scholarly journals Growth of Aspergillus fumigatus in Biofilms in Comparison to Candida albicans

2022 ◽  
Vol 8 (1) ◽  
pp. 48
Author(s):  
Eefje Subroto ◽  
Jacq van Neer ◽  
Ivan Valdes ◽  
Hans de Cock
Keyword(s):  
Aspergillus Fumigatus ◽  
Defense Mechanisms ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
Opportunistic Pathogen ◽  
Immune Recognition ◽  
Genetic Changes ◽  
Host Environment ◽  
Cell Dispersion ◽  
Protective Environment

Biofilm formation during infections with the opportunistic pathogen Aspergillus fumigatus can be very problematic in clinical settings, since it provides the fungal cells with a protective environment. Resistance against drug treatments, immune recognition as well as adaptation to the host environment allows fungal survival in the host. The exact molecular mechanisms behind most processes in the formation of biofilms are unclear. In general, the formation of biofilms can be categorized roughly in a few stages; adhesion, conidial germination and development of hyphae, biofilm maturation and cell dispersion. Fungi in biofilms can adapt to the in-host environment. These adaptations can occur on a level of phenotypic plasticity via gene regulation. However, also more substantial genetic changes of the genome can result in increased resistance and adaptation in the host, enhancing the survival chances of fungi in biofilms. Most research has focused on the development of biofilms. However, to tackle developing microbial resistance and adaptation in biofilms, more insight in mechanisms behind genetic adaptations is required to predict which defense mechanisms can be expected. This can be helpful in the development of novel and more targeted antifungal treatments to combat fungal infections.

Analyses of Immune Defense Mechanisms of Human Polymorphonuclear Neutrophils Co-Cultivated with Aspergillus fumigatus Germ Tubes.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3848-3848
Author(s):  
Juergen Loeffler ◽  
Markus Mezger ◽  
Hermann Einsele
Keyword(s):  
Aspergillus Fumigatus ◽  
Defense Mechanisms ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Early Stage ◽  
Immune Defense ◽  
Polymorphonuclear Neutrophils ◽  
Number Of Patients ◽  
Human Pmns ◽  
Germ Tubes

Abstract Invasive fungal infections with the opportunistic pathogen Aspergillus fumigatus show an increasing incidence due to a higher number of patients with hematological malignancies. Polymorphonuclear neutrophils (PMNs), as part of the innate immunity, recognize fungal pathogens at an early stage after infiltration. Besides phagocytotic mechanisms, PMNs kill pathogens by the release of reactive oxygen species (ROS). Human PMNs were isolated from blood of healthy donors and co-cultivated with A. fumigatus germ tubes for defined time points. Oxidative burst was determined in a kinetic measurement by the use of dichlorfluorescein. In parallel, PMNs were co-cultivated with A. fumigatus germ tubes, followed by whole genome expression analyses (Affymetrix U133 Plus 2.0 Array). We could demonstrate that A. fumigatus germlings of the clinical relevant strain ATCC 9197 represented a strong stimulus for the release of ROS. PMNs actively tracked germlings and directly attached to fungi as demonstrated by real-time microscopy. In addition, co-cultivation of PMNs with A. fumigatus germ tubes resulted in a strong upregulation of genes involved in self-protection against radicals (hämoxygenase, heat shock 70kDa protein HSPA8, thioredoxin, HSPA1B, HSP90AB1, Ferritin). After 6h of co-cultivation, 195 genes showed an at least 4fold altered gene expression. Therein, 4 genes encoding for cytokines and chemokines (IL-8, CCL3, CXCL2, IL1RN) were significantly upregulated. Luminex ELISA analyses confirmed array data and revealing IL-8 to be strongly released (5fold) by PMNs after fungal co-culturing. In conclusion, A. fumigatus had a substantial effect on the activity of human PMNs. In consequence, various defence strategies were activated, including phagocytosis, ROS release and mobilization of other immune effector cells by secretion of chemoattractant cytokines. A better understanding of innate immune defense mechanisms may provide new directions for antifungal therapies.

scholarly journals Inflammation: A Double-Edged Sword in the Response to Pseudomonas aeruginosa Infection

2017 ◽  
Vol 9 (3) ◽  
pp. 250-261 ◽  
Author(s):  
Christina K. Lin ◽  
Barbara I. Kazmierczak
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Defense Mechanisms ◽  
Opportunistic Pathogen ◽  
Innate Immune ◽  
Immune Recognition ◽  
Chronic Infections ◽  
Acute Infections ◽  
Pathogen Persistence ◽  
Pseudomonas Aeruginosa Infection ◽  
Pathogen Clearance

The Gram-negative opportunistic pathogen Pseudomonas aeruginosa exploits failures of barrier defense and innate immunity to cause acute infections at a range of anatomic sites. We review the defense mechanisms that normally protect against P. aeruginosa pulmonary infection, as well as the bacterial products and activities that trigger their activation. Innate immune recognition of P. aeruginosa is critical for pathogen clearance; nonetheless, inflammation is also associated with pathogen persistence and poor host outcomes. We describe P. aeruginosa adaptations that improve this pathogen's fitness in the inflamed airway, and briefly discuss strategies to manipulate inflammation to benefit the host. Such adjunct therapies may become increasingly important in the treatment of acute and chronic infections caused by this multi-drug-resistant pathogen.

scholarly journals Comparative Genome Sequence Analyses of Geographic Samples of Aspergillus fumigatus—Relevance for Amphotericin B Resistance

2020 ◽  
Vol 8 (11) ◽  
pp. 1673
Author(s):  
Yuying Fan ◽  
Yue Wang ◽  
Jianping Xu
Keyword(s):  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Fungal Pathogens ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
High Rate ◽  
Whole Genome ◽  
Nucleotide Polymorphisms ◽  
Genome Sequences ◽  
Resistant Strains

Amphotericin B (AMB) is a major fungicidal polyene agent that has a broad spectrum of action against invasive fungal infections. AMB is typically used as the last-line drug against serious and life-threatening infections when other drugs have failed to eliminate the fungal pathogens. Recently, AMB resistance in Aspergillus fumigatus has become more evident. For example, a high rate of AMB resistance (96%) was noted in the A. fumigatus population in Hamilton, Ontario, Canada. AMB-resistant strains have also been found in other countries. However, the mechanism of AMB resistance remains largely unknown. Here, we investigated the potential genes and mutations associated with AMB resistance using whole-genome sequences and examined AMB resistance distribution among genetic populations. A total of 196 whole-genome sequences representing strains from 11 countries were examined. Analyses of single nucleotide polymorphisms (SNPs) at the whole-genome level revealed that these strains belonged to three divergent genetic clusters, with the majority (90%) of AMB resistant strains located in one of the three clusters, Cluster 2. Our analyses identified over 60 SNPs significantly associated with AMB resistance. Together, these SNPs represent promising candidates from which to investigate the putative molecular mechanisms of AMB resistance and for their potential use in developing rapid diagnostic markers for clinical screening of AMB resistance in A. fumigatus.

scholarly journals Targeted Disruption of Nonribosomal Peptide Synthetasepes3Augments the Virulence of Aspergillus fumigatus

2011 ◽  
Vol 79 (10) ◽  
pp. 3978-3992 ◽  
Author(s):  
Karen A. O'Hanlon ◽  
Timothy Cairns ◽  
Deirdre Stack ◽  
Markus Schrettl ◽  
Elaine M. Bignell ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Opportunistic Pathogen ◽  
Immune Recognition ◽  
Phenotypic Analysis ◽  
Nonribosomal Peptide ◽  
Content Type ◽  
Targeted Gene Deletion ◽  
Wild Type Phenotype ◽  
Murine Tissue ◽  
Triacetylfusarinine C

ABSTRACTNonribosomal peptide synthesis (NRPS) is a documented virulence factor for the opportunistic pathogenAspergillus fumigatusand other fungi. Secreted or intracellularly located NRP products include the toxic molecule gliotoxin and the iron-chelating siderophores triacetylfusarinine C and ferricrocin. No structural or immunologically relevant NRP products have been identified in the organism. We investigated the function of the largest gene inA. fumigatus, which encodes the NRP synthetase Pes3 (AFUA_5G12730), by targeted gene deletion and extensive phenotypic analysis. It was observed that in contrast to other NRP synthetases, deletion ofpes3significantly increases the virulence ofA. fumigatus, whereby thepes3deletion strain (A. fumigatusΔpes3) exhibited heightened virulence (increased killing) in invertebrate (P< 0.001) and increased fungal burden (P= 0.008) in a corticosteroid model of murine pulmonary aspergillosis. Complementation restored the wild-type phenotype in the invertebrate model. Deletion ofpes3also resulted in increased susceptibility to the antifungal, voriconazole (P< 0.01), shorter germlings, and significantly reduced surface β-glucan (P= 0.0325). Extensive metabolite profiling revealed that Pes3 does not produce a secreted or intracellularly stored NRP inA. fumigatus. Macrophage infections and histological analysis of infected murine tissue indicate thatΔpes3heightened virulence appears to be mediated by aberrant innate immune recognition of the fungus. Proteome alterations inA. fumigatusΔpes3strongly suggest impaired germination capacity. Uniquely, our data strongly indicate a structural role for the Pes3-encoded NRP, a finding that appears to be novel for an NRP synthetase.

Molecular Mechanisms of Complement System Proteins and Matrix Metalloproteinases in the Pathogenesis of Age-Related Macular Degeneration

2019 ◽  
Vol 19 (10) ◽  
pp. 705-718 ◽  
Author(s):  
Naima Mansoor ◽  
Fazli Wahid ◽  
Maleeha Azam ◽  
Khadim Shah ◽  
Anneke I. den Hollander ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Macular Degeneration ◽  
Complement System ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Age Related Macular Degeneration ◽  
Genetic Changes ◽  
Complement System Proteins ◽  
Age Related ◽  
Common Genetic Variants

: Age-related macular degeneration (AMD) is an eye disorder affecting predominantly the older people above the age of 50 years in which the macular region of the retina deteriorates, resulting in the loss of central vision. The key factors associated with the pathogenesis of AMD are age, smoking, dietary, and genetic risk factors. There are few associated and plausible genes involved in AMD pathogenesis. Common genetic variants (with a minor allele frequency of >5% in the population) near the complement genes explain 40–60% of the heritability of AMD. The complement system is a group of proteins that work together to destroy foreign invaders, trigger inflammation, and remove debris from cells and tissues. Genetic changes in and around several complement system genes, including the CFH, contribute to the formation of drusen and progression of AMD. Similarly, Matrix metalloproteinases (MMPs) that are normally involved in tissue remodeling also play a critical role in the pathogenesis of AMD. MMPs are involved in the degradation of cell debris and lipid deposits beneath retina but with age their functions get affected and result in the drusen formation, succeeding to macular degeneration. In this review, AMD pathology, existing knowledge about the normal and pathological role of complement system proteins and MMPs in the eye is reviewed. The scattered data of complement system proteins, MMPs, drusenogenesis, and lipofusogenesis have been gathered and discussed in detail. This might add new dimensions to the understanding of molecular mechanisms of AMD pathophysiology and might help in finding new therapeutic options for AMD.

scholarly journals CD137 Signaling Is Critical in Fungal Clearance during Systemic Candida albicans Infection

2021 ◽  
Vol 7 (5) ◽  
pp. 382
Author(s):  
Vuvi G. Tran ◽  
Na N. Z. Nguyen ◽  
Byungsuk Kwon
Keyword(s):  
Candida Albicans ◽  
Defense Mechanisms ◽  
Tumor Necrosis ◽  
Fungal Infections ◽  
Fungal Growth ◽  
Wild Type ◽  
Agonistic Antibody ◽  
Innate Defense ◽  
Surface Receptor ◽  
Candida Albicans Infection

Invasive fungal infections by Candida albicans frequently cause mortality in immunocompromised patients. Neutrophils are particularly important for fungal clearance during systemic C. albican infection, yet little has been known regarding which surface receptor controls neutrophils’ antifungal activities. CD137, which is encoded by Tnfrsf9, belongs to the tumor necrosis receptor superfamily and has been shown to regulate neutrophils in Gram-positive bacterial infection. Here, we used genetic and immunological tools to probe the involvement of neutrophil CD137 signaling in innate defense mechanisms against systemic C. albicans infection. We first found that Tnfrsf9−/− mice were susceptible to C. albicans infection, whereas injection of anti-CD137 agonistic antibody protected the host from infection, suggesting that CD137 signaling is indispensable for innate immunity against C. albicans infection. Priming of isolated neutrophils with anti-CD137 antibody promoted their phagocytic and fungicidal activities through phospholipase C. In addition, injection of anti-CD137 antibody significantly augmented restriction of fungal growth in Tnfrsf9−/− mice that received wild-type (WT) neutrophils. In conclusion, our results demonstrate that CD137 signaling contributes to defense mechanisms against systemic C. albicans infection by promoting rapid fungal clearance.

scholarly journals Nitrogen, Iron and Zinc Acquisition: Key Nutrients to Aspergillus fumigatus Virulence

2021 ◽  
Vol 7 (7) ◽  
pp. 518
Author(s):  
Uxue Perez-Cuesta ◽  
Xabier Guruceaga ◽  
Saioa Cendon-Sanchez ◽  
Eduardo Pelegri-Martinez ◽  
Fernando L. Hernando ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Opportunistic Pathogen ◽  
Zinc Metabolism ◽  
Wide Field ◽  
Regulation Process ◽  
Number Of Genes ◽  
Iron And Zinc ◽  
Fungal Nutrition

Aspergillus fumigatus is a ubiquitous soil decomposer and an opportunistic pathogen that is characterized by its large metabolic machinery for acquiring nutrients from media. Lately, an ever-increasing number of genes involved in fungal nutrition has been associated with its virulence. Of these, nitrogen, iron, and zinc metabolism-related genes are particularly noteworthy, since 78% of them have a direct implication in virulence. In this review, we describe the sensing, uptake and regulation process of the acquisition of these nutrients, the connections between pathways and the virulence-implicated genes. Nevertheless, only 40% of the genes mentioned in this review have been assayed for roles in virulence, leaving a wide field of knowledge that remains uncertain and might offer new therapeutic and diagnostic targets.

scholarly journals The allelic rice immune receptor Pikh confers extended resistance to strains of the blast fungus through a single polymorphism in the effector binding interface

2021 ◽  
Vol 17 (3) ◽  
pp. e1009368
Author(s):  
Juan Carlos De la Concepcion ◽  
Josephine H. R. Maidment ◽  
Apinya Longya ◽  
Gui Xiao ◽  
Marina Franceschetti ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Allelic Variation ◽  
Immune Recognition ◽  
In Planta ◽  
Pathogen Effectors ◽  
Binding Interface ◽  
Recognition Specificity ◽  
Blast Fungus ◽  
Resistance Specificity ◽  
Mechanistic Basis

Arms race co-evolution drives rapid adaptive changes in pathogens and in the immune systems of their hosts. Plant intracellular NLR immune receptors detect effectors delivered by pathogens to promote susceptibility, activating an immune response that halts colonization. As a consequence, pathogen effectors evolve to escape immune recognition and are highly variable. In turn, NLR receptors are one of the most diverse protein families in plants, and this variability underpins differential recognition of effector variants. The molecular mechanisms underlying natural variation in effector recognition by NLRs are starting to be elucidated. The rice NLR pair Pik-1/Pik-2 recognizes AVR-Pik effectors from the blast fungus Magnaporthe oryzae, triggering immune responses that limit rice blast infection. Allelic variation in a heavy metal associated (HMA) domain integrated in the receptor Pik-1 confers differential binding to AVR-Pik variants, determining resistance specificity. Previous mechanistic studies uncovered how a Pik allele, Pikm, has extended recognition to effector variants through a specialized HMA/AVR-Pik binding interface. Here, we reveal the mechanistic basis of extended recognition specificity conferred by another Pik allele, Pikh. A single residue in Pikh-HMA increases binding to AVR-Pik variants, leading to an extended effector response in planta. The crystal structure of Pikh-HMA in complex with an AVR-Pik variant confirmed that Pikh and Pikm use a similar molecular mechanism to extend their pathogen recognition profile. This study shows how different NLR receptor alleles functionally converge to extend recognition specificity to pathogen effectors.

scholarly journals Do Mast Cells Contribute to the Antifungal Host Defense?

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2510
Author(s):  
Paulina Żelechowska ◽  
Joanna Pastwińska ◽  
Ewa Brzezińska-Błaszczyk ◽  
Justyna Agier
Keyword(s):  
Mast Cells ◽  
Host Defense ◽  
Immune Cells ◽  
Defense Mechanisms ◽  
Fungal Infections ◽  
Current Knowledge ◽  
Extracellular Dna ◽  
Opportunistic Pathogens ◽  
Strategic Location ◽  
Fungal Kingdom

The fungal kingdom includes a group of microorganisms that are widely distributed in the environment, and therefore the exposure to them is almost constant. Furthermore, fungal components of the microbiome, i.e., mycobiome, could serve as a reservoir of potentially opportunistic pathogens. Despite close encounters with fungi, defense mechanisms that develop during fungal infections remain unexplored. The strategic location of mast cells (MCs) close to the external environment places them among the first cells to encounter pathogens along with the other innate immune cells. MCs are directly involved in the host defense through the ability to destroy pathogens or indirectly by activating other immune cells. Most available data present MCs’ involvement in antibacterial, antiviral, or antiparasitic defense mechanisms. However, less is known about their contribution in defense mechanisms against fungi. MCs may support immune responses to fungi or their specific molecules through initiated degranulation, synthesis and release of cytokines, chemokines, mediators, and generation of reactive oxygen species (ROS), as well as immune cells’ recruitment, phagocytosis, or provision of extracellular DNA traps. This review summarizes current knowledge on host defense mechanisms against fungi and MCs’ involvement in those processes. It also describes the effects of fungi or fungus-derived constituents on MCs’ activity.

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