Isolates during Infection of the Human Central Nervous System.

Journal Article mBio · December 21, 2021 Cryptococcus neoformans is a major human central nervous system (CNS) fungal pathogen causing considerable morbidity and mortality. In this study, we provide the widest view to date of the yeast transcriptome directly from the human subarachnoid space and ... Full text Link to item Cite

Comparison of Cryptococcus gattii/neoformans Species Complex to Related Genera (Papiliotrema and Naganishia) Reveal Variances in Virulence Associated Factors and Antifungal Susceptibility.

Journal Article Frontiers in cellular and infection microbiology · January 2021 Cryptococcosis is an infectious disease of worldwide distribution, caused by encapsulated yeasts belonging to the phylum Basidiomycota. The genus Cryptococcus includes several species distributed around the world. The C. gattii/neoformans< ... Full text Cite

Assessing the virulence of Cryptococcus neoformans causing meningitis in HIV infected and uninfected patients in Vietnam.

Journal Article Med Mycol · November 10, 2020 We previously observed a substantial burden of cryptococcal meningitis in Vietnam atypically arising in individuals who are uninfected with human immunodeficiency virus (HIV). This disease was associated with a single genotype of Cryptococcus neoformans (s ... Full text Link to item Cite

Landscape of gene expression variation of natural isolates of Cryptococcus neoformans in response to biologically relevant stresses.

Journal Article Microb Genom · January 2020 Cryptococcus neoformans is an opportunistic fungal pathogen that at its peak epidemic levels caused an estimated million cases of cryptococcal meningitis per year worldwide. This species can grow in diverse environmental (trees, soil and bird excreta) and ... Full text Link to item Cite

Regulatory Mechanism of the Atypical AP-1-Like Transcription Factor Yap1 in Cryptococcus neoformans.

Journal Article mSphere · November 20, 2019 AP-1-like transcription factors play evolutionarily conserved roles as redox sensors in eukaryotic oxidative stress responses. In this study, we aimed to elucidate the regulatory mechanism of an atypical yeast AP-1-like protein, Yap1, in the stress respons ... Full text Link to item Cite

Pharmacodynamics of Isavuconazole in a Rabbit Model of Cryptococcal Meningoencephalitis.

Journal Article Antimicrob Agents Chemother · September 2019 Cryptococcus spp., important fungal pathogens, are the leading cause of fungus-related mortality in human immunodeficiency virus-infected patients, and new therapeutic options are desperately needed. Isavuconazonium sulfate, a newer triazole antifungal age ... Full text Link to item Cite

Genotypic diversity and clinical outcome of cryptococcosis in renal transplant recipients in Brazil.

Journal Article Emerg Microbes Infect · 2019 Genotypic diversity and fluconazole susceptibility of 82 Cryptococcus neoformans and Cryptococcus gattii isolates from 60 renal transplant recipients in Brazil were characterized. Clinical characteristics of the patients and prognostic factors were analyse ... Full text Link to item Cite

In Vitro and In Vivo Evaluation of APX001A/APX001 and Other Gwt1 Inhibitors against Cryptococcus.

Journal Article Antimicrob Agents Chemother · August 2018 Cryptococcal meningitis (CM), caused primarily by Cryptococcus neoformans, is uniformly fatal if not treated. Treatment options are limited, especially in resource-poor geographical regions, and mortality rates remain high despite current therapies. Here w ... Full text Link to item Cite

Structural and In Vivo Studies on Trehalose-6-Phosphate Synthase from Pathogenic Fungi Provide Insights into Its Catalytic Mechanism, Biological Necessity, and Potential for Novel Antifungal Drug Design.

Journal Article mBio · July 25, 2017 The disaccharide trehalose is critical to the survival of pathogenic fungi in their human host. Trehalose-6-phosphate synthase (Tps1) catalyzes the first step of trehalose biosynthesis in fungi. Here, we report the first structures of eukaryotic Tps1s in c ... Full text Link to item Cite

Intracellular Action of a Secreted Peptide Required for Fungal Virulence.

Journal Article Cell Host Microbe · June 8, 2016 Quorum sensing (QS) is a bacterial communication mechanism in which secreted signaling molecules impact population function and gene expression. QS-like phenomena have been reported in eukaryotes with largely unknown contributing molecules, functions, and ... Full text Link to item Cite

The Cryptococcus neoformans transcriptome at the site of human meningitis.

Journal Article mBio · February 4, 2014 UNLABELLED: Cryptococcus neoformans is the leading cause of fungal meningitis worldwide. Previous studies have characterized the cryptococcal transcriptome under various stress conditions, but a comprehensive profile of the C. neoformans transcriptome in t ... Full text Open Access Link to item Cite

The Cryptococcus neoformans transcriptome at the site of human meningitis

Journal Article mBio · February 4, 2014 Cryptococcus neoformans is the leading cause of fungal meningitis worldwide. Previous studies have characterized the cryptococcal transcriptome under various stress conditions, but a comprehensive profile of the C. neoformans transcriptome in the human hos ... Full text Cite

Nitrogen source-dependent capsule induction in human-pathogenic cryptococcus species.

Journal Article Eukaryot Cell · November 2013 Cryptococcus neoformans and C. gattii cause meningoencephalitis and are an increasing human health threat. These pathogenic Cryptococcus species are neurotropic and persist in the cerebrospinal fluid (CSF) of the mammalian host during infection. In order t ... Full text Link to item Cite

Brain inositol is a novel stimulator for promoting Cryptococcus penetration of the blood-brain barrier.

Journal Article PLoS Pathog · 2013 Cryptococcus neoformans is the most common cause of fungal meningitis, with high mortality and morbidity. The reason for the frequent occurrence of Cryptococcus infection in the central nervous system (CNS) is poorly understood. The facts that human and an ... Full text Link to item Cite

Virulence factors identified by Cryptococcus neoformans mutant screen differentially modulate lung immune responses and brain dissemination.

Journal Article Am J Pathol · October 2012 Deletions of cryptococcal PIK1, RUB1, and ENA1 genes independently rendered defects in yeast survival in human CSF and within macrophages. We evaluated virulence potential of these genes by comparing wild-type Cryptococcus neoformans strain H99 with deleta ... Full text Link to item Cite

Identification of genes from the fungal pathogen Cryptococcus neoformans related to transmigration into the central nervous system.

Journal Article PLoS One · 2012 BACKGROUND: A mouse brain transmigration assessment (MBTA) was created to investigate the central nervous system (CNS) pathogenesis of cryptococcal meningoencephalitis. METHODOLOGY/PRINCIPAL FINDINGS: Two cryptococcal mutants were identified from a pool of ... Full text Link to item Cite

Pleiotropic effects of deubiquitinating enzyme Ubp5 on growth and pathogenesis of Cryptococcus neoformans.

Journal Article PLoS One · 2012 Ubiquitination is a reversible protein modification that influences various cellular processes in eukaryotic cells. Deubiquitinating enzymes remove ubiquitin, maintain ubiquitin homeostasis and regulate protein degradation via the ubiquitination pathway. C ... Full text Link to item Cite

Cryptococcus neoformans requires a functional glycolytic pathway for disease but not persistence in the host.

Journal Article mBio · 2011 Cryptococcus neoformans is an important fungal pathogen of immunocompromised individuals, with a close relative, Cryptococcus gattii, emerging as a serious threat for the immunocompetent. During initial infection, C. neoformans colonizes the airspaces of t ... Full text Link to item Cite

Cryptococcus neoformans requires a functional glycolytic pathway for disease but not persistence in the host

Journal Article mBio · January 1, 2011 Cryptococcus neoformans is an important fungal pathogen of immunocompromised individuals, with a close relative, Cryptococcus gattii, emerging as a serious threat for the immunocompetent. During initial infection, C. neoformans colonizes the airspaces of t ... Full text Cite

Survival defects of Cryptococcus neoformans mutants exposed to human cerebrospinal fluid result in attenuated virulence in an experimental model of meningitis.

Journal Article Infect Immun · October 2010 Cryptococcus neoformans is a fungal pathogen that encounters various microenvironments during growth in the mammalian host, including intracellular vacuoles, blood, and cerebrospinal fluid (CSF). Because the CSF is isolated by the blood-brain barrier, we h ... Full text Link to item Cite

The trehalose synthesis pathway is an integral part of the virulence composite for Cryptococcus gattii.

Journal Article Infect Immun · October 2009 The trehalose pathway is essential for stress tolerance and virulence in fungi. We investigated the importance of this pathway for virulence of the pathogenic yeast Cryptococcus gattii using the highly virulent Vancouver Island, Canada, outbreak strain R26 ... Full text Link to item Cite

Fatty acid synthesis is essential for survival of Cryptococcus neoformans and a potential fungicidal target.

Journal Article Antimicrob Agents Chemother · October 2007 Fatty acid synthase in the yeast Cryptococcus neoformans is composed of two subunits encoded by FAS1 and FAS2 genes. We inserted a copper-regulated promoter (P(CTR4-2)) to regulate FAS1 and FAS2 expression in Cryptococcus neoformans (strains P(CTR4-2)/FAS1 ... Full text Link to item Cite

Characterization and regulation of the trehalose synthesis pathway and its importance in the pathogenicity of Cryptococcus neoformans.

Journal Article Infect Immun · October 2006 The disaccharide trehalose has been found to play diverse roles, from energy source to stress protectant, and this sugar is found in organisms as diverse as bacteria, fungi, plants, and invertebrates but not in mammals. Recent studies in the pathobiology o ... Full text Link to item Cite

Cryptococcus neoformans mitochondrial genomes from serotype A and D strains do not influence virulence.

Journal Article Curr Genet · October 2004 Cryptococcus neoformans is an encapsulated pathogenic yeast producing meningoencephalitis. Two primary strains in genetic studies, serotype A H99 and serotype D JEC21, possess dramatic differences in virulence. Since it has been shown that mitochondrial ge ... Full text Link to item Cite

In vitro and in vivo efficacies of the new triazole albaconazole against Cryptococcus neoformans.

Journal Article Antimicrob Agents Chemother · February 2004 The activity of albaconazole (UR-9825; J. Uriach & Cía. S.A., Barcelona, Spain) was compared to that of fluconazole against 12 isolates of Cryptococcus neoformans in vitro and against 1 isolate in vivo in a rabbit model of cryptococcal meningitis. Albacona ... Full text Link to item Cite

Cryptococcus neoformans gene expression during experimental cryptococcal meningitis.

Journal Article Eukaryot Cell · December 2003 Cryptococcus neoformans, an encapsulated basidiomycete fungus of medical importance, is capable of crossing the blood-brain barrier and causing meningitis in both immunocompetent and immunocompromised individuals. To gain insight into the adaptation of the ... Full text Link to item Cite

Identification of App1 as a regulator of phagocytosis and virulence of Cryptococcus neoformans.

Journal Article J Clin Invest · October 2003 Cryptococcus neoformans is a fungal pathogen that, after inhalation, can disseminate to the brain. Host alveolar macrophages (AMs) represent the first defense against the fungus. Once phagocytosed by AMs, fungal cells are killed by a concerted mechanism, i ... Full text Link to item Cite

Sexual cycle of Cryptococcus neoformans var. grubii and virulence of congenic a and alpha isolates.

Journal Article Infect Immun · September 2003 Cryptococcus neoformans is a human-pathogenic fungus that has evolved into three distinct varieties that infect most prominently the central nervous system. A sexual cycle involving haploid cells of a and alpha mating types has been reported for two variet ... Full text Link to item Cite

Regulation of cytochrome c oxidase subunit 1 (COX1) expression in Cryptococcus neoformans by temperature and host environment.

Journal Article Microbiology (Reading) · April 2003 In the study of differential gene expression of Cryptococcus neoformans, a transcript of COX1 (cytochrome oxidase c subunit 1) was identified in a serotype A strain. The transcript was upregulated at 37 degrees C compared to 30 degrees C and expressed by y ... Full text Link to item Cite

Relationship of the glyoxylate pathway to the pathogenesis of Cryptococcus neoformans.

Journal Article Infect Immun · October 2002 Functional genomics has become a major focus in the study of microbial pathogenesis. This study used a functional genomic tool, differential display reverse transcription-PCR, to identify a transcriptional profile of Cryptococcus neoformans cells as they p ... Full text Link to item Cite

Roles for inositol-phosphoryl ceramide synthase 1 (IPC1) in pathogenesis of C. neoformans.

Journal Article Genes Dev · January 15, 2001 Cryptococcus neoformans is a leading cause of life-threatening fungal infection in immunocompromised patients. Inositol-phosphoryl ceramide synthase 1 (Ipc1) is a fungus-specific enzyme, encoded by the essential IPC1 gene, that catalyzes the formation of c ... Full text Link to item Cite

Topoisomerase I is essential in Cryptococcus neoformans: role In pathobiology and as an antifungal target.

Journal Article Genetics · May 1999 Topisomerase I is the target of several toxins and chemotherapy agents, and the enzyme is essential for viability in some organisms, including mice and drosophila. We have cloned the TOP1 gene encoding topoisomerase I from the opportunistic fungal pathogen ... Full text Link to item Cite

Cryptococcus neoformans differential gene expression detected in vitro and in vivo with green fluorescent protein.

Journal Article Infect Immun · April 1999 Synthetic green fluorescent protein (GFP) was used as a reporter to detect differential gene expression in the pathogenic fungus Cryptococcus neoformans. Promoters from the C. neoformans actin, GAL7, or mating-type alpha pheromone (MFalpha1) genes were fus ... Full text Link to item Cite

A glucan synthase FKS1 homolog in cryptococcus neoformans is single copy and encodes an essential function.

Journal Article J Bacteriol · January 1999 Cryptococcal meningitis is a fungal infection, caused by Cryptococcus neoformans, which is prevalent in immunocompromised patient populations. Treatment failures of this disease are emerging in the clinic, usually associated with long-term treatment with e ... Full text Link to item Cite

Biochemical role of the Cryptococcus neoformans ADE2 protein in fungal de novo purine biosynthesis.

Journal Article Arch Biochem Biophys · March 1, 1998 Comparative studies of 5-aminoimidazole ribonucleotide (AIR) carboxylases from Escherichia coli and Gallus gallus have identified this central step in de novo purine biosynthesis as a case for unusual divergence in primary metabolism. Recent discoveries es ... Full text Link to item Cite

Study of Cryptococcus neoformans actin gene regulation with a β-galactosidase-actin fusion

Journal Article Journal of Medical and Veterinary Mycology · November 24, 1997 An expression plasmid carrying a heterologous gene fusion between the Cryptococcus neoformans actin promoter and the Escherichia coli reporter gene, LACZ, was constructed to study actin regulation in C. neoformans. Two randomly stable transformants, design ... Cite

Calcineurin is required for virulence of Cryptococcus neoformans.

Journal Article EMBO J · May 15, 1997 Cyclosporin A (CsA) and FK506 are antimicrobial, immunosuppressive natural products that inhibit signal transduction. In T cells and Saccharomyces cerevisiae, CsA and FK506 bind to the immunophilins cyclophilin A and FKBP12 and the resulting complexes inhi ... Full text Link to item Cite

Study of Cryptococcus neoformans actin gene regulation with a beta-galactosidase-actin fusion.

Journal Article J Med Vet Mycol · 1997 An expression plasmid carrying a heterologous gene fusion between the Cryptococcus neoformans actin promoter and the Escherichia coli reporter gene, LACZ, was constructed to study actin regulation in C. neoformans. Two randomly stable transformants, design ... Link to item Cite

Dominant selection system for use in Cryptococcus neoformans.

Journal Article J Med Vet Mycol · 1996 Present transformation systems for Cryptococcus neoformans depend on complementation of auxotrophic mutants. We have developed a dominant selection system for transformation of wild-type strains of cryptococci in which resistance to the antibiotic hygromyc ... Link to item Cite

Dominant selection system for use in Cryptococcus neoformans

Journal Article Journal of Medical and Veterinary Mycology · January 1, 1996 Present transformation systems for Cryptococcus neoformans depend on complementation of auxotrophic mutants. We have developed a dominant selection system for transformation of wild-type strains of cryptococci in which resistance to the antibiotic hygromyc ... Full text Cite

Targeted gene replacement demonstrates that myristoyl-CoA: protein N-myristoyltransferase is essential for viability of Cryptococcus neoformans.

Journal Article Proc Natl Acad Sci U S A · December 6, 1994 Cryptococcus neoformans is a major cause of systemic fungal infection in immunocompromised patients. Myristoyl-CoA:protein N-myristoyltransferase (Nmt) catalyzes the transfer of myristate (C14:0) from myristoyl-CoA to the N-terminal glycine of a subset of ... Full text Link to item Cite

The gene encoding phosphoribosylaminoimidazole carboxylase (ADE2) is essential for growth of Cryptococcus neoformans in cerebrospinal fluid.

Journal Article Infect Immun · October 1993 A cryptococcal meningitis model in corticosteroid-treated rabbits was used to assess the requirement for the phosphoribosylaminoimidazole gene (ADE2) for virulence of Cryptococcus neoformans. A wild-type strain (H99), an ade2 auxotroph of H99 (M001), and a ... Full text Link to item Cite

Gene transfer in Cryptococcus neoformans by use of biolistic delivery of DNA.

Journal Article J Bacteriol · March 1993 A transformation scheme for Cryptococcus neoformans to yield high-frequency, integrative events was developed. Adenine auxotrophs from a clinical isolate of C. neoformans serotype A were complemented by the cryptococcal phosphoribosylaminoimidazole carboxy ... Full text Link to item Cite

Efficacy of immune therapy in early experimental Naegleria fowleri meningitis.

Journal Article Infect Immun · May 1987 Naegleria fowleri meningoencephalitis is usually fatal in humans despite treatment. As a new approach, we tested intracisternal passive immune therapy in rabbits with amebic meningoencephalitis by using antinaegleria immune serum, an immunoglobulin G fract ... Full text Link to item Cite

Augmentation of syngeneic tumor-specific immunity by semiallogeneic cell hybrids.

Journal Article J Immunol · June 1983 Hybrid cell lines were established from fusions between lipopolysaccharide- (LPS) stimulated C57BL/6J spleen cells and MPC-11 tumor cells (45.6TG1.7, abbreviated M45), and were tested for their ability to immunize semiallogeneic mice against a parental tum ... Link to item Cite