Differential Kinetics of Aspergillus nidulans and Aspergillus fumigatus Phagocytosis

Acknowledgements: The authors would like to acknowledge Fraser P. Coxon and Ian Ganley for providing LC3-GFP-mCherry BMDMs. M.S.G. was supported by an FEMS research grant and F.L.v.d.V. was supported by ZonMW under the name EURO-CMC frame of E-Rare-2, the ERA-Net for Research on Rare Diseases.Peer reviewedPublisher PD

The anti-inflammatory cytokine interleukin-37 is an inhibitor of trained immunity.

Summary Trained immunity (TI) is a de facto innate immune memory program induced in monocytes/macrophages by exposure to pathogens or vaccines, which evolved as protection against infections. TI is characterized by immunometabolic changes and histone post-translational modifications, which enhance production of pro-inflammatory cytokines. As aberrant activation of TI is implicated in inflammatory diseases, tight regulation is critical; however, the mechanisms responsible for this modulation remain elusive. Interleukin-37 (IL-37) is an anti-inflammatory cytokine that curbs inflammation and modulates metabolic pathways. In this study, we show that administration of recombinant IL-37 abrogates the protective effects of TI in vivo, as revealed by reduced host pro-inflammatory responses and survival to disseminated candidiasis. Mechanistically, IL-37 reverses the immunometabolic changes and histone post-translational modifications characteristic of TI in monocytes, thus suppressing cytokine production in response to infection. IL-37 thereby emerges as an inhibitor of TI and as a potential therapeutic target in immune-mediated pathologies

Human albumin enhances the pathogenic potential of Candida glabrata on vaginal epithelial cells

Funding: M.P., H.H., T.G., and B.H. received funding from the European Union Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 642095 (OPATHY). A.K. and B. H. received support from the European Union Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 812969 (FunHoMic). S.A. and B.H. were supported by funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 847507 (HDM-FUN). B.H. is further supported by the DFG within the Collaborative Research Centre (CRC)/Transregio (TRR) 124 “FungiNet” project C1 (DFG project number 210879364) and the Balance of the Microverse Cluster (Germany´s Excellence Strategy – EXC 2051 – Project-ID 390713860). M.S.G. was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft - DFG) Emmy Noether Program (project no. 434385622 / GR 5617/1-1), and a Research Grant 2019 from the European Society of Clinical Microbiology and Infectious Diseases (ESCMID). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. M.P. and H.H. received salary from grant agreement No 642095 (OPATHY) (2016-2019). A.K. received salary from grant agreement No 812969 (FunHoMic) (2019-2022).Peer reviewedPublisher PD

Integrated transcriptomic and proteomic analyses ofP. falciparumgametocytes: molecular insight into sex-specific processes and translational repression

Sexual differentiation of malaria parasites into gametocytes in the vertebrate host and subsequent gamete fertilization in mosquitoes is essential for the spreading of the disease. The molecular processes orchestrating these transitions are far from fully understood. Here, we report the first transcriptome analysis of male and female Plasmodium falciparum gametocytes coupled with a comprehensive proteome analysis. In male gametocytes there is an enrichment of proteins involved in the formation of flagellated gametes; proteins involved in DNA replication, chromatin organization and axoneme formation. On the other hand, female gametocytes are enriched in proteins required for zygote formation and functions after fertilization; protein-, lipid- and energy-metabolism. Integration of transcriptome and proteome data revealed 512 highly expressed maternal transcripts without corresponding protein expression indicating large scale translational repression in P. falciparum female gametocytes for the first time. Despite a high degree of conservation between Plasmodium species, 260 of these 'repressed transcripts' have not been previously described. Moreover, for some of these genes, protein expression is only reported in oocysts and sporozoites indicating that repressed transcripts can be partitioned into short- and long-term storage. Finally, these data sets provide an essential resource for identification of vaccine/drug targets and for further mechanistic studies

Genetic determinants of fungi-induced ROS production are associated with the risk of invasive pulmonary aspergillosis

© 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Reactive oxygen species (ROS) are an essential component of the host defense against fungal infections. However, little is known about how common genetic variation affects ROS-mediated antifungal host defense. In the present study, we investigated the genetic factors that regulate ROS production capacity in response to the two human fungal pathogens: Candida albicans and Aspergillus fumigatus. We investigated fungal-stimulated ROS production by immune cells isolated from a population-based cohort of approximately 200 healthy individuals (200FG cohort), and mapped ROS-quantitative trait loci (QTLs). We identified several genetic loci that regulate ROS levels (P < 9.99 × 10-6), with some of these loci being pathogen-specific, and others shared between the two fungi. These ROS-QTLs were investigated for their influence on the risk of invasive pulmonary aspergillosis (IPA) in a disease relevant context. We stratified hematopoietic stem-cell transplant (HSCT) recipients based on the donor's SNP genotype and tested their impact on the risk of IPA. We identified rs4685368 as a ROS-QTL locus that was significantly associated with an increased risk of IPA after controlling for patient age and sex, hematological malignancy, type of transplantation, conditioning regimen, acute graft-versus-host-disease grades III-IV, and antifungal prophylaxis. Collectively, this data provides evidence that common genetic variation can influence ROS production capacity, and, importantly, the risk of developing IPA among HSCT recipients. This evidence warrants further research for patient stratification based on the genetic profiling that would allow the identifications of patients at high-risk for an invasive fungal infection, and who would benefit the most from a preventive strategy.This study was supported by the European Union's Horizon 2020 research and innovation programme under grant agreement no. 847507 (HDM-FUN). MGN was supported by an ERC Advanced grant (833247) and a Spinoza grant of the Netherlands Association for Scientific Research. VK was supported by a Research Grant [2017] of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Hypatia tenure track grant. AC was supported by the Fundação para a Ciência e a Tecnologia (FCT) (UIDB/50026/2020 and UIDP/50026/2020), the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) (NORTE-01-0145-FEDER-000039), and the “la Caixa” Foundation (ID 100010434) and FCT under the agreement LCF/PR/HR17/52190003. CC was supported by FCT (CEECIND/04058/2018 and PTDC/SAU-SER/29,635/2017) and the Gilead Research Scholars Program – Antifungals. SMG was the recipient of a PhD fellowship funded by FCT (SFRH/BD/136,814/2018). MSG was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft - DFG) Emmy Noether Program (project no. 434385622/GR 5617/1-1).info:eu-repo/semantics/publishedVersio

The fungal peptide toxin Candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes

Clearance of invading microbes requires phagocytes of the innate immune system. However, successful pathogens have evolved sophisticated strategies to evade immune killing. The opportunistic human fungal pathogen Candida albicans is efficiently phagocytosed by macrophages, but causes inflammasome activation, host cytolysis, and escapes after hypha formation. Previous studies suggest that macrophage lysis by C. albicans results from early inflammasome-dependent cell death (pyroptosis), late damage due to glucose depletion and membrane piercing by growing hyphae. Here we show that Candidalysin, a cytolytic peptide toxin encoded by the hypha-associated gene ECE1, is both a central trigger for NLRP3 inflammasome-dependent caspase-1 activation via potassium efflux and a key driver of inflammasome-independent cytolysis of macrophages and dendritic cells upon infection with C. albicans. This suggests that Candidalysin-induced cell damage is a third mechanism of C. albicans-mediated mononuclear phagocyte cell death in addition to damage caused by pyroptosis and the growth of glucose-consuming hyphae

Uncoupling of IL-6 signaling and LC3-associated phagocytosis drives immunoparalysis during sepsis

Contains fulltext : 238107.pdf (Publisher’s version ) (Closed access)Immune deactivation of phagocytes is a central event in the pathogenesis of sepsis. Herein, we identify a master regulatory role of IL-6 signaling on LC3-associated phagocytosis (LAP) and reveal that uncoupling of these two processes during sepsis induces immunoparalysis in monocytes/macrophages. In particular, we demonstrate that activation of LAP by the human fungal pathogen Aspergillus fumigatus depends on ERK1/2-mediated phosphorylation of p47phox subunit of NADPH oxidase. Physiologically, autocrine IL-6/JAK2/Ninein axis orchestrates microtubule organization and dynamics regulating ERK recruitment to the phagosome and LC3(+) phagosome (LAPosome) formation. In sepsis, loss of IL-6 signaling specifically abrogates microtubule-mediated trafficking of ERK, leading to defective activation of LAP and impaired killing of bacterial and fungal pathogens by monocytes/macrophages, which can be selectively restored by IL-6 supplementation. Our work uncovers a molecular pathway linking IL-6 signaling with LAP and provides insight into the mechanisms underlying immunoparalysis in sepsis

Rewiring cellular metabolism via the AKT/mTOR pathway contributes to host defence against Mycobacterium tuberculosis in human and murine cells

Contains fulltext : 171426.pdf (publisher's version ) (Open Access)Cells in homeostasis metabolize glucose mainly through the tricarboxylic acid cycle and oxidative phosphorylation, while activated cells switch their basal metabolism to aerobic glycolysis. In this study, we examined whether metabolic reprogramming toward aerobic glycolysis is important for the host response to Mycobacterium tuberculosis (Mtb). Through transcriptional and metabolite analysis we show that Mtb induces a switch in host cellular metabolism toward aerobic glycolysis in human peripheral blood mononuclear cells (PBMCs). The metabolic switch is TLR2 dependent but NOD2 independent, and is mediated in part through activation of the AKT-mTOR (mammalian target of rapamycin) pathway. We show that pharmacological inhibition of the AKT/mTOR pathway inhibits cellular responses to Mtb both in vitro in human PBMCs, and in vivo in a model of murine tuberculosis. Our findings reveal a novel regulatory layer of host responses to Mtb that will aid understanding of host susceptibility to Mtb, and which may be exploited for host-directed therapy

IL1B and DEFB1 Polymorphisms Increase Susceptibility to Invasive Mold Infection After Solid-Organ Transplantation

Background. Single-nucleotide polymorphisms (SNPs) in immune genes have been associated with susceptibility to invasive mold infection (IMI) among hematopoietic stem cell but not solid-organ transplant (SOT) recipients. Methods. Twenty-four SNPs from systematically selected genes were genotyped among 1101 SOT recipients (715 kidney transplant recipients, 190 liver transplant recipients, 102 lung transplant recipients, 79 heart transplant recipients, and 15 recipients of other transplants) from the Swiss Transplant Cohort Study. Association between SNPs and the end point were assessed by log-rank test and Cox regression models. Cytokine production upon Aspergillus stimulation was measured by enzyme-linked immunosorbent assay in peripheral blood mononuclear cells (PBMCs) from healthy volunteers and correlated with relevant genotypes. Results. Mold colonization (n = 45) and proven/probable IMI (n = 26) were associated with polymorphisms in the genes encoding interleukin 1β (IL1B; rs16944; recessive mode, P = .001 for colonization and P = .00005 for IMI, by the log-rank test), interleukin 1 receptor antagonist (IL1RN; rs419598; P = .01 and P = .02, respectively), and β-defensin 1 (DEFB1; rs1800972; P = .001 and P = .0002, respectively). The associations with IL1B and DEFB1 remained significant in a multivariate regression model (P = .002 for IL1B rs16944; P = .01 for DEFB1 rs1800972). The presence of 2 copies of the rare allele of rs16944 or rs419598 was associated with reduced Aspergillus-induced interleukin 1β and tumor necrosis factor α secretion by PBMCs. Conclusions. Functional polymorphisms in IL1B and DEFB1 influence susceptibility to mold infection in SOT recipients. This observation may contribute to individual risk stratificatio

The impact of the Fungus-Host-Microbiota interplay upon Candida albicans infections : current knowledge and new perspectives

ACKNOWLEDGEMENTS: We thank our friends and colleagues in the medical mycology, fungal immunology and microbiota fields for many thought-provoking discussions. FUNDING: We received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie action, Innovative Training Network: FunHoMic; grant N° 812969. CdE received funding from the French Government ‘Investissement d’Avenir’ program (Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases, ANR-10-LABX-62-IBEID), the Agence Nationale de la Recherche (ERA-Net Infect-ERA, FUNCOMPATH, ANR-14-IFEC-0004), the EU Horizon2020 consortium “Host-Directed Medicine in invasive FUNgal infections” - HDM-FUN (Grant Agreement 847507). SLL and CdE received funding from the Swiss National Science Foundation (Sinergia program, #CRSII5_173863). BIOASTER received funding from the French Government ‘Investissement d’Avenir’ program (Grant No. ANR-10-AIRT-03). MSG was supported by a Humboldt Research Fellowship for Postdoctoral Researchers by the Alexander von Humboldt-Foundation and the Deutsche Forschungsgemeinschaft (DFG) Emmy Noether Program (project no. 434385622 / GR 5617/1-1). BH was supported by the Deutsche Forschungsgemeinschaft (DFG) project Hu 532/20-1, project C1 within the Collaborative Research Centre (CRC)/Transregio 124 FungiNet and the Balance of the Microverse Cluster under Germany´s Excellence Strategy – EXC 2051 – Project-ID 390713860, the EU Horizon2020 consortium “Host-Directed Medicine in invasive FUNgal infections” - HDM-FUN (Grant Agreement 847507), the Leibniz Association Campus InfectoOptics SAS-2015-HKI-LWC and the Wellcome Trust (215599/Z/19/Z). IDJ was supported by the Deutsche orschungsgemeinschaft (DFG) project C5 within the Collaborative Research Centre (CRC)/Transregio 124 FungiNet and the Balance of the Microverse Cluster under Germany´s Excellence Strategy – EXC 2051 – Project-ID 390713860, the Leibniz Association Campus InfectoOptics SAS-2015-HKI-LWC and the Wellcome Trust (Grant 215599/Z/19/Z). CM received funding from the the Instituto de Salud Carlos III/FEDER. MGN was supported by an ERC Advanced Grant (#833247) and a Spinoza grant of the Netherlands Organization for Scientific Research. CAM was supported by EU Horizon2020 consortium “Host-Directed Medicine in invasive FUNgal infections” -HDM-FUN (Grant Agreement 847507) and the Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology (097377/Z/11/Z). AWW receives core funding support from the Scottish Government’s Rural and Environment Science and Analytical Services (RESAS). AJPB was supported by a programme grant from the UK Medical Research Council (MR/M026663/1) and by the Medical Research Council Centre for Medical Mycology at the University of Exeter (MR/N006364/1).Peer reviewedPublisher PD