scholarly journals Fungal Melanin and the Mammalian Immune System

2021 ◽  
Vol 7 (4) ◽  
pp. 264
Author(s):  
Sichen Liu ◽  
Sirida Youngchim ◽  
Daniel Zamith-Miranda ◽  
Joshua D. Nosanchuk
Keyword(s):  
Immune System ◽  
Cryptococcus Neoformans ◽  
Pathogenic Fungi ◽  
Antibody Responses ◽  
Phagocytic Cells ◽  
Effector Molecules ◽  
Fungal Melanin ◽  
Complex Polymers ◽  
Mammalian Immune System ◽  
Diverse Interactions

Melanins are ubiquitous complex polymers that are commonly known in humans to cause pigmentation of our skin. Melanins are also present in bacteria, fungi, and helminths. In this review, we will describe the diverse interactions of fungal melanin with the mammalian immune system. We will particularly focus on Cryptococcus neoformans and also discuss other major melanotic pathogenic fungi. Melanin interacts with the immune system through diverse pathways, reducing the effectiveness of phagocytic cells, binding effector molecules and antifungals, and modifying complement and antibody responses.

scholarly journals Cryptococcus neoformans Cells in Biofilms Are Less Susceptible than Planktonic Cells to Antimicrobial Molecules Produced by the Innate Immune System

2006 ◽  
Vol 74 (11) ◽  
pp. 6118-6123 ◽  
Author(s):  
Luis R. Martinez ◽  
Arturo Casadevall
Keyword(s):  
Immune System ◽  
Antimicrobial Peptides ◽  
Cryptococcus Neoformans ◽  
Innate Immune System ◽  
Capsular Polysaccharide ◽  
Pathogenic Fungus ◽  
Innate Immune ◽  
Planktonic Cells ◽  
Phagocytic Cells ◽  
Immune Effector

ABSTRACT The human pathogenic fungus Cryptococcus neoformans can form biofilms on polystyrene plates and medical devices in a process that requires capsular polysaccharide release. Although biofilms are known to be less susceptible to antimicrobial drugs, little is known about their susceptibility to antimicrobial molecules produced by the innate immune system. In this study, we investigated the susceptibility of C. neoformans cells in biofilm and planktonic states to oxidative and nonoxidative antimicrobial molecules produced by phagocytic cells. The effects of various immune effector molecules on the fungal mass, metabolic activity, and architecture of C. neoformans biofilms were measured by colony counts, 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide reduction, and confocal microscopy, respectively. Biofilms were more resistant than planktonic cells to oxidative stress but remained vulnerable to cationic antimicrobial peptides. However, melanized biofilms were significantly less susceptible to antimicrobial peptides than nonmelanized biofilms. These results suggest that the biofilm phenotype increases resistance against host immune mechanisms, a phenomenon that could contribute to the ability of biofilm-forming microbes to establish persistent infections.

scholarly journals Phagocytosis and the actin cytoskeleton

2001 ◽  
Vol 114 (6) ◽  
pp. 1061-1077 ◽  
Author(s):  
R.C. May ◽  
L.M. Machesky
Keyword(s):  
Immune System ◽  
Actin Cytoskeleton ◽  
Fundamental Importance ◽  
Foreign Particle ◽  
Phagocytic Cells ◽  
Effector Molecules ◽  
Immune System Evolution ◽  
Unicellular Organisms ◽  
Similarities And Differences ◽  
Actin Remodelling

The process of engulfing a foreign particle - phagocytosis - is of fundamental importance for a wide diversity of organisms. From simple unicellular organisms that use phagocytosis to obtain their next meal, to complex metazoans in which phagocytic cells represent an essential branch of the immune system, evolution has armed cells with a fantastic repertoire of molecules that serve to bring about this complex event. Regardless of the organism or specific molecules concerned, however, all phagocytic processes are driven by a finely controlled rearrangement of the actin cytoskeleton. A variety of signals can converge to locally reorganise the actin cytoskeleton at a phagosome, and there are significant similarities and differences between different organisms and between different engulfment processes within the same organism. Recent advances have demonstrated the complexity of phagocytic signalling, such as the involvement of phosphoinostide lipids and multicomponent signalling complexes in transducing signals from phagocytic receptors to the cytoskeleton. Similarly, a wide diversity of ‘effector molecules’ are now implicated in actin-remodelling downstream of these receptors.

Recognition of Fungal Components by the Host Immune System

2020 ◽  
Vol 21 (3) ◽  
pp. 245-264 ◽  
Author(s):  
Laura C. García-Carnero ◽  
José A. Martínez-Álvarez ◽  
Luis M. Salazar-García ◽  
Nancy E. Lozoya-Pérez ◽  
Sandra E. González-Hernández ◽  
...  
Keyword(s):  
Immune System ◽  
Histoplasma Capsulatum ◽  
Paracoccidioides Brasiliensis ◽  
Sporothrix Schenckii ◽  
Clinical Importance ◽  
Pathogenic Fungi ◽  
Diagnostic Tools ◽  
Future Research ◽  
Host Immune System ◽  
Fungal Antigens

: By being the first point of contact of the fungus with the host, the cell wall plays an important role in the pathogenesis, having many molecules that participate as antigens that are recognized by immune cells, and also that help the fungus to establish infection. The main molecules reported to trigger an immune response are chitin, glucans, oligosaccharides, proteins, melanin, phospholipids, and others, being present in the principal pathogenic fungi with clinical importance worldwide, such as Histoplasma capsulatum, Paracoccidioides brasiliensis, Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans, Blastomyces dermatitidis, and Sporothrix schenckii. Knowledge and understanding of how the immune system recognizes and responds to fungal antigens are relevant for the future research and development of new diagnostic tools and treatments for the control of mycosis caused by these fungi.

scholarly journals The novel Dbl homology/BAR domain protein, MsgA, of Talaromyces marneffei regulates yeast morphogenesis during growth inside host cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Harshini Weerasinghe ◽  
Hayley E. Bugeja ◽  
Alex Andrianopoulos
Keyword(s):  
Pathogenic Fungi ◽  
Host Cells ◽  
Microbial Pathogens ◽  
Mammalian Host ◽  
Host Immune System ◽  
Nucleotide Exchange ◽  
Phagocytic Cells ◽  
Macrophage Infection ◽  
Bar Domain ◽  
Talaromyces Marneffei

AbstractMicrobial pathogens have evolved many strategies to evade recognition by the host immune system, including the use of phagocytic cells as a niche within which to proliferate. Dimorphic pathogenic fungi employ an induced morphogenetic transition, switching from multicellular hyphae to unicellular yeast that are more compatible with intracellular growth. A switch to mammalian host body temperature (37 °C) is a key trigger for the dimorphic switch. This study describes a novel gene, msgA, from the dimorphic fungal pathogen Talaromyces marneffei that controls cell morphology in response to host cues rather than temperature. The msgA gene is upregulated during murine macrophage infection, and deletion results in aberrant yeast morphology solely during growth inside macrophages. MsgA contains a Dbl homology domain, and a Bin, Amphiphysin, Rvs (BAR) domain instead of a Plekstrin homology domain typically associated with guanine nucleotide exchange factors (GEFs). The BAR domain is crucial in maintaining yeast morphology and cellular localisation during infection. The data suggests that MsgA does not act as a canonical GEF during macrophage infection and identifies a temperature independent pathway in T. marneffei that controls intracellular yeast morphogenesis.

scholarly journals Changes in epigenetic profiles throughout early childhood and their relationship to the response to pneumococcal vaccination

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Sara Pischedda ◽  
Daniel O’Connor ◽  
Benjamin P. Fairfax ◽  
Antonio Salas ◽  
Federico Martinon-Torres ◽  
...  
Keyword(s):  
Early Childhood ◽  
Immune System ◽  
T Cell Activation ◽  
Specific Antibody ◽  
Cell Activation ◽  
Pneumococcal Vaccination ◽  
Antibody Responses ◽  
Healthy Children ◽  
Epigenetic Changes ◽  
Pneumococcal Infections

Abstract Background Pneumococcal infections are a major cause of morbidity and mortality in young children and immaturity of the immune system partly underlies poor vaccine responses seen in the young. Emerging evidence suggests a key role for epigenetics in the maturation and regulation of the immune system in health and disease. The study aimed to investigate epigenetic changes in early life and to understand the relationship between the epigenome and antigen-specific antibody responses to pneumococcal vaccination. Methods The epigenetic profiles from 24 healthy children were analyzed at 12 months prior to a booster dose of the 13-valent pneumococcal conjugate vaccine (PCV-13), and at 24 months of age, using the Illumina Methylation 450 K assay and assessed for differences over time and between high and low vaccine responders. Results Our analysis revealed 721 significantly differentially methylated positions between 12 and 24 months (FDR < 0.01), with significant enrichment in pathways involved in the regulation of cell–cell adhesion and T cell activation. Comparing high and low vaccine responders, we identified differentially methylated CpG sites (P value < 0.01) associated with HLA-DPB1 and IL6. Conclusion These data imply that epigenetic changes that occur during early childhood may be associated with antigen-specific antibody responses to pneumococcal vaccines.

Sordarins: In Vitro Activities of New Antifungal Derivatives against Pathogenic Yeasts, Pneumocystis carinii, and Filamentous Fungi

1998 ◽  
Vol 42 (11) ◽  
pp. 2863-2869 ◽  
Author(s):  
E. Herreros ◽  
C. M. Martinez ◽  
M. J. Almela ◽  
M. S. Marriott ◽  
F. Gomez De Las Heras ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Filamentous Fungi ◽  
Fungal Pathogens ◽  
Pneumocystis Carinii ◽  
Pathogenic Fungi ◽  
Pseudallescheria Boydii ◽  
Absidia Corymbifera ◽  
Wide Range ◽  
Blastoschizomyces Capitatus

ABSTRACT GM 193663, GM 211676, GM 222712, and GM 237354 are new semisynthetic derivatives of the sordarin class. The in vitro antifungal activities of GM 193663, GM 211676, GM 222712, and GM 237354 against 111 clinical yeast isolates of Candida albicans,Candida kefyr, Candida glabrata, Candida parapsilosis, Candida krusei, and Cryptococcus neoformans were compared. The in vitro activities of some of these compounds against Pneumocystis carinii, 20 isolates each of Aspergillus fumigatus and Aspergillus flavus, and 30 isolates of emerging less-common mold pathogens and dermatophytes were also compared. The MICs of GM 193663, GM 211676, GM 222712, and GM 237354 at which 90% of the isolates were inhibited (MIC90s) were 0.03, 0.03, 0.004, and 0.015 μg/ml, respectively, for C. albicans, including strains with decreased susceptibility to fluconazole; 0.5, 0.5, 0.06, and 0.12 μg/ml, respectively, for C. tropicalis; and 0.004, 0.015, 0.008, and 0.03 μg/ml, respectively, forC. kefyr. GM 222712 and GM 237354 were the most active compounds against C. glabrata, C. parapsilosis, and Cryptococcus neoformans. AgainstC. glabrata and C. parapsilosis, the MIC90s of GM 222712 and GM 237354 were 0.5 and 4 μg/ml and 1 and 16 μg/ml, respectively. The MIC90s of GM 222712 and GM 237354 againstCryptococcus neoformans were 0.5 and 0.25 μg/ml, respectively. GM 193663, GM 211676, GM 222712, and GM 237354 were extremely active against P. carinii. The efficacies of sordarin derivatives against this organism were determined by measuring the inhibition of the uptake and incorporation of radiolabelled methionine into newly synthesized proteins. All compounds tested showed 50% inhibitory concentrations of <0.008 μg/ml. Against A. flavus and A. fumigatus, the MIC90s of GM 222712 and GM 237354 were 1 and 32 μg/ml and 32 and >64 μg/ml, respectively. In addition, GM 237354 was tested against the most important emerging fungal pathogens which affect immunocompromised patients. Cladosporium carrioni, Pseudallescheria boydii, and the yeast-like fungi Blastoschizomyces capitatus and Geotrichum clavatum were the most susceptible of the fungi to GM 237354, with MICs ranging from ≤0.25 to 2 μg/ml. The MICs of GM 237354 against Trichosporon beigelii and the zygomycetesAbsidia corymbifera, Cunninghamella bertholletiae, and Rhizopus arrhizus ranged from ≤0.25 to 8 μg/ml. Against dermatophytes, GM 237354 MICs were ≥2 μg/ml. In summary, we concluded that some sordarin derivatives, such as GM 222712 and GM 237354, showed excellent in vitro activities against a wide range of pathogenic fungi, includingCandida spp., Cryptococcus neoformans, P. carinii, and some filamentous fungi and emerging invasive fungal pathogens.

scholarly journals Adaptation of Cryptococcus neoformans to Mammalian Hosts: Integrated Regulation of Metabolism and Virulence

2011 ◽  
Vol 11 (2) ◽  
pp. 109-118 ◽  
Author(s):  
Jim Kronstad ◽  
Sanjay Saikia ◽  
Erik David Nielson ◽  
Matthias Kretschmer ◽  
Wonhee Jung ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cryptococcus Neoformans ◽  
Central Carbon Metabolism ◽  
Yeast Cells ◽  
Phagocytic Cells ◽  
Content Type ◽  
The Central Nervous System ◽  
Mechanisms Of Adaptation ◽  
Complex Integration

ABSTRACTThe basidiomycete fungusCryptococcus neoformansinfects humans via inhalation of desiccated yeast cells or spores from the environment. In the absence of effective immune containment, the initial pulmonary infection often spreads to the central nervous system to result in meningoencephalitis. The fungus must therefore make the transition from the environment to different mammalian niches that include the intracellular locale of phagocytic cells and extracellular sites in the lung, bloodstream, and central nervous system. Recent studies provide insights into mechanisms of adaptation during this transition that include the expression of antiphagocytic functions, the remodeling of central carbon metabolism, the expression of specific nutrient acquisition systems, and the response to hypoxia. Specific transcription factors regulate these functions as well as the expression of one or more of the major known virulence factors ofC. neoformans. Therefore, virulence factor expression is to a large extent embedded in the regulation of a variety of functions needed for growth in mammalian hosts. In this regard, the complex integration of these processes is reminiscent of the master regulators of virulence in bacterial pathogens.

scholarly journals Structure and inhibition of Cryptococcus neoformans sterylglucosidase to develop antifungal agents

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nivea Pereira de Sa ◽  
Adam Taouil ◽  
Jinwoo Kim ◽  
Timothy Clement ◽  
Reece M. Hoffmann ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Rational Design ◽  
Antifungal Agents ◽  
Pathogenic Fungus ◽  
Pathogenic Fungi ◽  
Growth Defect ◽  
Wild Type ◽  
Secondary Infections ◽  
Heavy Burden

AbstractPathogenic fungi exhibit a heavy burden on medical care and new therapies are needed. Here, we develop the fungal specific enzyme sterylglucosidase 1 (Sgl1) as a therapeutic target. Sgl1 converts the immunomodulatory glycolipid ergosterol 3β-D-glucoside to ergosterol and glucose. Previously, we found that genetic deletion of Sgl1 in the pathogenic fungus Cryptococcus neoformans (Cn) results in ergosterol 3β-D-glucoside accumulation, renders Cn non-pathogenic, and immunizes mice against secondary infections by wild-type Cn, even in condition of CD4+ T cell deficiency. Here, we disclose two distinct chemical classes that inhibit Sgl1 function in vitro and in Cn cells. Pharmacological inhibition of Sgl1 phenocopies a growth defect of the Cn Δsgl1 mutant and prevents dissemination of wild-type Cn to the brain in a mouse model of infection. Crystal structures of Sgl1 alone and with inhibitors explain Sgl1’s substrate specificity and enable the rational design of antifungal agents targeting Sgl1.

scholarly journals The capsule ofCryptococcus neoformansmodulates phagosomal pH through its acid-base properties

2018 ◽  
Author(s):  
Carlos M. De Leon-Rodriguez ◽  
Man Shun Fu ◽  
M. Osman Corbali ◽  
Radames J.B. Cordero ◽  
Arturo Casadevall
Keyword(s):  
Cryptococcus Neoformans ◽  
Capsular Polysaccharide ◽  
Glucuronic Acid ◽  
Pathogenic Fungus ◽  
Weak Acid ◽  
Phagocytic Cells ◽  
Acid Base ◽  
Encapsulated Cells ◽  
Human Pathogenic Fungus ◽  
Base Properties

AbstractPhagosomal acidification is a critical cellular mechanism for the inhibition and killing of ingested microbes by phagocytic cells. The acidic environment activates microbicidal proteins and creates an unfavorable environment for the growth of many microbes. Consequently, numerous pathogenic microbes have developed strategies for countering phagosomal acidification through various mechanisms that include interference with phagosome maturation. The human pathogenic fungusCryptococcus neoformansresides in acidic phagosome after macrophage ingestion that actually provides a favorable environment for replication since the fungus replicates faster at acidic pH. We hypothesized that the glucuronic acid residues in the capsular polysaccharide had the capacity to affect phagosome acidity through their acid-base properties. A ratiometric fluorescence comparison of imaged phagosomes containingC. neoformansto those containing beads showed that the latter were significantly more acidic. Similarly, phagosomes containing non-encapsulatedC. neoformanscells were more acidic than those containing encapsulated cells. Acid-base titrations of isolatedC. neoformanspolysaccharide revealed that it behaves as a weak acid with maximal buffering capacity around pH 4-5. We interpret these results as indicating that the glucuronic acid residues in theC. neoformanscapsular polysaccharide can buffer phagosomal acidification. Interference with phagosomal acidification represents a new function for the cryptococcal capsule in virulence and suggests the importance of considering the acid-base properties of microbial capsules in the host-microbe interaction for other microbes with charged residues in their capsules.ImportanceCryptococcus neoformansis the causative agent of cryptococcosis, a devastating fungal disease that affects thousands of individuals worldwide. This fungus has the capacity to survive inside phagocytic cells, which contributes to persistence of infection and dissemination. One of the major mechanisms of host phagocytes is to acidify the phagosomal compartment after ingestion of microbes. This study shows that the capsule ofC. neoformanscan interfere with full phagosomal acidification by serving as a buffer.

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