scholarly journals Altered Immune Response Differentially Enhances Susceptibility to Cryptococcus neoformans and Cryptococcus gattii Infection in Mice Expressing the HIV-1 Transgene

2013 ◽  
Vol 81 (4) ◽  
pp. 1100-1113 ◽  
Author(s):  
Kassandre Leongson ◽  
Vincent Cousineau-Côté ◽  
Mathieu Goupil ◽  
Francine Aumont ◽  
Serge Sénéchal ◽  
...  
Keyword(s):  
Immune Response ◽  
Cryptococcus Neoformans ◽  
Transgene Expression ◽  
Inflammatory Cell ◽  
Differential Susceptibility ◽  
Lung Parenchyma ◽  
Cryptococcus Gattii ◽  
Content Type ◽  
Altered Immune Response ◽  
Hiv 1

ABSTRACTCryptococcus neoformansvar.grubiiis the most frequent cause of AIDS-associated cryptococcosis worldwide, whileCryptococcus gattiiusually infects immunocompetent people. To understand the mechanisms which cause differential susceptibility to these cryptococcal species in HIV infection, we established and characterized a model of cryptococcosis in CD4C/HIVMutAtransgenic (Tg) mice expressing gene products of HIV-1 and developing an AIDS-like disease. Tg mice infected intranasally withC. neoformansvar.grubiistrain H99 or C23 consistently displayed reduced survival compared to non-Tg mice at three graded inocula, while shortened survival of Tg mice infected withC. gattiistrain R265 or R272 was restricted to a single high inoculum. HIV-1 transgene expression selectively augmented systemic dissemination to the liver and spleen for strains H99 and C23 but not strains R265 and R272. Histopathologic examination of lungs of Tg mice revealed large numbers of widely scattered H99 cells, with a minimal inflammatory cell response, while in the non-Tg mice H99 was almost completely embedded within extensive mixed inflammatory cell infiltrates. In contrast to H99, R265 was dispersed throughout the lung parenchyma and failed to induce a strong inflammatory response in both Tg and non-Tg mice. HIV-1 transgene expression reduced pulmonary production of CCL2 and CCL5 after infection with H99 or R265, and production of these two chemokines was lower after infection with R265. These results indicate that an altered immune response in these Tg mice markedly enhancesC. neoformansbut notC. gattiiinfection. This model therefore provides a powerful new tool to further investigate the immunopathogenesis of cryptococcosis.

scholarly journals Pulmonary Iron Limitation Induced by Exogenous Type I IFN Protects Mice fromCryptococcus gattiiIndependently of T Cells

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Michael J. Davis ◽  
Shannon Moyer ◽  
Elizabeth S. Hoke ◽  
Edward Sionov ◽  
Katrin D. Mayer-Barber ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cryptococcus Neoformans ◽  
Cryptococcus Gattii ◽  
Iron Limitation ◽  
Type I ◽  
Type I Ifn ◽  
Aids Patients ◽  
Content Type ◽  
Immune Pathways

ABSTRACTCryptococcus neoformanscauses deadly mycosis primarily in AIDS patients, whereasCryptococcus gattiiinfects mostly non-HIV patients, even in regions with high burdens of HIV/AIDS and an established environmental presence ofC. gattii. As HIV induces type I IFN (t1IFN), we hypothesized that t1IFN would differentially affect the outcome ofC. neoformansandC. gattiiinfections. Exogenous t1IFN induction using stabilized poly(I·C) (pICLC) improved murine outcomes in either cryptococcal infection. InC. neoformans-infected mice, pICLC activity was associated withC. neoformanscontainment and classical Th1 immunity. In contrast, pICLC activity againstC. gattiidid not require any immune factors previously associated withC. neoformansimmunity: T, B, and NK cells, IFN-γ, and macrophages were all dispensable. Interestingly,C. gattiipICLC activity depended on β-2-microglobulin, which impacts iron levels among other functions. Iron supplementation reversed pICLC activity, suggestingC. gattiipICLC activity requires iron limitation. Also, pICLC induced a set of iron control proteins, some of which were directly inhibitory to cryptococcusin vitro, suggesting t1IFN regulates iron availability in the pulmonary air space fluids. Thus, exogenous induction of t1IFN significantly improves the outcome of murine infection byC. gattiiandC. neoformansbut by distinct mechanisms; theC. gattiieffect was mediated by iron limitation, while the effect onC. neoformansinfection was through induction of classical T-cell-dependent immunity. Together this difference in types of T-cell-dependent t1IFN immunity for differentCryptococcusspecies suggests a possible mechanism by which HIV infection may select againstC. gattiibut notC. neoformans.IMPORTANCECryptococcus neoformansandCryptococcus gattiicause fatal infection in immunodeficient and immunocompetent individuals. While these fungi are sibling species,C. gattiiinfects very few AIDS patients, whileC. neoformansinfection is an AIDS-defining illness, suggesting that the host response to HIV selectsC. neoformansoverC. gattii. We used a viral mimic molecule (pICLC) to stimulate the immune response, and pICLC treatment improved mouse outcomes from both species. pICLC-induced action againstC. neoformanswas due to activation of well-defined immune pathways known to deterC. neoformans, whereas these immune pathways were dispensable for pICLC treatment ofC. gattii. Since these immune pathways are eventually destroyed by HIV/AIDS, our data help explain why the antiviral immune response in AIDS patients is unable to controlC. neoformansinfection but is protective againstC. gattii. Furthermore, pICLC induced tighter control of iron in the lungs of mice, which inhibitedC. gattii, thus suggesting an entirely new mode of nutritional immunity activated by viral signals.

scholarly journals DAP12 Inhibits Pulmonary Immune Responses to Cryptococcus neoformans

2016 ◽  
Vol 84 (6) ◽  
pp. 1879-1886 ◽  
Author(s):  
Lena J. Heung ◽  
Tobias M. Hohl
Keyword(s):  
Immune Response ◽  
Nk Cells ◽  
Cryptococcus Neoformans ◽  
Molecular Mechanisms ◽  
Content Type ◽  
Effector Cells ◽  
Opportunistic Fungal Pathogen ◽  
Efficient Uptake ◽  
Bacteria And Fungi

Cryptococcus neoformansis an opportunistic fungal pathogen that is inhaled into the lungs and can lead to life-threatening meningoencephalitis in immunocompromised patients. Currently, the molecular mechanisms that regulate the mammalian immune response to respiratory cryptococcal challenge remain poorly defined. DAP12, a signaling adapter for multiple pattern recognition receptors in myeloid and natural killer (NK) cells, has been shown to play both activating and inhibitory roles during lung infections by different bacteria and fungi. In this study, we demonstrate that DAP12 plays an important inhibitory role in the immune response toC. neoformans. Infectious outcomes in DAP12−/−mice, including survival and lung fungal burden, are significantly improved compared to those in C57BL/6 wild-type (WT) mice. We find that eosinophils and macrophages are decreased while NK cells are increased in the lungs of infected DAP12−/−mice. In contrast to WT NK cells, DAP12−/−NK cells are able to repressC. neoformansgrowthin vitro. Additionally, DAP12−/−macrophages are more highly activated than WT macrophages, with increased production of tumor necrosis factor (TNF) and CCL5/RANTES and more efficient uptake and killing ofC. neoformans. These findings suggest that DAP12 acts as a brake on the pulmonary immune response toC. neoformansby promoting pulmonary eosinophilia and by inhibiting the activation and antifungal activities of effector cells, including NK cells and macrophages.

scholarly journals The Investigational Fungal Cyp51 Inhibitor VT-1129 Demonstrates PotentIn VitroActivity against Cryptococcus neoformans and Cryptococcus gattii

2016 ◽  
Vol 60 (4) ◽  
pp. 2528-2531 ◽  
Author(s):  
Shawn R. Lockhart ◽  
Annette W. Fothergill ◽  
Naureen Iqbal ◽  
Carol B. Bolden ◽  
Nina T. Grossman ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Geometric Mean ◽  
Cryptococcus Gattii ◽  
The Novel ◽  
Content Type ◽  
Large Panel

ABSTRACTThein vitroactivities of the novel fungal Cyp51 inhibitor VT-1129 were evaluated against a large panel ofCryptococcus neoformansandCryptococcus gattiiisolates. VT-1129 demonstrated potent activities against bothCryptococcusspecies as demonstrated by low MIC50and MIC90values. ForC. gattii, thein vitropotency was maintained against all genotypes. In addition, significantly lower geometric mean MICs were observed for VT-1129 than for fluconazole againstC. neoformans, including isolates with reduced fluconazole susceptibility.

scholarly journals STAT1 Signaling within Macrophages Is Required for Antifungal Activity against Cryptococcus neoformans

2015 ◽  
Vol 83 (12) ◽  
pp. 4513-4527 ◽  
Author(s):  
Chrissy M. Leopold Wager ◽  
Camaron R. Hole ◽  
Karen L. Wozniak ◽  
Michal A. Olszewski ◽  
Mathias Mueller ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Immune Response ◽  
Cryptococcus Neoformans ◽  
Macrophage Activation ◽  
Virulent Strain ◽  
T Helper 1 ◽  
Pulmonary Tissue ◽  
Content Type ◽  
M1 Macrophage ◽  
Opportunistic Fungal Pathogen

Cryptococcus neoformans, the predominant etiological agent of cryptococcosis, is an opportunistic fungal pathogen that primarily affects AIDS patients and patients undergoing immunosuppressive therapy. In immunocompromised individuals,C. neoformanscan lead to life-threatening meningoencephalitis. Studies using a virulent strain ofC. neoformansengineered to produce gamma interferon (IFN-γ), denoted H99γ, demonstrated that protection against pulmonaryC. neoformansinfection is associated with the generation of a T helper 1 (Th1)-type immune response and signal transducer and activator of transcription 1 (STAT1)-mediated classical (M1) macrophage activation. However, the critical mechanism by which M1 macrophages mediate their anti-C. neoformansactivity remains unknown. The current studies demonstrate that infection withC. neoformansstrain H99γ in mice with macrophage-specific STAT1 ablation resulted in severely increased inflammation of the pulmonary tissue, a dysregulated Th1/Th2-type immune response, increased fungal burden, deficient M1 macrophage activation, and loss of protection. STAT1-deficient macrophages produced significantly less nitric oxide (NO) than STAT1-sufficient macrophages, correlating with an inability to control intracellular cryptococcal proliferation, even in the presence of reactive oxygen species (ROS). Furthermore, macrophages from inducible nitric oxide synthase knockout mice, which had intact ROS production, were deficient in anticryptococcal activity. These data indicate that STAT1 activation within macrophages is required for M1 macrophage activation and anti-C. neoformansactivity via the production of NO.

scholarly journals Identification of Pathogen Genomic Differences That Impact Human Immune Response and Disease during Cryptococcus neoformans Infection

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Aleeza C. Gerstein ◽  
Katrina M. Jackson ◽  
Tami R. McDonald ◽  
Yina Wang ◽  
Benjamin D. Lueck ◽  
...  
Keyword(s):  
Immune Response ◽  
Cryptococcus Neoformans ◽  
Candidate Genes ◽  
Cryptococcal Meningitis ◽  
Human Disease ◽  
Whole Genome ◽  
Content Type ◽  
Future Studies ◽  
Human Survival

ABSTRACT Patient outcomes during infection are due to a complex interplay between the quality of medical care, host immunity factors, and the infecting pathogen’s characteristics. To probe the influence of pathogen genotype on human survival, immune response, and other parameters of disease, we examined Cryptococcus neoformans isolates collected during the Cryptococcal Optimal Antiretroviral Therapy (ART) Timing (COAT) Trial in Uganda. We measured human participants’ survival, meningitis disease parameters, immunologic phenotypes, and pathogen in vitro growth characteristics. We compared those clinical data to whole-genome sequences from 38 C. neoformans isolates of the most frequently observed sequence type (ST), ST93, in our Ugandan participant population and to sequences from an additional 18 strains of 9 other sequence types representing the known genetic diversity within the Ugandan Cryptococcus clinical isolates. We focused our analyses on 652 polymorphisms that were variable among the ST93 genomes, were not in centromeres or extreme telomeres, and were predicted to have a fitness effect. Logistic regression and principal component analysis identified 40 candidate Cryptococcus genes and 3 hypothetical RNAs associated with human survival, immunologic response, or clinical parameters. We infected mice with 17 available KN99α gene deletion strains for these candidate genes and found that 35% (6/17) directly influenced murine survival. Four of the six gene deletions that impacted murine survival were novel. Such bedside-to-bench translational research identifies important candidate genes for future studies on virulence-associated traits in human Cryptococcus infections. IMPORTANCE Even with the best available care, mortality rates in cryptococcal meningitis range from 20% to 60%. Disease is often due to infection by the fungus Cryptococcus neoformans and involves a complex interaction between the human host and the fungal pathogen. Although previous studies have suggested genetic differences in the pathogen impact human disease, it has proven quite difficult to identify the specific C. neoformans genes that impact the outcome of the human infection. Here, we take advantage of a Ugandan patient cohort infected with closely related C. neoformans strains to examine the role of pathogen genetic variants on several human disease characteristics. Using a pathogen whole-genome sequencing approach, we showed that 40 C. neoformans genes are associated with human disease. Surprisingly, many of these genes are specific to Cryptococcus and have unknown functions. We also show deletion of some of these genes alters disease in a mouse model of infection, confirming their role in disease. These findings are particularly important because they are the first to identify C. neoformans genes associated with human cryptococcal meningitis and lay the foundation for future studies that may lead to new treatment strategies aimed at reducing patient mortality.

scholarly journals Protection against Experimental Cryptococcosis following Vaccination with Glucan Particles Containing Cryptococcus Alkaline Extracts

mBio ◽  
2015 ◽  
Vol 6 (6) ◽  
Author(s):  
Charles A. Specht ◽  
Chrono K. Lee ◽  
Haibin Huang ◽  
Donald J. Tipper ◽  
Zu T. Shen ◽  
...  
Keyword(s):  
At Risk ◽  
T Cell ◽  
Cryptococcus Neoformans ◽  
Delivery System ◽  
Cell Walls ◽  
Vaccine Development ◽  
Cryptococcus Gattii ◽  
Content Type ◽  
Alkaline Extract ◽  
Virulent Strains

ABSTRACTA vaccine capable of protecting at-risk persons against infections due toCryptococcus neoformansandCryptococcus gattiicould reduce the substantial global burden of human cryptococcosis. Vaccine development has been hampered though, by lack of knowledge as to which antigens are immunoprotective and the need for an effective vaccine delivery system. We made alkaline extracts from mutant cryptococcal strains that lacked capsule or chitosan. The extracts were then packaged into glucan particles (GPs), which are purifiedSaccharomyces cerevisiaecell walls composed primarily of β-1,3-glucans. Subcutaneous vaccination with the GP-based vaccines provided significant protection against subsequent pulmonary infection with highly virulent strains ofC. neoformansandC. gattii. The alkaline extract derived from the acapsular strain was analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS), and the most abundant proteins were identified. Separation of the alkaline extract by size exclusion chromatography revealed fractions that conferred protection when loaded in GP-based vaccines. Robust Th1- and Th17-biased CD4+T cell recall responses were observed in the lungs of vaccinated and infected mice. Thus, our preclinical studies have indicated promising cryptococcal vaccine candidates in alkaline extracts delivered in GPs. Ongoing studies are directed at identifying the individual components of the extracts that confer protection and thus would be promising candidates for a human vaccine.IMPORTANCEThe encapsulated yeastCryptococcus neoformansand its closely related sister species,Cryptococcus gattii, are major causes of morbidity and mortality, particularly in immunocompromised persons. This study reports on the preclinical development of vaccines to protect at-risk populations from cryptococcosis. Antigens were extracted fromCryptococcusby treatment with an alkaline solution. The extracted antigens were then packaged into glucan particles, which are hollow yeast cell walls composed mainly of β-glucans. The glucan particle-based vaccines elicited robust T cell immune responses and protected mice from otherwise-lethal challenge with virulent strains ofC. neoformansandC. gattii. The technology used for antigen extraction and subsequent loading into the glucan particle delivery system is relatively simple and can be applied to vaccine development against other pathogens.

scholarly journals Multicenter Study of Isavuconazole MIC Distributions and Epidemiological Cutoff Values for the Cryptococcus neoformans-Cryptococcus gattii Species Complex Using the CLSI M27-A3 Broth Microdilution Method

2014 ◽  
Vol 59 (1) ◽  
pp. 666-668 ◽  
Author(s):  
A. Espinel-Ingroff ◽  
A. Chowdhary ◽  
G. M. Gonzalez ◽  
J. Guinea ◽  
F. Hagen ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Multicenter Study ◽  
Species Complex ◽  
Cryptococcus Gattii ◽  
Broth Microdilution ◽  
Wild Type ◽  
Content Type ◽  
Microdilution Method ◽  
Cutoff Values ◽  
Broth Microdilution Method

ABSTRACTEpidemiological cutoff values (ECVs) of isavuconazole are not available forCryptococcusspp. The isavuconazole ECVs based on wild-type (WT) MIC distributions for 438Cryptococcus neoformansnongenotyped isolates, 870 isolates of genotype VNI, and 406Cryptococcus gattiiisolates from six laboratories and different geographical areas were 0.06, 0.12, and 0.25 μg/ml, respectively. These ECVs may aid in detecting non-WT isolates with reduced susceptibilities to isavuconazole.

scholarly journals Adaptation to Fluconazole via Aneuploidy Enables Cross-Adaptation to Amphotericin B and Flucytosine in Cryptococcus neoformans

2021 ◽  
Author(s):  
Feng Yang ◽  
Vladimir Gritsenko ◽  
Hui Lu ◽  
Cheng Zhen ◽  
Lu Gao ◽  
...  
Keyword(s):  
Fungal Infection ◽  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Invasive Fungal Infection ◽  
Cryptococcus Gattii ◽  
Content Type ◽  
Therapeutic Drugs ◽  
Cross Adaptation ◽  
Pyrimidine Analogues ◽  
Globally Distributed

Cryptococcosis is a globally distributed invasive fungal infection caused by infections with Cryptococcus neoformans or Cryptococcus gattii . Only three classes of therapeutic drugs are clinically available for treating cryptococcosis: polyenes (amphotericin B), azoles (fluconazole), and pyrimidine analogues (flucytosine).

scholarly journals A Peptide from Budding Yeast GAPDH Serves as a Promising Antifungal against Cryptococcus neoformans

2022 ◽  
Author(s):  
Yang Zhang ◽  
Liyan Zhou ◽  
Yan Liu ◽  
Xi Zhao ◽  
Xianqiang Lian ◽  
...  
Keyword(s):  
Mortality Rate ◽  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
High Mortality ◽  
Budding Yeast ◽  
Cryptococcus Gattii ◽  
Content Type

Cryptococcus neoformans and Cryptococcus gattii can cause cryptococcosis, which has a high mortality rate. To treat the disease, amphotericin B and fluconazole are often used in clinic.

scholarly journals Literature-Based Gene Curation and Proposed Genetic Nomenclature for Cryptococcus

2014 ◽  
Vol 13 (7) ◽  
pp. 878-883 ◽  
Author(s):  
Diane O. Inglis ◽  
Marek S. Skrzypek ◽  
Edward Liaw ◽  
Venkatesh Moktali ◽  
Gavin Sherlock ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Functional Data ◽  
Scientific Literature ◽  
Research Community ◽  
Cryptococcus Gattii ◽  
Immunocompromised Patients ◽  
Genome Database ◽  
Content Type ◽  
Central Source ◽  
Gene Information

ABSTRACTCryptococcus, a major cause of disseminated infections in immunocompromised patients, kills over 600,000 people per year worldwide. Genes involved in the virulence of the meningitis-causing fungus are being characterized at an increasing rate, and to date, at least 648Cryptococcusgene names have been published. However, these data are scattered throughout the literature and are challenging to find. Furthermore, conflicts in locus identification exist, so that named genes have been subsequently published under new names or names associated with one locus have been used for another locus. To avoid these conflicts and to provide a central source ofCryptococcusgene information, we have collected all publishedCryptococcusgene names from the scientific literature and associated them with standardCryptococcuslocus identifiers and have incorporated them into FungiDB (www.fungidb.org). FungiDB is a panfungal genome database that collects gene information and functional data and provides search tools for 61 species of fungi and oomycetes. We applied these published names to a manually curated ortholog set of allCryptococcusspecies currently in FungiDB, includingCryptococcus neoformansvar.neoformansstrains JEC21 and B-3501A,C. neoformansvar.grubiistrain H99, andCryptococcus gattiistrains R265 and WM276, and have written brief descriptions of their functions. We also compiled a protocol for gene naming that summarizes guidelines proposed by members of theCryptococcusresearch community. The centralization of genomic and literature-based information forCryptococcusat FungiDB will help researchers communicate about genes of interest, such as those related to virulence, and will further facilitate research on the pathogen.

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