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Secreted fungal effector triggers allergic inflammation via Toll-like receptor 4 to enable lethal infection

ABSTRACT: Invasive fungal pathogens are major causes of human mortality and morbidity1,2. While numerous secreted effector proteins that reprogram innate immunity to promote virulence have been identified in pathogenic bacteria, there are no examples of analogous secreted effector proteins produced by human fungal pathogens. Cryptococcus neoformans, the most common cause of fungal meningitis and a major AIDS pathogen, induces a pathogenic type 2 response characterized by pulmonary eosinophilia and alternatively activated macrophages3-8. Here, we identify Cpl1 as an effector protein secreted by C. neoformans that drives alternative activation (also known as M2 polarization) of macrophages to enable pulmonary infection. We observed that Cpl1-enhanced macrophage polarization requires Toll-like receptor 4, best known as a receptor for bacterial endotoxin, but is also a poorly understood mediator of allergen-induced type 2 responses9-12. We show that this effect is due to Cpl1 itself and not contamination by lipopolysaccharide. Cpl1 is essential for virulence, drives polarization of interstitial macrophages in vivo, and requires type 2 cytokine signaling for its impact on infectivity. Strikingly, C. neoformans selectively associates with polarized interstitial macrophages during infection, suggesting a mechanism by which C. neoformans generates its own intracellular replication niche within the host. This work identifies a novel circuit whereby a secreted effector protein produced by a human fungal pathogen reprograms innate immunity, revealing an unexpected role for Toll-like receptor 4 in pathogenesis of infectious disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE203483 | GEO | 2022/08/12

REPOSITORIES: GEO

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Convergent evolution of peptide-based quorum sensing required for virulence in a eukaryotic pathogen

Project description:Bacterial quorum sensing (QS) systems are characterized by the regulated biogenesis and sensing of specialized signaling molecules. Here, we describe a peptide, Qsp1, secreted by the fungal pathogen Cryptococcus neoformans. Mutants lacking Qsp1 are attenuated for infection, pulmonary accumulation, and growth within macrophages. Qsp1 promotes density-dependent cell wall integrity and resistance to extreme environments. Qsp1 is also required for a secreted aspartyl protease activity required for virulence. Further biochemical and large-scale genetic investigations reveal that cleavage of Qsp1 from the C-terminal of a pro-peptide requires a cell-associated serine protease and Qsp1 sensing requires a predicted oligopeptide importer. Strikingly, these features closely mirror the hallmarks of a peptide-based QS system found in gram-positive bacteria, despite no ancestral relationship between individual components. Our studies thus reveal a convergently evolved, peptide-based QS system required for the virulence of a fungal pathogen.

2016-06-08 | GSE73203 | GEO

The transcriptional response of Cryptococcus neoformans to ingestion by Acanthamoeba castellanii and murine macrophages

Project description:Virulence of Cryptococcus neoformans for mammals was proposed to emerge from evolutionary pressures on its natural environment by protozoan predators, which selected for strategies that allow survival within macrophages. In fact, Acanthamoeba castellanii ingests yeast cells, which then replicate intracellularly. In addition, most fungal factors needed to establish infection in the mammalian host are also important for survival within the amoeba. To better understand the origin of C. neoformans virulence, we compared the transcriptional profile of yeast cells internalized by amoebae and murine macrophages after 6 h of infection. Our results showed 656 and 293 genes whose expression changed at least two-fold in response to the intracellular environments of amoebae and macrophages, respectively. Among the genes common to both groups, we focused on the ORF CNAG_05662, which was potentially related to sugar transport. We constructed a mutant strain and evaluated its ability to grow on various carbon sources. The results showed that this gene, named PTP1 (Polyol Transporter Protein 1), is involved in the transport of 5- and 6-carbon polyols but its absence had no effect on virulence. Overall, our results are consistent with the hypothesis that mammalian virulence originated from fungal-protozoal interactions and provide a better understanding of how C. neoformans adapts to the mammalian host. Four conditions, pairwise-compared: cells in vegetative growth at 28C versus cells within amoebae at 28C; and cells in vegetative growth at 37C/5% CO2 versus cells within macrophages at 37C/5% CO2. Three biological replicates for each condition. One replicate per array.

2013-03-14 | E-GEOD-45027 | biostudies-arrayexpress

The transcriptional response of Cryptococcus neoformans to ingestion by Acanthamoeba castellanii and murine macrophages

2013-03-14 | GSE45027 | GEO

Amoeba Predation of Cryptococcus: A Quantitative and Population Genomic Evaluation of the Accidental Pathogen Hypothesis

Project description:The “Amoeboid Predator-Fungal Animal Virulence Hypothesis” posits that interactions with environmental phagocytes shape the evolution of virulence traits in fungal pathogens. In this hypothesis, selection to avoid predation by amoeba inadvertently selects for traits that contribute to fungal escape from phagocytic immune cells. Here, we investigate this hypothesis in the human fungalpathogens Cryptococcus neoformans and Cryptococcus deneoformans. Applying quantitative trait locus (QTL) mapping and comparative genomics, we discovered a cross-species QTL region that is responsible for variation in resistance to amoeba predation. In C. neoformans, this same QTL was found to have pleiotropic effects on melanization, an established virulence factor. Through fine mapping and population genomic comparisons, we identified the gene encoding the transcription factor BZP4 that underlies this pleiotropic QTL and we show that decreased expression of this gene reduces melanization and increases susceptibility to amoeba predation. Despite the joint effects of BZP4 on amoeba resistance and melanin production, we find no relationship between BZP4 genotype and escape from macrophages or virulence in murine models of disease. Our findings provide new perspectives on how microbial ecology shapes the genetic architecture of fungal virulence, and suggests the need for more nuanced models for the evolution of pathogenesis that account for the complexities of both microbe-microbe and microbe-host interactions.

2023-07-25 | GSE238170 | GEO

Expression profiling of Fusarium oxysporum infected wild-type Arabidopsis and a 35S Fusarium SIX4 overexpression line.

Project description:Fungal effectors play important roles in inciting disease development on host plants. We identified an effector (Secreted in Xylem4, SIX4) in an Arabidopsis infecting isolate (Fo5176) of the root-infecting fungal pathogen Fusarium oxysporum and demonstrated this effector is required for full virulence. To explore the role of Fo5176_SIX4 we use whole transcriptome profiling of root tissues from plants overexpressing this effector (35sSIX4) versus wild-type (Col-0) plants after F. oxysporum infection. Published in DOI:10.1007/978-3-319-42319-7_4. Belowground Defence Strategies in Plants.

2016-05-31 | GSE75928 | GEO

Real time quantitative PCR analysis of murine macrophages

2012-08-09 | GSE39990 | GEO

Casein kinase 2 complex: a central regulator of multiple pathobiological signaling pathways in Cryptococcus neoformans

Project description:Casein kinase 2 (CK2) is a potential therapeutic target for several human diseases due to its crucial roles in growth, differentiation, and metabolic homeostasis. This study delves into the role of the CK2 complex in Cryptococcus neoformans, a key fungal pathogen causing meningitis. In C. neoformans, the CK2 complex is made up of a main catalytic subunit (Cka1) and two regulatory subunits (Ckb1 and Ckb2). The primary role of Cka1 is as a protein kinase, while Ckb1/2 assist in various cellular functions. Triple mutants without all three subunits exhibited more pronounced defects than mutants lacking only Cka1, hinting at potential independent functions of Ckb1/2. In animal studies, mutants without these subunits showed a sharp decline in virulence. Moreover, CK2 disruption affected many effector proteins and disrupted key signaling pathways crucial for the pathogenicity of C. neoformans. Overall, the findings highlight the importance of the CK2 complex in fungal biology and its potential as a target for new antifungal treatments.

2023-12-21 | GSE245849 | GEO

Real time quantitative PCR analysis of murine macrophages

Project description:Murine macrophages were isolated from the lungs of mice given a pulmonary challenge with C. neoformans strain H99. Mice were either given a protective (H99γ) or a mock (HKCn) immunization prior to C. neoformans H99 challenge, and macrophages were isolated from the lungs of mice 24 hours, 3 days, or 7 days post-challenge using anti-CD11b microbeads according to the Miltenyi cell sorting system. We used SA Biosciences Toll-like Receptor PCR assay panel to quantitate gene expression of signal transduction factors in total RNA isolated from macrophages derived from immunized mice compared to non-immunized. qPCR gene expression profiling. Macrophages from 5 mice per group were pooled and assayed as indicated in the summary. Each experiment was performed 3 times and the resulting Ct values of each group from each experiment averaged prior to data analysis. TIme points were analyzed separately

2012-08-09 | E-GEOD-39990 | biostudies-arrayexpress

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2023-03-11 | PXD024951 | Pride

rdi1∆ vs WT during macrophage co-culture

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