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12 pages, 1549 KiB

Open AccessArticle

In Vitro Analysis of Tandem Peptides from Human CD5 and CD6 Scavenger Receptors as Potential Anti-Cryptococcal Agents

by Gustavo Mourglia-Ettlin, María Clara González-Porcile, Violeta Planells-Romeo, Antonella Long-Albín, Laura Carrillo-Serradell, Sebastián Miles, Francisco Lozano and María Velasco-de-Andrés

J. Fungi 2024, 10(10), 667; https://doi.org/10.3390/jof10100667 - 24 Sep 2024

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Abstract

Cryptococcus neoformans is included in the World Health Organization fungal priority pathogen list, complied to expedite improved research and public-health interventions. The limited number of available antifungal drugs, their associated toxicity, and the emergence of drug-resistant strains make the development of new therapeutic [...] Read more.

Cryptococcus neoformans is included in the World Health Organization fungal priority pathogen list, complied to expedite improved research and public-health interventions. The limited number of available antifungal drugs, their associated toxicity, and the emergence of drug-resistant strains make the development of new therapeutic strategies mandatory. Pattern-recognition receptors (PRRs) from the host’s innate immune system constitute a potential source of new antimicrobial agents. CD5 and CD6 are lymphoid members of the ancient scavenger receptor cysteine-rich superfamily (SRCR-SF) which bind pathogen-associated molecular patterns (PAMPs) of fungal and bacterial origin. Evidence supports the concept that such binding maps to 11-mer sequences present in each of their three SRCR extracellular domains. Herein, we have designed synthetic peptides containing tandems of such 11-mer sequences (namely CD5-T and CD6-T) and analyzed their C. neoformans-binding properties in vitro. Our results show both inhibitory effects on fungal growth and an ability to impact capsule formation and titanization, two critical virulence factors of C. neoformans involved in immune evasion. These effects hold promise for CD5-T and CD6-T peptides as single or adjuvant therapeutic agents against cryptococcosis. Full article

(This article belongs to the Special Issue Cryptococcus Infections and Pathogenesis)

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18 pages, 3193 KiB

Open AccessArticle

Quantitative MRI of a Cerebral Cryptococcoma Mouse Model for In Vivo Distinction between Different Cryptococcal Molecular Types

by Luigi Musetta, Shannon Helsper, Lara Roosen, Dries Maes, Anca Croitor Sava, Liesbeth Vanherp, Willy Gsell, Greetje Vande Velde, Katrien Lagrou, Wieland Meyer and Uwe Himmelreich

J. Fungi 2024, 10(8), 593; https://doi.org/10.3390/jof10080593 - 22 Aug 2024

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Abstract

The controversially discussed taxonomy of the Cryptococcus neoformans/Cryptococcus gattii species complex encompasses at least eight major molecular types. Cerebral cryptococcomas are a common manifestation of cryptococcal neurological disease. In this study, we compared neurotypical symptoms and differential neurovirulence induced by one [...] Read more.

The controversially discussed taxonomy of the Cryptococcus neoformans/Cryptococcus gattii species complex encompasses at least eight major molecular types. Cerebral cryptococcomas are a common manifestation of cryptococcal neurological disease. In this study, we compared neurotypical symptoms and differential neurovirulence induced by one representative isolate for each of the eight molecular types studied. We compared single focal lesions caused by the different isolates and evaluated the potential relationships between the fungal burden and properties obtained with quantitative magnetic resonance imaging (qMRI) techniques such as diffusion MRI, T₂ relaxometry and magnetic resonance spectroscopy (MRS). We observed an inverse correlation between parametric data and lesion density, and we were able to monitor longitudinally biophysical properties of cryptococcomas induced by different molecular types. Because the MRI/MRS techniques are also clinically available, the same approach could be used to assess image-based biophysical properties that correlate with fungal cell density in lesions in patients to determine personalized treatments. Full article

(This article belongs to the Special Issue Cryptococcus Infections and Pathogenesis)

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25 pages, 7169 KiB

Open AccessArticle

Transcriptional and Post-Translational Roles of Calcineurin in Cationic Stress and Glycerol Biosynthesis in Cryptococcus neoformans

by Ronaldo Silva Santos, Gabriel Martins-Silva, Adrián Adolfo Álvarez Padilla, Mateus Possari, Sérgio Donnantuoni Degello, Otávio J. Bernardes Brustolini, Ana Tereza Ribeiro Vasconcelos, Marcelo Afonso Vallim and Renata C. Pascon

J. Fungi 2024, 10(8), 531; https://doi.org/10.3390/jof10080531 - 30 Jul 2024

Cited by 1 | Viewed by 928

Abstract

Stress management is an adaptive advantage for survival in adverse environments. Pathogens face this challenge during host colonization, requiring an appropriate stress response to establish infection. The fungal pathogen Cryptococcus neoformans undergoes thermal, oxidative, and osmotic stresses in the environment and animal host. [...] Read more.

Stress management is an adaptive advantage for survival in adverse environments. Pathogens face this challenge during host colonization, requiring an appropriate stress response to establish infection. The fungal pathogen Cryptococcus neoformans undergoes thermal, oxidative, and osmotic stresses in the environment and animal host. Signaling systems controlled by Ras1, Hog1, and calcineurin respond to high temperatures and osmotic stress. Cationic stress caused by Na⁺, K⁺, and Li⁺ can be overcome with glycerol, the preferred osmolyte. Deleting the glycerol phosphate phosphatase gene (GPP2) prevents cells from accumulating glycerol due to a block in the last step of its biosynthetic pathway. Gpp2 accumulates in a phosphorylated form in a cna1Δ strain, and a physical interaction between Gpp2 and Cna1 was found; moreover, the gpp2Δ strain undergoes slow growth and has attenuated virulence in animal models of infection. We provide biochemical evidence that growth in 1 M NaCl increases glycerol content in the wild type, whereas gpp2Δ, cna1Δ, and cnb1Δ mutants fail to accumulate it. The deletion of cnb1Δ or cna1Δ renders yeast cells sensitive to cationic stress, and the Gfp-Gpp2 protein assumes an abnormal localization. We suggest a mechanism in which calcineurin controls Gpp2 at the post-translational level, affecting its localization and activity, leading to glycerol biosynthesis. Also, we showed the transcriptional profile of glycerol-deficient mutants and established the cationic stress response mediated by calcineurin; among the biological processes differentially expressed are carbon utilization, translation, transmembrane transport, glutathione metabolism, oxidative stress response, and transcription regulation. To our knowledge, this is the first time that this transcriptional profile has been described. These results have implications for pathogen stress adaptability. Full article

(This article belongs to the Special Issue Cryptococcus Infections and Pathogenesis)

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8 pages, 806 KiB

Open AccessArticle

Efficacy of Liposomal Nystatin in a Rabbit Model of Cryptococcal Meningitis

by Charles D. Giamberardino, Wiley A. Schell, Jennifer L. Tenor, Dena L. Toffaletti and John R. Perfect

J. Fungi 2024, 10(8), 520; https://doi.org/10.3390/jof10080520 - 26 Jul 2024

Viewed by 738

Abstract

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. Treatment with systemic nystatin has been limited by toxicity, which is [...] Read more.

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. Treatment with systemic nystatin has been limited by toxicity, which is a consistent challenge with polyene therapeutics. One mechanism to improve the toxicity is usage of a liposomal form of the active agent. Previous data from a murine candidemia model indicated that liposomal nystatin may be an effective antifungal drug formulation. Since the rabbit model of CM is a highly predictive preclinical system for evaluating antifungal therapeutics, we tested the effectiveness of two doses of daily liposomal nystatin, 3 and 8 mg/kg in the rabbit model of CM. Treatment with liposomal nystatin in this model did not reduce the fungal burden in the cerebrospinal fluid. A subsequent clinical trial also did not find activity in a human population. These data indicate that liposomal nystatin in the current form and at the tested dosages is not an effective therapy for CM. The data provide further evidence for the predictive power of the rabbit model of CM as a vital preclinical system for testing novel antifungal therapeutics for CM. Full article

(This article belongs to the Special Issue Cryptococcus Infections and Pathogenesis)

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18 pages, 3779 KiB

Open AccessArticle

The CARD9 Gene in Koalas (Phascolarctos cinereus): Does It Play a Role in the Cryptococcus–Koala Interaction?

by Hannah P. Newton, Damien P. Higgins, Andrea Casteriano, Belinda R. Wright, Mark B. Krockenberger and Luisa H. M. Miranda

J. Fungi 2024, 10(6), 409; https://doi.org/10.3390/jof10060409 - 6 Jun 2024

Viewed by 869

Abstract

Cryptococcus is a genus of fungal pathogens that can infect and cause disease in a range of host species and is particularly prominent in koalas (Phascolarctos cinerus). Like other host species, koalas display a range of outcomes upon exposure to environmental [...] Read more.

Cryptococcus is a genus of fungal pathogens that can infect and cause disease in a range of host species and is particularly prominent in koalas (Phascolarctos cinerus). Like other host species, koalas display a range of outcomes upon exposure to environmental Cryptococcus, from external nasal colonization to asymptomatic invasive infection and, in rare cases, severe clinical disease resulting in death. Host factors contributing to these varied outcomes are poorly understood. Due to their close relationship with eucalypt trees (a key environmental niche for Cryptococcus gattii) and suspected continual exposure to the pathogen, koalas provide a unique opportunity to examine host susceptibility in natural infections. Caspase recruitment domain-containing protein 9 (CARD9) is a key intracellular signaling protein in the fungal innate immune response. Humans with mutations in CARD9 succumb to several different severe and chronic fungal infections. This study is the first to sequence and explore CARD9 variation in multiple koalas using Sanger sequencing. Four CARD9 exons were successfully sequenced in 22 koalas from a New South Wales, Australia population. We found minimal variation between koalas across all four exons, an observation that was also made when CARD9 sequences were compared between koalas and six other species, including humans and mice. Ten single-nucleotide polymorphisms (SNP) were identified in this study and explored in the context of cryptococcal exposure outcomes. While we did not find any significant association with variation in cryptococcal outcomes, we found a high degree of conservation between species at several SNP loci that requires further investigation. The findings from this study lay the groundwork for further investigations of CARD9 and Cryptococcus both in koalas and other species, and highlight several considerations for future studies. Full article

(This article belongs to the Special Issue Cryptococcus Infections and Pathogenesis)

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20 pages, 6852 KiB

Open AccessArticle

Inhibition of Microbicidal Activity of Canine Macrophages DH82 Cell Line by Capsular Polysaccharides from Cryptococcus neoformans

by Isabel F. LaRocque-de-Freitas, Elias Barbosa da Silva-Junior, Leticia Paixão Gemieski, Beatriz da Silva Dias Lima, Israel Diniz-Lima, Aislan de Carvalho Vivarini, Ulisses G. Lopes, Leonardo Freire-de-Lima, Alexandre Morrot, José Osvaldo Previato, Lucia Mendonça-Previato, Lucia Helena Pinto-da-Silva, Celio G. Freire-de-Lima and Debora Decote-Ricardo

J. Fungi 2024, 10(5), 339; https://doi.org/10.3390/jof10050339 - 8 May 2024

Cited by 3 | Viewed by 1336

Abstract

Cryptococcus neoformans is a lethal fungus that primarily affects the respiratory system and the central nervous system. One of the main virulence factors is the capsule, constituted by the polysaccharides glucuronoxylomannan (GXM) and glucuronoxylomanogalactan (GXMGal). Polysaccharides are immunomodulators. One of the target cell [...] Read more.

Cryptococcus neoformans is a lethal fungus that primarily affects the respiratory system and the central nervous system. One of the main virulence factors is the capsule, constituted by the polysaccharides glucuronoxylomannan (GXM) and glucuronoxylomanogalactan (GXMGal). Polysaccharides are immunomodulators. One of the target cell populations for modulation are macrophages, which are part of the first line of defense and important for innate and adaptive immunity. It has been reported that macrophages can be modulated to act as a “Trojan horse,” taking phagocytosed yeasts to strategic sites or having their machinery activation compromised. The scarcity of information on canine cryptococcosis led us to assess whether the purified capsular polysaccharides from C. neoformans would be able to modulate the microbicidal action of macrophages. In the present study, we observed that the capsular polysaccharides, GXM, GXMGal, or capsule total did not induce apoptosis in the DH82 macrophage cell line. However, it was possible to demonstrate that the phagocytic activity was decreased after treatment with polysaccharides. In addition, recovered yeasts from macrophages treated with polysaccharides after phagocytosis could be cultured, showing that their viability was not altered. The polysaccharides led to a reduction in ROS production and the mRNA expression of IL-12 and IL-6. We observed that GXMGal inhibits MHC class II expression and GXM reduces ERK phosphorylation. In contrast, GXMGal and GXM were able to increase the PPAR-γ expression. Furthermore, our data suggest that capsular polysaccharides can reduce the microbicidal activity of canine macrophages DH82. Full article

(This article belongs to the Special Issue Cryptococcus Infections and Pathogenesis)

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Review

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18 pages, 3124 KiB

Open AccessReview

Roles of Different Signaling Pathways in Cryptococcus neoformans Virulence

by Fawad Mahmood, Jun-Ming Chen, Ammar Mutahar Al-Huthaifi, Abdullah Ali Al-Alawi and Tong-Bao Liu

J. Fungi 2024, 10(11), 786; https://doi.org/10.3390/jof10110786 - 13 Nov 2024

Viewed by 547

Abstract

Cryptococcus neoformans is a widespread fungal pathogen that can infect the human central nervous system (CNS) and cause fungal meningitis, leading to hundreds of thousands of deaths worldwide each year. Previous studies have demonstrated that many signal transduction pathways are crucial for the [...] Read more.

Cryptococcus neoformans is a widespread fungal pathogen that can infect the human central nervous system (CNS) and cause fungal meningitis, leading to hundreds of thousands of deaths worldwide each year. Previous studies have demonstrated that many signal transduction pathways are crucial for the morphological development and virulence of C. neoformans. In this review, data from over 116 research articles have been compiled to show that many signaling pathways control various characteristics of C. neoformans, individually or in association with other pathways, and to establish strong links among them to better understand C. neoformans pathogenesis. Every characteristic of C. neoformans is closely linked to these signaling pathways, making this a rich area for further research. It is essential to thoroughly explore these pathways to address questions that remain and apply a molecular mechanistic approach to link them. Targeting these pathways is crucial for understanding the exact mechanism of infection pathogenesis and will facilitate the development of antifungal drugs as well as the diagnosis and prevention of cryptococcosis. Full article

(This article belongs to the Special Issue Cryptococcus Infections and Pathogenesis)

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12 pages, 819 KiB

Open AccessReview

A New Overview of Sex Bias in Fungal Infections

by Hari H. Rao and Erin E. McClelland

J. Fungi 2024, 10(9), 607; https://doi.org/10.3390/jof10090607 - 26 Aug 2024

Viewed by 672

Abstract

Fungal infections often disproportionately affect males over females. Since the NIH mandated in 2016 that researchers test their hypotheses in both biological sexes, numerous other fungal infections/colonizations have been found to exhibit sex-specific patterns. These patterns have been observed in various species, including [...] Read more.

Fungal infections often disproportionately affect males over females. Since the NIH mandated in 2016 that researchers test their hypotheses in both biological sexes, numerous other fungal infections/colonizations have been found to exhibit sex-specific patterns. These patterns have been observed in various species, including mice, drosophila, cats, and bats, suggesting significant implications for understanding these diseases and developing treatments. Despite the recognition of this sex bias, primary research explaining its underlying causes or mechanisms remains limited. Current evidence suggests that potential causes might be linked to sex hormones, genetic expression, and evolutionary behaviors. This review consolidates recent data on sex bias in fungal infections or colonizations among different species and proposes future research directions to address existing gaps. Thus, this review advances the comprehension of the intricate relationships between biological sex, fungal infections, and broader health implications. Full article

(This article belongs to the Special Issue Cryptococcus Infections and Pathogenesis)

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17 pages, 788 KiB

Open AccessReview

Inbred Mouse Models in Cryptococcus neoformans Research

by Minna Ding and Kirsten Nielsen

J. Fungi 2024, 10(6), 426; https://doi.org/10.3390/jof10060426 - 17 Jun 2024

Viewed by 1006

Abstract

Animal models are frequently used as surrogates to understand human disease. In the fungal pathogen Cryptococcus species complex, several variations of a mouse model of disease were developed that recapitulate different aspects of human disease. These mouse models have been implemented using various [...] Read more.

Animal models are frequently used as surrogates to understand human disease. In the fungal pathogen Cryptococcus species complex, several variations of a mouse model of disease were developed that recapitulate different aspects of human disease. These mouse models have been implemented using various inbred and outbred mouse backgrounds, many of which have genetic differences that can influence host response and disease outcome. In this review, we will discuss the most commonly used inbred mouse backgrounds in C. neoformans infection models. Full article

(This article belongs to the Special Issue Cryptococcus Infections and Pathogenesis)

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