scholarly journals IL-23 signaling prevents ferroptosis-driven renal immunopathology during candidiasis

2021 ◽  
Author(s):  
Nicolas Millet ◽  
Norma Veronica Solis ◽  
Diane Aquilar ◽  
Michail S. Lionakis ◽  
Robert T. Wheeler ◽  
...  
Keyword(s):  
Cell Death ◽  
Defense Mechanisms ◽  
Fungal Pathogens ◽  
Inflammatory Responses ◽  
Myeloid Cell ◽  
Immune Defense ◽  
Candida Infection ◽  
Critical Pathway ◽  
Immune Effector ◽  
Disseminated Candidiasis

During infection the host relies on pattern-recognition receptors to sense invading fungal pathogens to launch immune defense mechanisms. While fungal recognition and immune effector responses are organ and cell type specific, during disseminated candidiasis myeloid cells exacerbate collateral tissue damage. However, the complex interplay between protective antifungal immunity and immunopathology remains incompletely understood. The β-glucan receptor ephrin type-A 2 receptor (EphA2) is required to initiate mucosal inflammatory responses during oral Candida infection. Here we report that Epha2 promotes renal immunopathology during disseminated candidiasis. EphA2 deficiency leads to reduced renal inflammation and injury. Comprehensive analyses reveal that EphA2 limits IL-23 secretion in dendritic cells, while IL-23 signaling prevents ferroptotic myeloid cell death during infection. Further, ferroptosis aggravates inflammation during infection, while at the same time reducing the fungal killing capacity of macrophages. Thus, we identify ferroptotic cell death as a critical pathway of Candida-mediated renal immunopathology that opens a new avenue to tackle Candida infection and inflammation.

scholarly journals The Role of IL-33 in Host Response toCandida albicans

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
C. Rodríguez-Cerdeira ◽  
A. Lopez-Bárcenas ◽  
B. Sánchez-Blanco ◽  
R. Arenas
Keyword(s):  
Defense Mechanisms ◽  
Fungal Pathogens ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Case Reports ◽  
Pathogenic Fungi ◽  
Cell Types ◽  
Immune Defense ◽  
Beneficial Role

Background. Interleukin (IL) 33 is a recently identified pleiotropic cytokine that influences the activity of multiple cell types and orchestrates complex innate and adaptive immune responses.Methods. We performed an extensive review of the literature published between 2005 and 2013 on IL-33 and related cytokines, their functions, and their regulation of the immune system followingCandida albicanscolonization. Our literature review included cross-references from retrieved articles and specific data from our own studies.Results. IL-33 (IL-1F11) is a recently identified member of the IL-1 family of cytokines. Accumulating evidence suggests a pivotal role of the IL-33/ST2 axis in host immune defense against fungal pathogens, includingC. albicans. IL-33 induces a Th2-type inflammatory response and activates both innate and adaptive immunity. Studies in animal models have shown that Th2 inflammatory responses have a beneficial role in immunity against gastrointestinal and systemic infections byCandidaspp.Conclusions. This review summarizes the most important clinical studies and case reports describing the beneficial role of IL-33 in immunity and host defense mechanisms against pathogenic fungi. The finding that the IL-33/ST2 axis is involved in therapeutic target has implications for the prevention and treatment of inflammatory diseases, including acute or chronic candidiasis.

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 Immunological Aspects ofCandidaandAspergillusSystemic Fungal Infections

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Christoph Mueller-Loebnitz ◽  
Helmut Ostermann ◽  
Anke Franzke ◽  
Juergen Loeffler ◽  
Lutz Uharek ◽  
...  
Keyword(s):  
High Risk ◽  
Defense Mechanisms ◽  
Fungal Infections ◽  
Current Knowledge ◽  
Immunosuppressive Drugs ◽  
Immune Defense ◽  
Immunological Mechanism ◽  
Immune Effector ◽  
Effector Cells ◽  
Risk Patients

Patients with allogeneic stem cell transplantation (SCT) have a high risk of invasive fungal infections (IFIs) even after neutrophil regeneration. Immunological aspects might play a very important role in the IFI development in these patients. Some data are available supporting the identification of high-risk patients with IFI for example patients receiving stem cells from TLR4 haplotype S4 positive donors. Key defense mechanisms against IFI include the activation of neutrophils, the phagocytosis of germinating conidia by dendritic cells, and the fight of the cells of the innate immunity such as monocytes and natural killer cells against germlings and hyphae. Furthermore, immunosuppressive drugs interact with immune effector cells influencing the specific fungal immune defense and antimycotic drugs might interact with immune response. Based on the current knowledge on immunological mechanism inAspergillus fumigatus, the first approaches of an immunotherapy using human T cells are in development. This might be an option for the future of aspergillosis patients having a poor prognosis with conventional treatment.

scholarly journals Interplay between Candida albicans and the Antimicrobial Peptide Armory

2014 ◽  
Vol 13 (8) ◽  
pp. 950-957 ◽  
Author(s):  
Marc Swidergall ◽  
Joachim F. Ernst
Keyword(s):  
Candida Albicans ◽  
Defense Mechanisms ◽  
Fungal Pathogens ◽  
Pathogenic Fungi ◽  
Resistance Mechanisms ◽  
Immune Defense ◽  
Basal Resistance ◽  
Content Type ◽  
Normal Human ◽  
Molecular Patterns

ABSTRACTAntimicrobial peptides (AMPs) are key elements of innate immunity, which can directly kill multiple bacterial, viral, and fungal pathogens. The medically important fungusCandida albicanscolonizes different host niches as part of the normal human microbiota. Proliferation ofC. albicansis regulated through a complex balance of host immune defense mechanisms and fungal responses. Expression of AMPs against pathogenic fungi is differentially regulated and initiated by interactions of a variety of fungal pathogen-associated molecular patterns (PAMPs) with pattern recognition receptors (PRRs) on human cells. Inflammatory signaling and other environmental stimuli are also essential to control fungal proliferation and to prevent parasitism. To persist in the host,C. albicanshas developed a three-phase AMP evasion strategy, including secretion of peptide effectors, AMP efflux pumps, and regulation of signaling pathways. These mechanisms preventC. albicansfrom the antifungal activity of the major AMP classes, including cathelicidins, histatins, and defensins leading to a basal resistance. This minireview summarizes human AMP attack andC. albicansresistance mechanisms and current developments in the use of AMPs as antifungal agents.

scholarly journals Autophagy genes in myeloid cells counteract IFNγ-induced TNF-mediated cell death and fatal TNF-induced shock

2019 ◽  
Vol 116 (33) ◽  
pp. 16497-16506 ◽  
Author(s):  
Anthony Orvedahl ◽  
Michael R. McAllaster ◽  
Amy Sansone ◽  
Bria F. Dunlap ◽  
Chandni Desai ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Survival Function ◽  
Myeloid Cell ◽  
Critical Function ◽  
Interacting Protein ◽  
Autophagy Gene ◽  
Genome Wide

Host inflammatory responses must be tightly regulated to ensure effective immunity while limiting tissue injury. IFN gamma (IFNγ) primes macrophages to mount robust inflammatory responses. However, IFNγ also induces cell death, and the pathways that regulate IFNγ-induced cell death are incompletely understood. Using genome-wide CRISPR/Cas9 screening, we identified autophagy genes as central mediators of myeloid cell survival during the IFNγ response. Hypersensitivity of autophagy gene-deficient cells to IFNγ was mediated by tumor necrosis factor (TNF) signaling via receptor interacting protein kinase 1 (RIPK1)- and caspase 8-mediated cell death. Mice with myeloid cell-specific autophagy gene deficiency exhibited marked hypersensitivity to fatal systemic TNF administration. This increased mortality in myeloid autophagy gene-deficient mice required the IFNγ receptor, and mortality was completely reversed by pharmacologic inhibition of RIPK1 kinase activity. These findings provide insight into the mechanism of IFNγ-induced cell death via TNF, demonstrate a critical function of autophagy genes in promoting cell viability in the presence of inflammatory cytokines, and implicate this cell survival function in protection against mortality during the systemic inflammatory response.

scholarly journals An untargeted metabolomic approach to identify antiviral defense mechanisms in memory leukocytes secreting in vitro IgG anti-SARS-Cov-2

2021 ◽  
Author(s):  
Anna Maria Timperio ◽  
Federica Gevi ◽  
Giuseppina Fanelli ◽  
Veronica Lelli ◽  
Gianpaolo Zarletti ◽  
...  
Keyword(s):  
Defense Mechanisms ◽  
Mononuclear Cells ◽  
Inflammatory Responses ◽  
Cell Metabolism ◽  
Immune Defense ◽  
Igg Antibody ◽  
Peripheral Blood Mononuclear ◽  
Multiple Organs ◽  
Metabolic Activities

Available knowledge shows that individuals infected by SARS-CoV-2 undergo an altered metabolic state in multiple organs. Metabolic activities are directly involved in modulating the immune responses against infectious diseases, yet our understanding remains limited on how host metabolism relates with inflammatory responses. To better elucidate the underlying biochemistry of leukocytes response, we focused our analysis on the possible relationships between SARS-CoV-2 post-infection stages and distinct metabolic pathways. Indeed, in cultures of peripheral blood mononuclear cells (PBMC, n=48) obtained 60-90 days after infection and showing in vitro IgG antibody memory for spike-S1 antigen (n=19), we observed a significant altered metabolism of tryptophan and urea cycle pathways. This work for the first time identifies metabolic routes in cell metabolism possibly related to later stages of immune defense against SARS-Cov-2 infection, namely when circulating antibodies may be absent, but an antibody memory is present. The results suggest a reprogramming of leukocyte metabolism after viral pathogenesis through activation of specific amino acid pathways possibly related to protective immunity against SARS-CoV-2.

scholarly journals Early Sex Differences in the Immune-Inflammatory Responses to Neonatal Ischemic Stroke

2019 ◽  
Vol 20 (15) ◽  
pp. 3809 ◽  
Author(s):  
Sonia Villapol ◽  
Valerie Faivre ◽  
Pooja Joshi ◽  
Raffaella Moretti ◽  
Valerie C. Besson ◽  
...  
Keyword(s):  
Cell Death ◽  
Sex Differences ◽  
Macrophage Activation ◽  
Inflammatory Responses ◽  
Myeloid Cell ◽  
Artery Occlusion ◽  
Lesion Volume ◽  
Female Mice ◽  
Neonatal Ischemia ◽  
Cerebral Artery Occlusion

We recently reported that neonatal ischemia induces microglia/macrophage activation three days post-ischemia. We also found that female mice sustained smaller infarcts than males three months post-ischemia. The objective of our current study was to examine whether differential acute neuroinflammatory response and infiltrated immune cells occurs between male and females after three days post-ischemia. Permanent middle cerebral artery occlusion was induced in male and female postnatal 9-day-old (P9) mice, and mice were sacrificed three days after ischemia. Brains were analyzed for mRNA transcription after microglia magnetic cell sorting to evaluate M1 and M2 markers. FACS analysis was performed to assess myeloid infiltration and microglial expression of CX3 chemokine receptor 1 (CX3CR1). Inflammatory cytokine expression and microglia/macrophage activation were analyzed via in situ hybridization combined with immunofluorescence techniques. Lesion volume and cell death were measured. An increase in microglia/macrophages occurred in male versus female mice. The cells exhibited amoeboid morphology, and TNFα and ptgs2 (Cox-2) genes were more expressed in males. More myeloid cell infiltration was found in male versus female brains. However, we did not observe sex-dependent differences in the injured volume or cell death density. Our data show that sex differences in the acute microglial and immune responses to neonatal ischemia are likely both gene- and region-specific.

Immune Response of Human Polymorphnuclear Neutrophils to Aspergillus Fumigatus

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1257-1257
Author(s):  
Juergen Loeffler ◽  
Iwona Wozniok ◽  
Markus Mezger ◽  
Hermann Einsele
Keyword(s):  
Gene Expression ◽  
Aspergillus Fumigatus ◽  
Fungal Pathogens ◽  
Inflammatory Responses ◽  
Fungal Infections ◽  
Polymorphonuclear Neutrophils ◽  
Clinical Strain ◽  
Immune Effector ◽  
Effector Cells ◽  
Human Pmns

Abstract Invasive fungal infections with Aspergillus fumigatus show an increasing incidence due to the growing number of severely immunocompromised patients. Polymorphonuclear neutrophils (PMNs), as part of the innate immune system, are key players in antifungal immune responses, recognizing fungal pathogens at an early step of infection. Besides phagocytic mechanisms, PMNs kill pathogens by the release of reactive oxygen species (ROS). Human PMNs were isolated from blood of healthy donors using Biocoll separation. Cells were co-cultivated with conidia, germlings and hyphae of the clinical strain ATCC 9197. The oxidative burst was determined in a kinetic measurement quantifying dichlorfluorescein production. Chemotaxis was analyzed by transwell assays. Furthermore, total RNA was extracted and gene expression profiling was performed using Affymetrix U133Plus2.0 arrays. We could demonstrate that A. fumigatus represents a strong stimulus releasing ROS, depending on the morphotype; germlings revealed high ROS release, whereas resting conidia showed low stimulation capacity. PMNs actively tracked germlings and directly attached to fungi as demonstrated by real-time microscopy. Transwell assays revealed that chemotaxis of PMN is strongly dependent on the fungal morphotype; PMN showed only weak chemotaxis in the presence of conidia, whereas in the presence of germlings, high chemotactic activity was achieved. Furthermore, after 6h co-cultivation of PMNs and A. fumigatus germ tubes, 195 (1.273) genes showed an at least 4fold (2fold) altered gene expression. We observed upregulation of genes (hemoxygenase, heat shock 70kDa protein, HSPA8, HSPA1B, HSP90AB1, Ferritin) involved in self-protection against radicals. Additionally, genes involved in inflammatory responses (IL-8, CCL3, CXCL2, IL1RN) were significantly upregulated. Luminex analysis was performed for TNF-a, IL-12, GM-CSF, IFN-γ, IL-6, IL-8, IL-10 and IL-1b to identify secreted cytokines, thereby confirming array data. In conclusion, A. fumigatus had substantial effects on the activation of human PMNs. Various defence strategies were initiated, including phagocytosis, ROS release and mobilization of other immune effector cells by secretion of chemoattractants.

Natural killer cell–derived human granzyme H induces an alternative, caspase-independent cell-death program

Blood ◽  
2007 ◽  
Vol 110 (2) ◽  
pp. 544-552 ◽  
Author(s):  
Edward Fellows ◽  
Shirley Gil-Parrado ◽  
Dieter E. Jenne ◽  
Florian C. Kurschus
Keyword(s):  
Cell Death ◽  
Natural Killer ◽  
Serine Proteases ◽  
Chromatin Condensation ◽  
Killer Cell ◽  
Immune Defense ◽  
Host Cells ◽  
Ros Generation ◽  
Immune Effector ◽  
Cell Death Pathway

Abstract Granzyme H (GzmH) belongs to a family of 5 human serine proteases that are expressed by cytotoxic immune effector cells. Although GzmH is most closely related to the caspase-activating granzyme B (GzmB), neither a natural substrate nor a role in immune defense reactions has been demonstrated for this orphan granzyme. In rodents, multiple related genes exist, but none of these can be regarded as functional homologs. Here we show that host cells are efficiently killed by GzmH after perforin and streptolysin O–mediated delivery into the cytosol. Dying cells show typical hallmarks of programmed cell death, such as mitochondrial depolarization, reactive oxygen species (ROS) generation, DNA degradation, and chromatin condensation. Contrary to GzmB, cell death by GzmH does not involve the activation of executioner caspases, the cleavage of Bid or inhibitor of caspase-activated DNase (ICAD), or the release of cytochrome c. The high expression levels of GzmH in naive natural killer (NK) cells and its potent killing ability strongly support the role of the protease in triggering an alternative cell-death pathway in innate immunity.

scholarly journals Nanoparticle decoration impacts airborne fungal pathobiology

2018 ◽  
Vol 115 (27) ◽  
pp. 7087-7092 ◽  
Author(s):  
Dana Westmeier ◽  
Djamschid Solouk-Saran ◽  
Cecilia Vallet ◽  
Svenja Siemer ◽  
Dominic Docter ◽  
...  
Keyword(s):  
Complex Formation ◽  
Self Assembly ◽  
Fungal Pathogens ◽  
Inflammatory Responses ◽  
Fungal Spores ◽  
Immune Defense ◽  
Hybrid Structures ◽  
Spore Surface ◽  
Respiratory Tract Diseases ◽  
Cell Toxicity

Airborne fungal pathogens, predominantly Aspergillus fumigatus, can cause severe respiratory tract diseases. Here we show that in environments, fungal spores can already be decorated with nanoparticles. Using representative controlled nanoparticle models, we demonstrate that various nanoparticles, but not microparticles, rapidly and stably associate with spores, without specific functionalization. Nanoparticle-spore complex formation was enhanced by small nanoparticle size rather than by material, charge, or “stealth” modifications and was concentration-dependently reduced by the formation of environmental or physiological biomolecule coronas. Assembly of nanoparticle-spore surface hybrid structures affected their pathobiology, including reduced sensitivity against defensins, uptake into phagocytes, lung cell toxicity, and TLR/cytokine-mediated inflammatory responses. Following infection of mice, nanoparticle-spore complexes were detectable in the lung and less efficiently eliminated by the pulmonary immune defense, thereby enhancing A. fumigatus infections in immunocompromised animals. Collectively, self-assembly of nanoparticle-fungal complexes affects their (patho)biological identity, which may impact human health and ecology.

Sign in / Sign up

Export Citation Format

Share Document