Human pathogenic fungus Trichophyton schoenleinii activates the NLRP3 inflammasome

Iron is an essential micronutrient for most organisms and fungi are no exception. Iron uptake by fungi is facilitated by receptor-mediated internalization of siderophores, heme and reductive iron assimilation (RIA). The RIA employs three protein groups: (i) the ferric reductases (Fre5 proteins), (ii) the multicopper ferroxidases (Fet3) and (iii) the high-affinity iron permeases (Ftr1). Phenotyping under different iron concentrations revealed detrimental effects on spore swelling and hyphal formation under iron depletion, but yeast-like morphology under iron excess. Since access to iron is limited during pathogenesis, pathogens are placed under stress due to nutrient limitations. To combat this, gene duplication and differential gene expression of key iron uptake genes are utilized to acquire iron against the deleterious effects of iron depletion. In the genome of the human pathogenic fungus L. corymbifera, three, four and three copies were identified for FRE5, FTR1 and FET3 genes, respectively. As in other fungi, FET3 and FTR1 are syntenic and co-expressed in L. corymbifera. Expression of FRE5, FTR1 and FET3 genes is highly up-regulated during iron limitation (Fe-), but lower during iron excess (Fe+). Fe- dependent upregulation of gene expression takes place in LcFRE5 II and III, LcFTR1 I and II, as well as LcFET3 I and II suggesting a functional role in pathogenesis. The syntenic LcFTR1 I–LcFET3 I gene pair is co-expressed during germination, whereas LcFTR1 II- LcFET3 II is co-expressed during hyphal proliferation. LcFTR1 I, II and IV were overexpressed in Saccharomyces cerevisiae to represent high and moderate expression of intracellular transport of Fe3+, respectively. Challenge of macrophages with the yeast mutants revealed no obvious role for LcFTR1 I, but possible functions of LcFTR1 II and IVs in recognition by macrophages. RIA expression pattern was used for a new model of interaction between L. corymbifera and macrophages.

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Deletion of pksA attenuates the melanogenesis, growth and sporulation ability and causes increased sensitivity to stress response and antifungal drugs in the human pathogenic fungus Fonsecaea monophora

Microbiological Research ◽

10.1016/j.micres.2020.126668 ◽

2021 ◽

Vol 244 ◽

pp. 126668

Author(s):

Xing Xiao ◽

Yu Li ◽

Yu Lan ◽

Jing Zhang ◽

Ya He ◽

...

Keyword(s):

Stress Response ◽

Pathogenic Fungus ◽

Antifungal Drugs ◽

Fonsecaea Monophora ◽

Increased Sensitivity ◽

Human Pathogenic Fungus

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Comparative Genomics Suggests That the Human Pathogenic Fungus Pneumocystis jirovecii Acquired Obligate Biotrophy through Gene Loss

Genome Biology and Evolution ◽

10.1093/gbe/evu155 ◽

2014 ◽

Vol 6 (8) ◽

pp. 1938-1948 ◽

Cited By ~ 31

Author(s):

Ousmane H. Cissé ◽

Marco Pagni ◽

Philippe M. Hauser

Keyword(s):

Comparative Genomics ◽

Gene Loss ◽

Pathogenic Fungus ◽

Pneumocystis Jirovecii ◽

Human Pathogenic Fungus

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Immunosuppression in vitro by a metabolite of a human pathogenic fungus.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.81.12.3835 ◽

1984 ◽

Vol 81 (12) ◽

pp. 3835-3837 ◽

Cited By ~ 104

Author(s):

A. Mullbacher ◽

R. D. Eichner

Keyword(s):

Pathogenic Fungus ◽

Human Pathogenic Fungus

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What Are the Best Parents for Hybrid Progeny? An Investigation into the Human Pathogenic Fungus Cryptococcus

Journal of Fungi ◽

10.3390/jof7040299 ◽

2021 ◽

Vol 7 (4) ◽

pp. 299

Author(s):

Man You ◽

Jianping Xu

Keyword(s):

Pathogenic Fungus ◽

Sequence Divergence ◽

Hybrid Vigor ◽

Phenotypic Trait ◽

Hybrid Progeny ◽

Melanin Production ◽

Fluconazole Resistance ◽

Human Pathogenic Fungus ◽

Two Temperatures ◽

The Relationship

Hybridization between more divergent organisms is likely to generate progeny with more novel genetic interactions and genetic variations. However, the relationship between parental genetic divergence and progeny phenotypic variation remains largely unknown. Here, using strains of the human pathogenic Cryptococcus, we investigated the patterns of such a relationship. Twenty-two strains with up to 15% sequence divergence were mated. Progeny were genotyped at 16 loci. Parental strains and their progeny were phenotyped for growth ability at two temperatures, melanin production at seven conditions, and susceptibility to the antifungal drug fluconazole. We observed three patterns of relationships between parents and progeny for each phenotypic trait, including (i) similar to one of the parents, (ii) intermediate between the parents, and (iii) outside the parental phenotypic range. We found that as genetic distance increases between parental strains, progeny showed increased fluconazole resistance and growth at 37 °C but decreased melanin production under various oxidative and nitrosative stresses. Our findings demonstrate that, depending on the traits, both evolutionarily more similar strains and more divergent strains may be better parents to generate progeny with hybrid vigor. Together, the results indicate the enormous potential of Cryptococcus hybrids in their evolution and adaptation to diverse conditions.

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The CDC42 Homolog of the Dimorphic FungusPenicillium marneffei Is Required for Correct Cell Polarization during Growth but Not Development

Journal of Bacteriology ◽

10.1128/jb.183.11.3447-3457.2001 ◽

2001 ◽

Vol 183 (11) ◽

pp. 3447-3457 ◽

Cited By ~ 63

Author(s):

Kylie J. Boyce ◽

Michael J. Hynes ◽

Alex Andrianopoulos

Keyword(s):

Cell Shape ◽

Pathogenic Fungus ◽

Cell Polarization ◽

Dominant Negative ◽

Yeast Cells ◽

Polarized Growth ◽

Temperature Dependent ◽

Human Pathogenic Fungus ◽

Rho Family

ABSTRACT The opportunistic human pathogenic fungus Penicillium marneffei is dimorphic and is thereby capable of growth either as filamentous multinucleate hyphae or as uninucleate yeast cells which divide by fission. The dimorphic switch is temperature dependent and requires regulated changes in morphology and cell shape. Cdc42p is a Rho family GTPase which in Saccharomyces cerevisiae is required for changes in polarized growth during mating and pseudohyphal development. Cdc42p homologs in higher organisms are also associated with changes in cell shape and polarity. We have cloned a highly conserved CDC42 homolog from P. marneffeinamed cflA. By the generation of dominant-negative and dominant-activated cflA transformants, we have shown that CflA initiates polarized growth and extension of the germ tube and subsequently maintains polarized growth in the vegetative mycelium. CflA is also required for polarization and determination of correct cell shape during yeast-like growth, and active CflA is required for the separation of yeast cells. However, correct cflAfunction is not required for dimorphic switching and does not appear to play a role during the generation of specialized structures during asexual development. In contrast, heterologous expression ofcflA alleles in Aspergillus nidulansprevented conidiation.

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

10.1101/390328 ◽

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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The Putative APSES Transcription Factor RgdA Governs Growth, Development, Toxigenesis, and Virulence in Aspergillus fumigatus

mSphere ◽

10.1128/msphere.00998-20 ◽

2020 ◽

Vol 5 (6) ◽

Author(s):

Sang-Cheol Jun ◽

Yong-Ho Choi ◽

Min-Woo Lee ◽

Jae-Hyuk Yu ◽

Kwang-Soo Shin

Keyword(s):

Transcription Factor ◽

Aspergillus Fumigatus ◽

Molecular Mechanisms ◽

Pathogenic Fungus ◽

Mrna Levels ◽

Transcript Levels ◽

Content Type ◽

Asexual Sporulation ◽

Human Pathogenic Fungus ◽

Growth Development

ABSTRACT The APSES transcription factor (TF) in Aspergillus species is known to govern diverse cellular processes, including growth, development, and secondary metabolism. Here, we investigated functions of the rgdA gene (Afu3g13920) encoding a putative APSES TF in the opportunistic human-pathogenic fungus Aspergillus fumigatus. The rgdA deletion resulted in significantly decreased hyphal growth and asexual sporulation. Consistently, transcript levels of the key asexual developmental regulators abaA, brlA, and wetA were decreased in the ΔrgdA mutant compared to those in the wild type (WT). Moreover, ΔrgdA resulted in reduced spore germination rates and elevated transcript levels of genes associated with conidium dormancy. The conidial cell wall hydrophobicity and architecture were changed, and levels of the RodA protein were decreased in the ΔrgdA mutant. Comparative transcriptomic analyses revealed that the ΔrgdA mutant showed higher mRNA levels of gliotoxin (GT)-biosynthetic genes and GT production. While the ΔrgdA mutant exhibited elevated production of GT, ΔrgdA strains showed reduced virulence in the mouse model. In addition, mRNA levels of genes associated with the cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway and the SakA mitogen-activated protein (MAP) kinase pathway were increased in the ΔrgdA mutant. In summary, RgdA plays multiple roles in governing growth, development, GT production, and virulence which may involve attenuation of PKA and SakA signaling. IMPORTANCE Immunocompromised patients are susceptible to infections with the opportunistic human-pathogenic fungus Aspergillus fumigatus. This fungus causes systemic infections such as invasive aspergillosis (IA), which is one of the most life-threatening fungal diseases. To control this serious disease, it is critical to identify new antifungal drug targets. In fungi, the transcriptional regulatory proteins of the APSES family play crucial roles in controlling various biological processes, including mating, asexual sporulation and dimorphic growth, and virulence traits. This study found that a putative APSES transcription factor, RgdA, regulates normal growth, asexual development, conidium germination, spore wall architecture and hydrophobicity, toxin production, and virulence in A. fumigatus. Better understanding the molecular mechanisms of RgdA in human-pathogenic fungi may reveal a novel antifungal target for future drug development.

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The Opportunistic Human Pathogenic Fungus Aspergillus fumigatus Evades the Host Complement System

Infection and Immunity ◽

10.1128/iai.01037-07 ◽

2007 ◽

Vol 76 (2) ◽

pp. 820-827 ◽

Cited By ~ 80

Author(s):

Judith Behnsen ◽

Andrea Hartmann ◽

Jeannette Schmaler ◽

Alexander Gehrke ◽

Axel A. Brakhage ◽

...

Keyword(s):

Aspergillus Fumigatus ◽

Complement System ◽

Developmental Stages ◽

Fungal Infections ◽

Alternative Pathway ◽

Pathogenic Fungus ◽

Factor H ◽

Human Sera ◽

Human Pathogenic Fungus ◽

Complement Regulators

ABSTRACT The opportunistic human pathogenic fungus Aspergillus fumigatus causes severe systemic infections and is a major cause of fungal infections in immunocompromised patients. A. fumigatus conidia activate the alternative pathway of the complement system. In order to assess the mechanisms by which A. fumigatus evades the activated complement system, we analyzed the binding of host complement regulators to A. fumigatus. The binding of factor H and factor H-like protein 1 (FHL-1) from human sera to A. fumigatus conidia was shown by adsorption assays and immunostaining. In addition, factor H-related protein 1 (FHR-1) bound to conidia. Adsorption assays with recombinant factor H mutants were used to localize the binding domains. One binding region was identified within N-terminal short consensus repeats (SCRs) 1 to 7 and a second one within C-terminal SCR 20. Plasminogen was identified as the fourth host regulatory molecule that binds to A. fumigatus conidia. In contrast to conidia, other developmental stages of A. fumigatus, like swollen conidia or hyphae, did not bind to factor H, FHR-1, FHL-1, and plasminogen, thus indicating the developmentally regulated expression of A. fumigatus surface ligands. Both factor H and plasminogen maintained regulating activity when they were bound to the conidial surface. Bound factor H acted as a cofactor to the factor I-mediated cleavage of C3b. Plasminogen showed proteolytic activity when activated to plasmin by urokinase-type plasminogen activator. These data show that A. fumigatus conidia bind to complement regulators, and these bound host regulators may contribute to evasion of a host complement attack.

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