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Crouch AL, Monsey L, Rambeau M, Ramos C, Yracheta JM, Anderson MZ. Metagenomic discovery of microbial eukaryotes in stool microbiomes. mBio 2024; 15:e0206324. [PMID: 39207108 PMCID: PMC11481512 DOI: 10.1128/mbio.02063-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 08/05/2024] [Indexed: 09/04/2024] Open
Abstract
Host-associated microbiota form complex microbial communities that are increasingly associated with host behavior and disease. While these microbes include bacterial, archaeal, viral, and eukaryotic constituents, most studies have focused on bacteria due to their dominance in the human host and available tools for investigation. Accumulating evidence suggests microbial eukaryotes in the microbiome play pivotal roles in host health, but our understandings of these interactions are limited to a few readily identifiable taxa because of technical limitations in unbiased eukaryote exploration. Here, we combined cell sorting, optimized eukaryotic cell lysis, and shotgun sequencing to accelerate metagenomic discovery and analysis of host-associated microbial eukaryotes. Using synthetic communities with a 1% microbial eukaryote representation, the eukaryote-optimized cell lysis and DNA recovery method alone yielded a 38-fold increase in eukaryotic DNA. Automated sorting of eukaryotic cells from stool samples of healthy adults increased the number of microbial eukaryote reads in metagenomic pools by up to 28-fold compared to commercial kits. Read frequencies for identified fungi increased by 10,000× on average compared to the Human Microbiome Project and allowed for the identification of novel taxa, de novo assembly of contigs from previously unknown microbial eukaryotes, and gene prediction from recovered genomic segments. These advances pave the way for the unbiased inclusion of microbial eukaryotes in deciphering determinants of health and disease in the host-associated microbiome.IMPORTANCEMicrobial eukaryotes are common constituents of the human gut where they can contribute to local ecology and host health, but they are often overlooked in microbiome studies. The lack of attention is due to current technical limitations that are heavily biased or poorly recovered DNA from microbial eukaryotes. We developed a method to increase the representation of these eukaryotes in metagenomic sequencing of microbiome samples that allows to improve their detection compared to prior methods and allows for the identification of new species. Application of the technique to gut microbiome samples improved detection of fungi, protists, and helminths. New eukaryotic taxa and their encoded genes could be identified by sequencing a small number of samples. This approach can improve the inclusion of eukaryotes into microbiome research.
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Affiliation(s)
- Audra L. Crouch
- Department of Microbiology, The Ohio State University, Columbus, Ohio, USA
| | - Laine Monsey
- Department of Microbiology, The Ohio State University, Columbus, Ohio, USA
| | - Molly Rambeau
- Department of Microbiology, The Ohio State University, Columbus, Ohio, USA
| | - Cameron Ramos
- Department of Microbiology, The Ohio State University, Columbus, Ohio, USA
| | | | - Matthew Z. Anderson
- Department of Microbiology, The Ohio State University, Columbus, Ohio, USA
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA
- Center for Genomic Science Innovation, University of Wisconsin - Madison, Madison, Wisconsin, USA
- Laboratory of Genetics, University of Wisconsin - Madison, Madison, Wisconsin, USA
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Rosati D, Pradhan A, van Heck JIP, Helder L, Jaeger M, Gow NAR, Joosten LAB, Williams DL, Brown AJP, Bruno M, Netea MG. Candida albicans N-Linked Mannans Potentiate the Induction of Trained Immunity via Dectin-2. J Infect Dis 2024; 230:768-777. [PMID: 38446996 PMCID: PMC11420807 DOI: 10.1093/infdis/jiae112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 01/23/2024] [Accepted: 02/28/2024] [Indexed: 03/08/2024] Open
Abstract
The interaction between the Candida albicans cell wall and pattern recognition receptors is crucial for the initiation of host immune responses, which, ultimately, contribute to the clearance of this pathogenic fungus. In the present study, we investigate the ability of C. albicans mannans to modulate immune response and induce innate immune memory (also termed trained immunity). Using mutants of C. albicans that are defective in or lack mannosyl residues, we show that alterations in the mannosylation of the C. albicans cell wall affect the innate cytokine response and strongly reduce the secretion of T-cell-derived cytokines. Subsequently, we demonstrate that the branching of N-linked mannan, but not O-linked mannan, is essential to potentiate the induction of trained immunity, a process mediated by dectin 2. In conclusion, N-linked mannan is needed, in addition to β-glucans, for an effective induction of trained immunity by C. albicans.
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Affiliation(s)
- Diletta Rosati
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, the Netherlands
| | - Arnab Pradhan
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter EX4 4QD, United Kingdom
| | - Julia I P van Heck
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, the Netherlands
| | - Leonie Helder
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, the Netherlands
| | - Martin Jaeger
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, the Netherlands
| | - Neil A R Gow
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter EX4 4QD, United Kingdom
| | - Leo A B Joosten
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, the Netherlands
- Department of Medical Genetics, Iuliu Hatieganu University of Medicine and PharmacyCluj-Napoca, Romania
| | - David L Williams
- Departments of Surgery, Biomedical Sciences and Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
| | - Alistair J P Brown
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter EX4 4QD, United Kingdom
| | - Mariolina Bruno
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, the Netherlands
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, the Netherlands
- Department for Immunology and Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
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Katsipoulaki M, Stappers MHT, Malavia-Jones D, Brunke S, Hube B, Gow NAR. Candida albicans and Candida glabrata: global priority pathogens. Microbiol Mol Biol Rev 2024; 88:e0002123. [PMID: 38832801 PMCID: PMC11332356 DOI: 10.1128/mmbr.00021-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2024] Open
Abstract
SUMMARYA significant increase in the incidence of Candida-mediated infections has been observed in the last decade, mainly due to rising numbers of susceptible individuals. Recently, the World Health Organization published its first fungal pathogen priority list, with Candida species listed in medium, high, and critical priority categories. This review is a synthesis of information and recent advances in our understanding of two of these species-Candida albicans and Candida glabrata. Of these, C. albicans is the most common cause of candidemia around the world and is categorized as a critical priority pathogen. C. glabrata is considered a high-priority pathogen and has become an increasingly important cause of candidemia in recent years. It is now the second most common causative agent of candidemia in many geographical regions. Despite their differences and phylogenetic divergence, they are successful as pathogens and commensals of humans. Both species can cause a broad variety of infections, ranging from superficial to potentially lethal systemic infections. While they share similarities in certain infection strategies, including tissue adhesion and invasion, they differ significantly in key aspects of their biology, interaction with immune cells, host damage strategies, and metabolic adaptations. Here we provide insights on key aspects of their biology, epidemiology, commensal and pathogenic lifestyles, interactions with the immune system, and antifungal resistance.
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Affiliation(s)
- Myrto Katsipoulaki
- Department of Microbial Pathogenicity Mechanisms, Hans Knoell Institute, Jena, Germany
| | - Mark H. T. Stappers
- MRC Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom
| | - Dhara Malavia-Jones
- MRC Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom
| | - Sascha Brunke
- Department of Microbial Pathogenicity Mechanisms, Hans Knoell Institute, Jena, Germany
| | - Bernhard Hube
- Department of Microbial Pathogenicity Mechanisms, Hans Knoell Institute, Jena, Germany
- Institute of Microbiology, Friedrich Schiller University, Jena, Germany
| | - Neil A. R. Gow
- MRC Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom
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Zhou T, Solis NV, Marshall M, Yao Q, Garleb R, Yang M, Pearlman E, Filler SG, Liu H. Hyphal Als proteins act as CR3 ligands to promote immune responses against Candida albicans. Nat Commun 2024; 15:3926. [PMID: 38724513 PMCID: PMC11082240 DOI: 10.1038/s41467-024-48093-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 04/19/2024] [Indexed: 05/12/2024] Open
Abstract
Patients with decreased levels of CD18 (β2 integrins) suffer from life-threatening bacterial and fungal infections. CD11b, the α subunit of integrin CR3 (CD11b/CD18, αMβ2), is essential for mice to fight against systemic Candida albicans infections. Live elongating C. albicans activates CR3 in immune cells. However, the hyphal ligands that activate CR3 are not well defined. Here, we discovered that the C. albicans Als family proteins are recognized by the I domain of CD11b in macrophages. This recognition synergizes with the β-glucan-bound lectin-like domain to activate CR3, thereby promoting Syk signaling and inflammasome activation. Dectin-2 activation serves as the "outside-in signaling" for CR3 activation at the entry site of incompletely sealed phagosomes, where a thick cuff of F-actin forms to strengthen the local interaction. In vitro, CD18 partially contributes to IL-1β release from dendritic cells induced by purified hyphal Als3. In vivo, Als3 is vital for C. albicans clearance in mouse kidneys. These findings uncover a novel family of ligands for the CR3 I domain that promotes fungal clearance.
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Affiliation(s)
- Tingting Zhou
- Department of Biological Chemistry, University of California, Irvine, CA, USA
| | - Norma V Solis
- Division of Infectious Diseases, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Michaela Marshall
- Department of Physiology and Biophysics, University of California, Irvine, CA, USA
| | - Qing Yao
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
- Gilead Sciences Inc., Foster City, CA, USA
| | - Rachel Garleb
- Department of Biological Chemistry, University of California, Irvine, CA, USA
| | - Mengli Yang
- Department of Biological Chemistry, University of California, Irvine, CA, USA
- Zymo Research Corporation, Irvine, CA, USA
| | - Eric Pearlman
- Department of Physiology and Biophysics, University of California, Irvine, CA, USA
| | - Scott G Filler
- Division of Infectious Diseases, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
- David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Haoping Liu
- Department of Biological Chemistry, University of California, Irvine, CA, USA.
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Yang Z, Wang X, Dong T, Zhao WJ, Li H. Impact of glucocorticoids and rapamycin on autophagy in Candida glabrata-infected macrophages from BALB/c mice. Front Immunol 2024; 15:1367048. [PMID: 38585259 PMCID: PMC10995521 DOI: 10.3389/fimmu.2024.1367048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 02/19/2024] [Indexed: 04/09/2024] Open
Abstract
Objective In the defense against microorganisms like Candida albicans, macrophages recruit LC3(Microtubule-associated protein 1A/1B-light chain 3) to the periplasm, engaging in the elimination process through the formation of a single-membrane phagosome known as LC3-associated phagocytosis (LAP). Building on this, we propose the hypothesis that glucocorticoids may hinder macrophage phagocytosis of Candida glabrata by suppressing LAP, and rapamycin could potentially reverse this inhibitory effect. Methods RAW264.7 cells were employed for investigating the immune response to Candida glabrata infection. Various reagents, including dexamethasone, rapamycin, and specific antibodies, were utilized in experimental setups. Assays, such as fluorescence microscopy, flow cytometry, ELISA (Enzyme-Linked Immunosorbent Assay), Western blot, and confocal microscopy, were conducted to assess phagocytosis, cytokine levels, protein expression, viability, and autophagy dynamics. Results Glucocorticoids significantly inhibited macrophage autophagy, impairing the cells' ability to combat Candida glabrata. Conversely, rapamycin exhibited a dual role, initially inhibiting and subsequently promoting phagocytosis of Candida glabrata by macrophages. Glucocorticoids hinder macrophage autophagy in Candida glabrata infection by suppressing the MTOR pathway(mammalian target of rapamycin pathway), while the activation of MTOR pathway by Candida glabrata diminishes over time. Conclusion Our study elucidates the intricate interplay between glucocorticoids, rapamycin, and macrophage autophagy during Candida glabrata infection. Understanding the implications of these interactions not only sheds light on the host immune response dynamics but also unveils potential therapeutic avenues for managing fungal infections.
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Affiliation(s)
| | | | | | | | - Hongbin Li
- Department of Dermatology and Venereology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
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Li S, Liu Y, Weng L, Zhao Y, Zhang Y, Zhang Z, Yang Y, Chen Q, Liu X, Zhang H. The F 1F o-ATP synthase α subunit of Candida albicans induces inflammatory responses by controlling amino acid catabolism. Virulence 2023; 14:2190645. [PMID: 36914568 PMCID: PMC10072111 DOI: 10.1080/21505594.2023.2190645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 02/08/2023] [Accepted: 03/09/2023] [Indexed: 03/15/2023] Open
Abstract
Sepsis is a leading cause of fatality in invasive candidiasis. The magnitude of the inflammatory response is a determinant of sepsis outcomes, and inflammatory cytokine imbalances are central to the pathophysiological processes. We previously demonstrated that a Candida albicans F1Fo-ATP synthase α subunit deletion mutant was nonlethal to mice. Here, the potential effects of the F1Fo-ATP synthase α subunit on host inflammatory responses and the mechanism were studied. Compared with wild-type strain, the F1Fo-ATP synthase α subunit deletion mutant failed to induce inflammatory responses in Galleria mellonella and murine systemic candidiasis models and significantly decreased the mRNA levels of the proinflammatory cytokines IL-1β, IL-6 and increased those of the anti-inflammatory cytokine IL-4 in the kidney. During C. albicans-macrophage co-culture, the F1Fo-ATP synthase α subunit deletion mutant was trapped inside macrophages in yeast form, and its filamentation, a key factor in inducing inflammatory responses, was inhibited. In the macrophage-mimicking microenvironment, the F1Fo-ATP synthase α subunit deletion mutant blocked the cAMP/PKA pathway, the core filamentation-regulating pathway, because it failed to alkalinize environment by catabolizing amino acids, an important alternative carbon source inside macrophages. The mutant downregulated Put1 and Put2, two essential amino acid catabolic enzymes, possibly due to severely impaired oxidative phosphorylation. Our findings reveal that the C. albicans F1Fo-ATP synthase α subunit induces host inflammatory responses by controlling its own amino acid catabolism and it is significant to find drugs that inhibit F1Fo-ATP synthase α subunit activity to control the induction of host inflammatory responses.
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Affiliation(s)
- Shuixiu Li
- Department of Dermatology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
- Institute of Mycology, Jinan University, Guangzhou, Guangdong, China
| | - Yuting Liu
- Department of Dermatology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
- Institute of Mycology, Jinan University, Guangzhou, Guangdong, China
| | - Luobei Weng
- Department of Dermatology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
- Institute of Mycology, Jinan University, Guangzhou, Guangdong, China
| | - Yajing Zhao
- Department of Dermatology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
- Institute of Mycology, Jinan University, Guangzhou, Guangdong, China
| | - Yishan Zhang
- Department of Dermatology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
- Institute of Mycology, Jinan University, Guangzhou, Guangdong, China
| | - Zhanpeng Zhang
- Department of Dermatology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
- Institute of Mycology, Jinan University, Guangzhou, Guangdong, China
| | - Yang Yang
- Department of Dermatology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
- Institute of Mycology, Jinan University, Guangzhou, Guangdong, China
| | - Qiaoxin Chen
- Department of Dermatology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
- Institute of Mycology, Jinan University, Guangzhou, Guangdong, China
| | - Xiaocong Liu
- Department of Dermatology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
- Institute of Mycology, Jinan University, Guangzhou, Guangdong, China
| | - Hong Zhang
- Department of Dermatology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
- Institute of Mycology, Jinan University, Guangzhou, Guangdong, China
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Carlson SL, Mathew L, Savage M, Kok K, Lindsay JO, Munro CA, McCarthy NE. Mucosal Immunity to Gut Fungi in Health and Inflammatory Bowel Disease. J Fungi (Basel) 2023; 9:1105. [PMID: 37998910 PMCID: PMC10672531 DOI: 10.3390/jof9111105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 11/09/2023] [Accepted: 11/12/2023] [Indexed: 11/25/2023] Open
Abstract
The gut microbiome is a diverse microbial community composed of bacteria, viruses, and fungi that plays a major role in human health and disease. Dysregulation of these gut organisms in a genetically susceptible host is fundamental to the pathogenesis of inflammatory bowel disease (IBD). While bacterial dysbiosis has been a predominant focus of research for many years, there is growing recognition that fungal interactions with the host immune system are an important driver of gut inflammation. Candida albicans is likely the most studied fungus in the context of IBD, being a near universal gut commensal in humans and also a major barrier-invasive pathogen. There is emerging evidence that intra-strain variation in C. albicans virulence factors exerts a critical influence on IBD pathophysiology. In this review, we describe the immunological impacts of variations in C. lbicans colonisation, morphology, genetics, and proteomics in IBD, as well as the clinical and therapeutic implications.
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Affiliation(s)
- Sean L. Carlson
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London E1 2AT, UK
- Gastroenterology Department, Royal London Hospital, Barts Health NHS Trust, London E1 1BB, UK
| | - Liya Mathew
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London E1 2AT, UK
| | - Michael Savage
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London E1 2AT, UK
| | - Klaartje Kok
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London E1 2AT, UK
- Gastroenterology Department, Royal London Hospital, Barts Health NHS Trust, London E1 1BB, UK
| | - James O. Lindsay
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London E1 2AT, UK
- Gastroenterology Department, Royal London Hospital, Barts Health NHS Trust, London E1 1BB, UK
| | - Carol A. Munro
- Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB24 3FX, UK
| | - Neil E. McCarthy
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London E1 2AT, UK
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Proctor DM, Drummond RA, Lionakis MS, Segre JA. One population, multiple lifestyles: Commensalism and pathogenesis in the human mycobiome. Cell Host Microbe 2023; 31:539-553. [PMID: 37054674 PMCID: PMC10155287 DOI: 10.1016/j.chom.2023.02.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 02/12/2023] [Accepted: 02/23/2023] [Indexed: 04/15/2023]
Abstract
Candida auris and Candida albicans can result in invasive fungal diseases. And yet, these species can stably and asymptomatically colonize human skin and gastrointestinal tracts. To consider these disparate microbial lifestyles, we first review factors shown to influence the underlying microbiome. Structured by the damage response framework, we then consider the molecular mechanisms deployed by C. albicans to switch between commensal and pathogenic lifestyles. Next, we explore this framework with C. auris to highlight how host physiology, immunity, and/or antibiotic receipt are associated with progression from colonization to infection. While treatment with antibiotics increases the risk that an individual will succumb to invasive candidiasis, the underlying mechanisms remain unclear. Here, we describe several hypotheses that may explain this phenomenon. We conclude by highlighting future directions integrating genomics with immunology to advance our understanding of invasive candidiasis and human fungal disease.
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Affiliation(s)
- Diana M Proctor
- Microbial Genomics Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Rebecca A Drummond
- Institute of Immunology & Immunotherapy, Institute of Microbiology & Infection, University of Birmingham, Birmingham B15 2TT, UK
| | - Michail S Lionakis
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy & Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Julia A Segre
- Microbial Genomics Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Wang H, Wu H, Li KD, Wang YY, Huang RG, Du YJ, Jin X, Zhang QR, Li XB, Li BZ. Intestinal fungi and systemic autoimmune diseases. Autoimmun Rev 2023; 22:103234. [PMID: 36423833 DOI: 10.1016/j.autrev.2022.103234] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 11/17/2022] [Indexed: 11/23/2022]
Abstract
Nearly 20 years of studies have shown that fungi and the human immune system (non-specific immunity and specific immunity) and bacterial--fungal interactions maintain a balance that can't lead to diseases. Fungi--microorganism that lives in human intestine--may play an important role in human health and disease. Population studies and animal models in some diseases have found the changes in the diversity and composition of fungi. The dysregulation of the fungi can disrupt the normal "running" of the immune system and bacteria, which triggers the development of inflammatory diseases. The latest studies of fungi in inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis and type 1 diabetes mellitus were summarized. This review considers how the healthy host protect against the potential harm of intestinal fungi through the immune system and how fungal dysregulation alters host immunity.
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Affiliation(s)
- Hua Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Hong Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Kai-Di Li
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Yi-Yu Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Rong-Gui Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Yu-Jie Du
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Xue Jin
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Qian-Ru Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China; Department of Cardiovascular Surgery, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Xian-Bao Li
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Bao-Zhu Li
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China.
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10
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Xue S, Rogers LR, Zheng M, He J, Piermarocchi C, Mias GI. Applying differential network analysis to longitudinal gene expression in response to perturbations. Front Genet 2022; 13:1026487. [PMID: 36324501 PMCID: PMC9618823 DOI: 10.3389/fgene.2022.1026487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 10/03/2022] [Indexed: 11/17/2022] Open
Abstract
Differential Network (DN) analysis is a method that has long been used to interpret changes in gene expression data and provide biological insights. The method identifies the rewiring of gene networks in response to external perturbations. Our study applies the DN method to the analysis of RNA-sequencing (RNA-seq) time series datasets. We focus on expression changes: (i) in saliva of a human subject after pneumococcal vaccination (PPSV23) and (ii) in primary B cells treated ex vivo with a monoclonal antibody drug (Rituximab). The DN method enabled us to identify the activation of biological pathways consistent with the mechanisms of action of the PPSV23 vaccine and target pathways of Rituximab. The community detection algorithm on the DN revealed clusters of genes characterized by collective temporal behavior. All saliva and some B cell DN communities showed characteristic time signatures, outlining a chronological order in pathway activation in response to the perturbation. Moreover, we identified early and delayed responses within network modules in the saliva dataset and three temporal patterns in the B cell data.
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Affiliation(s)
- Shuyue Xue
- Department of Physics and Astronomy, Michigan State University, East Lansing, MI, United States
- Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, United States
| | - Lavida R.K. Rogers
- Department of Biological Sciences, University of the Virgin Islands, St Thomas, US Virgin Islands
| | - Minzhang Zheng
- Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, United States
| | - Jin He
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, United States
| | - Carlo Piermarocchi
- Department of Physics and Astronomy, Michigan State University, East Lansing, MI, United States
| | - George I. Mias
- Department of Physics and Astronomy, Michigan State University, East Lansing, MI, United States
- Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, United States
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, United States
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11
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Bruno M, Davidson L, Koenen HJPM, van den Reek JMPA, van Cranenbroek B, de Jong EMGJ, van de Veerdonk FL, Kullberg BJ, Netea MG. Immunological effects of anti-IL-17/12/23 therapy in patients with psoriasis complicated by Candida infections. J Invest Dermatol 2022; 142:2929-2939.e8. [PMID: 35662644 DOI: 10.1016/j.jid.2022.05.1083] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 05/08/2022] [Accepted: 05/24/2022] [Indexed: 12/12/2022]
Abstract
Biologics that block the T-helper-17 pathway are very effective in the treatment of psoriasis and other inflammatory diseases. However, interleukin-17 is also crucial for antifungal host defense, and clinical trial data suggest an increase in the incidence of Candida infections during IL-17 inhibitor (IL-17i) therapy. We investigated the innate and adaptive immune responses of psoriasis patients with a history of skin and/or mucosal candidiasis during IL-17i or IL-12/23i therapy, comparing those responses to healthy controls. Psoriasis patients with IL-17i showed significantly lower CD4+Th1-like (CCR6-CXCR3+CCR4-) and Th1Th17-like (CD4+CCR6+CXCR3+CCR4-) cell percentages. Patient cells stimulated with Candida albicans produced significantly lower IL-6 in the IL-12/23i group and IL-1β production in the IL-17i group, while the release of TNF-α and ROS was similar between patients and controls. IFN-γ and IL-10 production in response to several stimuli after 7 days was particularly decreased in patients receiving IL-17i therapy. Finally, after stimulation with the polarizing cytokines IL-1β and IL-23, the Th17 cytokine response was significantly lower in the IL-17i patient group. These innate and adaptive immune response defects can diminish antifungal host immune response and thereby increase susceptibility to candidiasis in patients treated with IL-17i or IL-12/23i.
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Affiliation(s)
- Mariolina Bruno
- Radboud University Medical Center Center for Infectious Diseases (RCI), Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
| | - Linda Davidson
- Radboud University Medical Center Center for Infectious Diseases (RCI), Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Hans J P M Koenen
- Laboratory Medical Immunology, Radboud University Medical Center, the Netherlands
| | | | - Bram van Cranenbroek
- Laboratory Medical Immunology, Radboud University Medical Center, the Netherlands
| | - Elke M G J de Jong
- Department of Dermatology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Frank L van de Veerdonk
- Radboud University Medical Center Center for Infectious Diseases (RCI), Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; Radboud Center for Infectious Disease (RCI), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Bart-Jan Kullberg
- Radboud University Medical Center Center for Infectious Diseases (RCI), Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Mihai G Netea
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; Radboud Center for Infectious Disease (RCI), Radboud University Medical Center, Nijmegen, the Netherlands; Department of Immunology and Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
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12
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Lin D, Hu Q, Yang L, Zeng X, Xiao Y, Wang D, Dai W, Lu H, Fang J, Tang Z, Wang Z. The niche-specialist and age-related oral microbial ecosystem: crosstalk with host immune cells in homeostasis. Microb Genom 2022; 8. [PMID: 35731208 PMCID: PMC9455711 DOI: 10.1099/mgen.0.000811] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Although characterization of the baseline oral microbiota has been discussed, the current literature seems insufficient to draw a definitive conclusion on the interactions between the microbes themselves or with the host. This study focuses on the spatial and temporal characteristics of the oral microbial ecosystem in a mouse model and its crosstalk with host immune cells in homeostasis. The V3V4 regions of the 16S rRNA gene of 20 samples from four niches (tongue, buccal mucosa, keratinized gingiva and hard palate) and 10 samples from two life stages (adult and old) were analysed. Flow cytometry (FCM) was used to investigate the resident immune cells. The niche-specialist and age-related communities, characterized based on the microbiota structure, interspecies communications, microbial functions and interactions with immune cells, were addressed. The phylum Firmicutes was the major component in the oral community. The microbial community profiles at the genus level showed that the relative abundances of the genera Bacteroides, Lactobacillus and Porphyromonas were enriched in the gingiva. The abundance of the genera Streptococcus, Faecalibaculum and Veillonella was increased in palatal samples, while the abundance of Neisseria and Bradyrhizobium was enriched in buccal samples. The genera Corynebacterium, Stenotrophomonas, Streptococcus and Fusobacterium were proportionally enriched in old samples, while Prevotella and Lacobacillus were enriched in adult samples. Network analysis showed that the genus Lactobacillus performed as a central node in the buccal module, while in the gingiva module, the central nodes were Nesterenkonia and Hydrogenophilus. FCM showed that the proportion of Th1 cells in the tongue samples (38.18 % [27.03–49.34 %]) (mean [range]) was the highest. The proportion of γδT cells in the buccal mucosa (25.82 % [22.1–29.54 %]) and gingiva (20.42 % [18.31–22.53 %]) samples was higher (P<0.01) than those in the palate (14.18 % [11.69–16.67 %]) and tongue (9.38 % [5.38–13.37 %] samples. The proportion of Th2 (31.3 % [16.16–46.44 %]), Th17 (27.06 % [15.76–38.36 %]) and Treg (29.74 % [15.71–43.77 %]) cells in the old samples was higher than that in the adult samples (P<0.01). Further analysis of the interplays between the microbiomes and immune cells indicated that Th1 cells in the adult group, nd Th2, Th17 and Treg cells in the old group were the main immune factors strongly associated with the oral microbiota. For example, Th2, Th17 and Treg cells showed a significantly positive correlation with age-related microorganisms such as Sphingomonas, Streptococcus and Acinetobacter, while Th1 cells showed a negative correlation. Another positive correlation occurred between Th1 cells and several commensal microbiomes such as Lactobacillus, Jeotgalicoccus and Sporosarcina. Th2, Th17 and Treg cells showed the opposite trend. Together, our findings identify the niche-specialist and age-related characteristics of the oral microbial ecosystem and the potential associations between the microbiomes and the mucosal immune cells, providing critical insights into mucosal microbiology.
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Affiliation(s)
- Dongjia Lin
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, PR China
| | - Qiannan Hu
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, PR China
| | - Lisa Yang
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, PR China
| | - Xian Zeng
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, PR China
| | - Yiwei Xiao
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, PR China
| | - Dikan Wang
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, PR China
| | - Wenxiao Dai
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, PR China
| | - Huanzi Lu
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, PR China
| | - Juan Fang
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, PR China
| | - Zhonghui Tang
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, PR China
| | - Zhi Wang
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, PR China
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13
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Li M, Zhang R, Li J, Li J. The Role of C-Type Lectin Receptor Signaling in the Intestinal Microbiota-Inflammation-Cancer Axis. Front Immunol 2022; 13:894445. [PMID: 35619716 PMCID: PMC9127077 DOI: 10.3389/fimmu.2022.894445] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 04/04/2022] [Indexed: 12/13/2022] Open
Abstract
As a subset of pattern recognition receptors (PRRs), C-type lectin-like receptors (CLRs) are mainly expressed by myeloid cells as both transmembrane and soluble forms. CLRs recognize not only pathogen associated molecular patterns (PAMPs), but also damage-associated molecular patterns (DAMPs) to promote innate immune responses and affect adaptive immune responses. Upon engagement by PAMPs or DAMPs, CLR signaling initiates various biological activities in vivo, such as cytokine secretion and immune cell recruitment. Recently, several CLRs have been implicated as contributory to the pathogenesis of intestinal inflammation, which represents a prominent risk factor for colorectal cancer (CRC). CLRs function as an interface among microbiota, intestinal epithelial barrier and immune system, so we firstly discussed the relationship between dysbiosis caused by microbiota alteration and inflammatory bowel disease (IBD), then focused on the role of CLRs signaling in pathogenesis of IBD (including Mincle, Dectin-3, Dectin-1, DCIR, DC-SIGN, LOX-1 and their downstream CARD9). Given that CLRs mediate intricate inflammatory signals and inflammation plays a significant role in tumorigenesis, we finally highlight the specific effects of CLRs on CRC, especially colitis-associated cancer (CAC), hoping to open new horizons on pathogenesis and therapeutics of IBD and CAC.
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Affiliation(s)
- Muhan Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Gut Microbiota Translational Medicine Research, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Runfeng Zhang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Gut Microbiota Translational Medicine Research, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ji Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Gut Microbiota Translational Medicine Research, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jingnan Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Gut Microbiota Translational Medicine Research, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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14
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Crosstalk between Body Microbiota and the Regulation of Immunity. J Immunol Res 2022; 2022:6274265. [PMID: 35647199 PMCID: PMC9135571 DOI: 10.1155/2022/6274265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/19/2022] [Accepted: 04/25/2022] [Indexed: 11/26/2022] Open
Abstract
The microbiome corresponds to the genetic component of microorganisms (archaea, bacteria, phages, viruses, fungi, and protozoa) that coexist with an individual. During the last two decades, research on this topic has become massive demonstrating that in both homeostasis and disease, the microbiome plays an important role, and in some cases, a decisive one. To date, microbiota have been identified at different body locations, such as the eyes, lung, gastrointestinal and genitourinary tracts, and skin, and technological advances have permitted the taxonomic characterization of resident species and their metabolites, in addition to the cellular and molecular components of the host that maintain a crosstalk with local microorganisms. Here, we summarize recent studies regarding microbiota residing in different zones of the body and their relationship with the immune system. We emphasize the immune components underlying pathological conditions and how they interact with local (and distant) microbiota.
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15
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Gutierrez MW, van Tilburg Bernardes E, Changirwa D, McDonald B, Arrieta MC. "Molding" immunity-modulation of mucosal and systemic immunity by the intestinal mycobiome in health and disease. Mucosal Immunol 2022; 15:573-583. [PMID: 35474360 DOI: 10.1038/s41385-022-00515-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 03/24/2022] [Accepted: 04/04/2022] [Indexed: 02/04/2023]
Abstract
Fungi are important yet understudied contributors to the microbial communities of the gastrointestinal tract. Starting at birth, the intestinal mycobiome undergoes a period of dynamic maturation under the influence of microbial, host, and extrinsic influences, with profound functional implications for immune development in early life, and regulation of immune homeostasis throughout life. Candida albicans serves as a model organism for understanding the cross-talk between fungal colonization dynamics and immunity, and exemplifies unique mechanisms of fungal-immune interactions, including fungal dimorphism, though our understanding of other intestinal fungi is growing. Given the prominent role of the gut mycobiome in promoting immune homeostasis, emerging evidence points to fungal dysbiosis as an influential contributor to immune dysregulation in a variety of inflammatory and infectious diseases. Here we review current knowledge on the factors that govern host-fungi interactions in the intestinal tract and immunological outcomes in both mucosal and systemic compartments.
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Affiliation(s)
- Mackenzie W Gutierrez
- Immunology Research Group, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Department of Pediatrics, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.,Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,International Microbiome Centre, University of Calgary, Calgary, AB, Canada
| | - Erik van Tilburg Bernardes
- Immunology Research Group, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Department of Pediatrics, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.,Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,International Microbiome Centre, University of Calgary, Calgary, AB, Canada
| | - Diana Changirwa
- Immunology Research Group, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,International Microbiome Centre, University of Calgary, Calgary, AB, Canada.,Department of Critical Care Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Braedon McDonald
- Immunology Research Group, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,International Microbiome Centre, University of Calgary, Calgary, AB, Canada.,Department of Critical Care Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Marie-Claire Arrieta
- Immunology Research Group, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. .,Department of Pediatrics, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada. .,Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. .,International Microbiome Centre, University of Calgary, Calgary, AB, Canada.
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16
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Yang M, Solis NV, Marshall M, Garleb R, Zhou T, Wang D, Swidergall M, Pearlman E, Filler SG, Liu H. Control of β-glucan exposure by the endo-1,3-glucanase Eng1 in Candida albicans modulates virulence. PLoS Pathog 2022; 18:e1010192. [PMID: 34995333 PMCID: PMC8775328 DOI: 10.1371/journal.ppat.1010192] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 01/20/2022] [Accepted: 12/13/2021] [Indexed: 01/09/2023] Open
Abstract
Candida albicans is a major opportunistic pathogen of humans. It can grow as morphologically distinct yeast, pseudohyphae and hyphae, and the ability to switch reversibly among different forms is critical for its virulence. The relationship between morphogenesis and innate immune recognition is not quite clear. Dectin-1 is a major C-type lectin receptor that recognizes β-glucan in the fungal cell wall. C. albicans β-glucan is usually masked by the outer mannan layer of the cell wall. Whether and how β-glucan masking is differentially regulated during hyphal morphogenesis is not fully understood. Here we show that the endo-1,3-glucanase Eng1 is differentially expressed in yeast, and together with Yeast Wall Protein 1 (Ywp1), regulates β-glucan exposure and Dectin-1-dependent immune activation of macrophage by yeast cells. ENG1 deletion results in enhanced Dectin-1 binding at the septa of yeast cells; while eng1 ywp1 yeast cells show strong overall Dectin-1 binding similar to hyphae of wild-type and eng1 mutants. Correlatively, hyphae of wild-type and eng1 induced similar levels of cytokines in macrophage. ENG1 expression and Eng1-mediated β-glucan trimming are also regulated by antifungal drugs, lactate and N-acetylglucosamine. Deletion of ENG1 modulates virulence in the mouse model of hematogenously disseminated candidiasis in a Dectin-1-dependent manner. The eng1 mutant exhibited attenuated lethality in male mice, but enhanced lethality in female mice, which was associated with a stronger renal immune response and lower fungal burden. Thus, Eng1-regulated β-glucan exposure in yeast cells modulates the balance between immune protection and immunopathogenesis during disseminated candidiasis.
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Affiliation(s)
- Mengli Yang
- Department of Biological Chemistry, University of California, Irvine, California, United States of America
- School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, California, United States of America
| | - Norma V. Solis
- Division of Infectious Diseases, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, United States of America
| | - Michaela Marshall
- Department of Physiology and Biophysics, University of California, Irvine, California, United States of America
| | - Rachel Garleb
- Department of Biological Chemistry, University of California, Irvine, California, United States of America
| | - Tingting Zhou
- Department of Biological Chemistry, University of California, Irvine, California, United States of America
| | - Daidong Wang
- Amgen Inc. Thousand Oaks, California, United States of America
| | - Marc Swidergall
- Division of Infectious Diseases, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, United States of America
- David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
| | - Eric Pearlman
- Department of Physiology and Biophysics, University of California, Irvine, California, United States of America
- Institute of Immunology, University of California, Irvine, California, United States of America
| | - Scott G. Filler
- Division of Infectious Diseases, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, United States of America
- David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
| | - Haoping Liu
- Department of Biological Chemistry, University of California, Irvine, California, United States of America
- School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, California, United States of America
- Institute of Immunology, University of California, Irvine, California, United States of America
- * E-mail:
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17
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Ding X, Kambara H, Guo R, Kanneganti A, Acosta-Zaldívar M, Li J, Liu F, Bei T, Qi W, Xie X, Han W, Liu N, Zhang C, Zhang X, Yu H, Zhao L, Ma F, Köhler JR, Luo HR. Inflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages. Nat Commun 2021; 12:6699. [PMID: 34795266 PMCID: PMC8602704 DOI: 10.1038/s41467-021-27034-9] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 10/25/2021] [Indexed: 12/11/2022] Open
Abstract
Candida albicans is the most common cause of fungal sepsis. Inhibition of inflammasome activity confers resistance to polymicrobial and LPS-induced sepsis; however, inflammasome signaling appears to protect against C. albicans infection, so inflammasome inhibitors are not clinically useful for candidiasis. Here we show disruption of GSDMD, a known inflammasome target and key pyroptotic cell death mediator, paradoxically alleviates candidiasis, improving outcomes and survival of Candida-infected mice. Mechanistically, C. albicans hijacked the canonical inflammasome-GSDMD axis-mediated pyroptosis to promote their escape from macrophages, deploying hyphae and candidalysin, a pore-forming toxin expressed by hyphae. GSDMD inhibition alleviated candidiasis by preventing C. albicans escape from macrophages while maintaining inflammasome-dependent but GSDMD-independent IL-1β production for anti-fungal host defenses. This study demonstrates key functions for GSDMD in Candida's escape from host immunity in vitro and in vivo and suggests that GSDMD may be a potential therapeutic target in C. albicans-induced sepsis.
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Affiliation(s)
- Xionghui Ding
- Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA
- Department of Burn and Plastic Surgery, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China
| | - Hiroto Kambara
- Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA
| | - Rongxia Guo
- Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, CAMS Key laboratory for prevention and control of hematological disease treatment related infection, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Apurva Kanneganti
- Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA
| | - Maikel Acosta-Zaldívar
- Division of Infectious Diseases, Boston Children's Hospital/Harvard Medical School, Boston, MA, 02115, USA
| | - Jiajia Li
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, CAMS Key laboratory for prevention and control of hematological disease treatment related infection, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Fei Liu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, CAMS Key laboratory for prevention and control of hematological disease treatment related infection, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Ting Bei
- Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA
| | - Wanjun Qi
- Division of Infectious Diseases, Boston Children's Hospital/Harvard Medical School, Boston, MA, 02115, USA
| | - Xuemei Xie
- Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA
| | - Wenli Han
- Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA
| | - Ningning Liu
- Division of Infectious Diseases, Boston Children's Hospital/Harvard Medical School, Boston, MA, 02115, USA
| | - Cunling Zhang
- Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA
| | - Xiaoyu Zhang
- Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA
| | - Hongbo Yu
- VA Boston Healthcare System, Department of Pathology and Laboratory Medicine, 1400 VFW Parkway West Roxbury, Boston, MA, 02132, USA
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA
| | - Li Zhao
- Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA
| | - Fengxia Ma
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, CAMS Key laboratory for prevention and control of hematological disease treatment related infection, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Julia R Köhler
- Division of Infectious Diseases, Boston Children's Hospital/Harvard Medical School, Boston, MA, 02115, USA
| | - Hongbo R Luo
- Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA.
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18
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Ferreira-Gomes M, Wich M, Böde S, Hube B, Jacobsen ID, Jungnickel B. B Cell Recognition of Candida albicans Hyphae via TLR 2 Promotes IgG1 and IL-6 Secretion for T H17 Differentiation. Front Immunol 2021; 12:698849. [PMID: 34819929 PMCID: PMC8606576 DOI: 10.3389/fimmu.2021.698849] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 10/19/2021] [Indexed: 01/05/2023] Open
Abstract
Candida albicans is usually a benign member of the human gut microbiota, but can become pathogenic under certain circumstances, for example in an immunocompromised host. The innate immune system, in particular neutrophils and macrophages, constitutes a crucial first line of defense against fungal invasion, however adaptive immunity may provide long term protection and thus allow vaccination of at risk patients. While TH1 and TH17 cells are important for antifungal responses, the role of B cells and antibodies in protection from C. albicans infection is less well defined. In this study, we show that C. albicans hyphae but not yeast, as well as fungal cell wall components, directly activate B cells via MyD88 signaling triggered by Toll- like receptor 2, leading to increased IgG1 production. While Dectin-1 signals and specific recognition by the B cell receptor are dispensable for B cell activation in this system, TLR2/MyD88 signals cooperate with CD40 signals in promoting B cell activation. Importantly, recognition of C. albicans via MyD88 signaling is also essential for induction of IL-6 secretion by B cells, which promotes TH17 polarization in T-B cell coculture experiments. B cells may thus be activated directly by C. albicans in its invasive form, leading to production of antibodies and T cell help for fungal clearance.
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Affiliation(s)
- Marta Ferreira-Gomes
- Institute of Biochemistry and Biophysics, Faculty of Biological Sciences, Friedrich Schiller University, Jena, Germany
| | - Melissa Wich
- Institute of Biochemistry and Biophysics, Faculty of Biological Sciences, Friedrich Schiller University, Jena, Germany
| | - Sally Böde
- Institute of Biochemistry and Biophysics, Faculty of Biological Sciences, Friedrich Schiller University, Jena, Germany
| | - Bernhard Hube
- Department Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany
- Institute of Microbiology, Faculty of Biological Sciences, Friedrich Schiller University, Jena, Germany
| | - Ilse D. Jacobsen
- Institute of Microbiology, Faculty of Biological Sciences, Friedrich Schiller University, Jena, Germany
- Research Group Microbial Immunology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany
| | - Berit Jungnickel
- Institute of Biochemistry and Biophysics, Faculty of Biological Sciences, Friedrich Schiller University, Jena, Germany
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19
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Sun S, Sun L, Wang K, Qiao S, Zhao X, Hu X, Chen W, Zhang S, Li H, Dai H, Liu H. The gut commensal fungus, Candida parapsilosis, promotes high fat-diet induced obesity in mice. Commun Biol 2021; 4:1220. [PMID: 34697386 PMCID: PMC8546080 DOI: 10.1038/s42003-021-02753-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 10/05/2021] [Indexed: 01/07/2023] Open
Abstract
Gut fungi is known to play many important roles in human health regulations. Herein, we investigate the anti-obesity efficacy of the antifungal antibiotics (amphotericin B, fluconazole and 5-fluorocytosine) in the high fat diet-fed (HFD) mice. Supplementation of amphotericin B or fluconazole in water can effectively inhibit obesity and its related disorders, whereas 5-fluorocytosine exhibit little effects. The gut fungus Candida parapsilosis is identified as a key commensal fungus related to the diet-induced obesity by the culture-dependent method and the inoculation assay with C. parapsilosis in the fungi-free mice. In addition, the increase of free fatty acids in the gut due to the production of fungal lipases from C. parapsilosis is confirmed as one mechanism by which C. parapsilosis promotes obesity. The current study demonstrates the gut C. parapsilosis as a causal fungus for the development of diet-induced obesity in mice and highlights the therapeutic strategy targeting the gut fungi. Shanshan Sun, Li Sun, Kai Wang, et al. report that the gut commensal Candida parapsilosis is a causative fungus for the development of high fat-diet induced obesity in mice. Their results suggest that fungi could represent possible targets for combating obesity.
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Affiliation(s)
- Shanshan Sun
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.,School of Life Sciences, University of Science and Technology of China, Hefei, China.,The Second Hospital of Anhui Medical University, Hefei, China
| | - Li Sun
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Kai Wang
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Shanshan Qiao
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xinyue Zhao
- Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China
| | - Xiaomin Hu
- Department of Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China
| | - Wei Chen
- Department of Clinical Nutrition, Dept. of Health Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuyang Zhang
- Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China
| | - Hantian Li
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Huanqin Dai
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China. .,University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Hongwei Liu
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China. .,University of Chinese Academy of Sciences, Beijing, 100049, China.
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20
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Pandiyan P, McCormick TS. Regulation of IL-17A-Producing Cells in Skin Inflammatory Disorders. J Invest Dermatol 2021; 142:867-875. [PMID: 34561088 DOI: 10.1016/j.jid.2021.06.036] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 06/09/2021] [Accepted: 06/22/2021] [Indexed: 12/11/2022]
Abstract
This review focuses on the IL-17A family of cytokines produced by T lymphocytes and other immune cells and how they are involved in cutaneous pathogenic responses. It will also discuss cutaneous dysbiosis and FOXP3+ regulatory T cells in the context of inflammatory conditions linked to IL-17 responses in the skin. Specifically, it will review key literature on chronic mucocutaneous candidiasis and psoriasis.
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Affiliation(s)
- Pushpa Pandiyan
- Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, Ohio, USA; Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
| | - Thomas S McCormick
- Department of Dermatology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
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21
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Ibe C, Munro CA. Fungal Cell Wall Proteins and Signaling Pathways Form a Cytoprotective Network to Combat Stresses. J Fungi (Basel) 2021; 7:jof7090739. [PMID: 34575777 PMCID: PMC8466366 DOI: 10.3390/jof7090739] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/01/2021] [Accepted: 09/04/2021] [Indexed: 12/13/2022] Open
Abstract
Candida species are part of the normal flora of humans, but once the immune system of the host is impaired and they escape from commensal niches, they shift from commensal to pathogen causing candidiasis. Candida albicans remains the primary cause of candidiasis, accounting for about 60% of the global candidiasis burden. The cell wall of C. albicans and related fungal pathogens forms the interface with the host, gives fungal cells their shape, and also provides protection against stresses. The cell wall is a dynamic organelle with great adaptive flexibility that allows remodeling, morphogenesis, and changes in its components in response to the environment. It is mainly composed of the inner polysaccharide rich layer (chitin, and β-glucan) and the outer protein coat (mannoproteins). The highly glycosylated protein coat mediates interactions between C. albicans cells and their environment, including reprograming of wall architecture in response to several conditions, such as carbon source, pH, high temperature, and morphogenesis. The mannoproteins are also associated with C. albicans adherence, drug resistance, and virulence. Vitally, the mannoproteins contribute to cell wall construction and especially cell wall remodeling when cells encounter physical and chemical stresses. This review describes the interconnected cell wall integrity (CWI) and stress-activated pathways (e.g., Hog1, Cek1, and Mkc1 mediated pathways) that regulates cell wall remodeling and the expression of some of the mannoproteins in C. albicans and other species. The mannoproteins of the surface coat is of great importance to pathogen survival, growth, and virulence, thus understanding their structure and function as well as regulatory mechanisms can pave the way for better management of candidiasis.
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Affiliation(s)
- Chibuike Ibe
- Department of Microbiology, Faculty of Biological Sciences, Abia State University, Uturu 441107, Nigeria
- Correspondence:
| | - Carol A. Munro
- Aberdeen Fungal Group, Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB24 3FX, UK;
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22
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d'Enfert C, Kaune AK, Alaban LR, Chakraborty S, Cole N, Delavy M, Kosmala D, Marsaux B, Fróis-Martins R, Morelli M, Rosati D, Valentine M, Xie Z, Emritloll Y, Warn PA, Bequet F, Bougnoux ME, Bornes S, Gresnigt MS, Hube B, Jacobsen ID, Legrand M, Leibundgut-Landmann S, Manichanh C, Munro CA, Netea MG, Queiroz K, Roget K, Thomas V, Thoral C, Van den Abbeele P, Walker AW, Brown AJP. The impact of the Fungus-Host-Microbiota interplay upon Candida albicans infections: current knowledge and new perspectives. FEMS Microbiol Rev 2021; 45:fuaa060. [PMID: 33232448 PMCID: PMC8100220 DOI: 10.1093/femsre/fuaa060] [Citation(s) in RCA: 161] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Accepted: 11/18/2020] [Indexed: 12/11/2022] Open
Abstract
Candida albicans is a major fungal pathogen of humans. It exists as a commensal in the oral cavity, gut or genital tract of most individuals, constrained by the local microbiota, epithelial barriers and immune defences. Their perturbation can lead to fungal outgrowth and the development of mucosal infections such as oropharyngeal or vulvovaginal candidiasis, and patients with compromised immunity are susceptible to life-threatening systemic infections. The importance of the interplay between fungus, host and microbiota in driving the transition from C. albicans commensalism to pathogenicity is widely appreciated. However, the complexity of these interactions, and the significant impact of fungal, host and microbiota variability upon disease severity and outcome, are less well understood. Therefore, we summarise the features of the fungus that promote infection, and how genetic variation between clinical isolates influences pathogenicity. We discuss antifungal immunity, how this differs between mucosae, and how individual variation influences a person's susceptibility to infection. Also, we describe factors that influence the composition of gut, oral and vaginal microbiotas, and how these affect fungal colonisation and antifungal immunity. We argue that a detailed understanding of these variables, which underlie fungal-host-microbiota interactions, will present opportunities for directed antifungal therapies that benefit vulnerable patients.
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Affiliation(s)
- Christophe d'Enfert
- Unité Biologie et Pathogénicité Fongiques, Département de Mycologie, Institut Pasteur, USC 2019 INRA, 25, rue du Docteur Roux, 75015 Paris, France
| | - Ann-Kristin Kaune
- Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen, Ashgrove Road West, Foresterhill, Aberdeen AB25 2ZD, UK
| | - Leovigildo-Rey Alaban
- BIOASTER Microbiology Technology Institute, 40 avenue Tony Garnier, 69007 Lyon, France
- Université de Paris, Sorbonne Paris Cité, 25, rue du Docteur Roux, 75015 Paris, France
| | - Sayoni Chakraborty
- Microbial Immunology Research Group, Emmy Noether Junior Research Group Adaptive Pathogenicity Strategies, and the Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute, Beutenbergstraße 11a, 07745 Jena, Germany
- Institute of Microbiology, Friedrich Schiller University, Neugasse 25, 07743 Jena, Germany
| | - Nathaniel Cole
- Gut Microbiology Group, Rowett Institute, University of Aberdeen, Ashgrove Road West, Foresterhill, Aberdeen AB25 2ZD, UK
| | - Margot Delavy
- Unité Biologie et Pathogénicité Fongiques, Département de Mycologie, Institut Pasteur, USC 2019 INRA, 25, rue du Docteur Roux, 75015 Paris, France
- Université de Paris, Sorbonne Paris Cité, 25, rue du Docteur Roux, 75015 Paris, France
| | - Daria Kosmala
- Unité Biologie et Pathogénicité Fongiques, Département de Mycologie, Institut Pasteur, USC 2019 INRA, 25, rue du Docteur Roux, 75015 Paris, France
- Université de Paris, Sorbonne Paris Cité, 25, rue du Docteur Roux, 75015 Paris, France
| | - Benoît Marsaux
- ProDigest BV, Technologiepark 94, B-9052 Gent, Belgium
- Center for Microbial Ecology and Technology (CMET), Department of Biotechnology, Faculty of Bioscience Engineering, Ghent University, Coupure Links, 9000 Ghent, Belgium
| | - Ricardo Fróis-Martins
- Immunology Section, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 266a, Zurich 8057, Switzerland
- Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, Zürich 8057, Switzerland
| | - Moran Morelli
- Mimetas, Biopartner Building 2, J.H. Oortweg 19, 2333 CH Leiden, The Netherlands
| | - Diletta Rosati
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands
| | - Marisa Valentine
- Microbial Immunology Research Group, Emmy Noether Junior Research Group Adaptive Pathogenicity Strategies, and the Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute, Beutenbergstraße 11a, 07745 Jena, Germany
| | - Zixuan Xie
- Gut Microbiome Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119–129, 08035 Barcelona, Spain
| | - Yoan Emritloll
- Unité Biologie et Pathogénicité Fongiques, Département de Mycologie, Institut Pasteur, USC 2019 INRA, 25, rue du Docteur Roux, 75015 Paris, France
| | - Peter A Warn
- Magic Bullet Consulting, Biddlecombe House, Ugbrook, Chudleigh Devon, TQ130AD, UK
| | - Frédéric Bequet
- BIOASTER Microbiology Technology Institute, 40 avenue Tony Garnier, 69007 Lyon, France
| | - Marie-Elisabeth Bougnoux
- Unité Biologie et Pathogénicité Fongiques, Département de Mycologie, Institut Pasteur, USC 2019 INRA, 25, rue du Docteur Roux, 75015 Paris, France
| | - Stephanie Bornes
- Université Clermont Auvergne, INRAE, VetAgro Sup, UMRF0545, 20 Côte de Reyne, 15000 Aurillac, France
| | - Mark S Gresnigt
- Microbial Immunology Research Group, Emmy Noether Junior Research Group Adaptive Pathogenicity Strategies, and the Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute, Beutenbergstraße 11a, 07745 Jena, Germany
| | - Bernhard Hube
- Microbial Immunology Research Group, Emmy Noether Junior Research Group Adaptive Pathogenicity Strategies, and the Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute, Beutenbergstraße 11a, 07745 Jena, Germany
| | - Ilse D Jacobsen
- Microbial Immunology Research Group, Emmy Noether Junior Research Group Adaptive Pathogenicity Strategies, and the Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute, Beutenbergstraße 11a, 07745 Jena, Germany
| | - Mélanie Legrand
- Unité Biologie et Pathogénicité Fongiques, Département de Mycologie, Institut Pasteur, USC 2019 INRA, 25, rue du Docteur Roux, 75015 Paris, France
| | - Salomé Leibundgut-Landmann
- Immunology Section, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 266a, Zurich 8057, Switzerland
- Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, Zürich 8057, Switzerland
| | - Chaysavanh Manichanh
- Gut Microbiome Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119–129, 08035 Barcelona, Spain
| | - Carol A Munro
- Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen, Ashgrove Road West, Foresterhill, Aberdeen AB25 2ZD, UK
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands
| | - Karla Queiroz
- Mimetas, Biopartner Building 2, J.H. Oortweg 19, 2333 CH Leiden, The Netherlands
| | - Karine Roget
- NEXBIOME Therapeutics, 22 allée Alan Turing, 63000 Clermont-Ferrand, France
| | - Vincent Thomas
- BIOASTER Microbiology Technology Institute, 40 avenue Tony Garnier, 69007 Lyon, France
| | - Claudia Thoral
- NEXBIOME Therapeutics, 22 allée Alan Turing, 63000 Clermont-Ferrand, France
| | | | - Alan W Walker
- Gut Microbiology Group, Rowett Institute, University of Aberdeen, Ashgrove Road West, Foresterhill, Aberdeen AB25 2ZD, UK
| | - Alistair J P Brown
- MRC Centre for Medical Mycology, Department of Biosciences, University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter EX4 4QD, UK
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23
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Bhaskaran N, Jayaraman S, Quigley C, Mamileti P, Ghannoum M, Weinberg A, Thuener J, Pan Q, Pandiyan P. The Role of Dectin-1 Signaling in Altering Tumor Immune Microenvironment in the Context of Aging. Front Oncol 2021; 11:669066. [PMID: 33968777 PMCID: PMC8100664 DOI: 10.3389/fonc.2021.669066] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 04/06/2021] [Indexed: 01/10/2023] Open
Abstract
An increased accumulation of immune-dysfunction-associated CD4+Foxp3+ regulatory T cells (Tregs) is observed in aging oral mucosa during infection. Here we studied the function of Tregs during oral cancer development in aging mucosa. First, we found heightened proportions of Tregs and myeloid-derived suppressor cells (MDSC) accumulating in mouse and human oral squamous cell carcinoma (OSCC) tissues. Using the mouse 4-Nitroquinoline 1-oxide(4-NQO) oral carcinogenesis model, we found that tongues of aged mice displayed increased propensity for epithelial cell dysplasia, hyperplasia, and accelerated OSCC development, which coincided with significantly increased abundance of IL-1β, Tregs, and MDSC in tongues. Partial depletion of Tregs reduced tumor burden. Moreover, fungal abundance and dectin-1 signaling were elevated in aged mice suggesting a potential role for dectin-1 in modulating immune environment and tumor development. Confirming this tenet, dectin-1 deficient mice showed diminished IL-1β, reduced infiltration of Tregs and MDSC in the tongues, as well as slower progression and reduced severity of tumor burden. Taken together, these data identify an important role of dectin-1 signaling in establishing the intra-tumoral immunosuppressive milieu and promoting OSCC tumorigenesis in the context of aging.
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Affiliation(s)
- Natarajan Bhaskaran
- Department of Biological Sciences, School of Dental Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
| | - Sangeetha Jayaraman
- Department of Biological Sciences, School of Dental Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
| | - Cheriese Quigley
- Department of Biological Sciences, School of Dental Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
| | - Prerna Mamileti
- Department of Biological Sciences, School of Dental Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
| | - Mahmoud Ghannoum
- Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, United States.,Dermatology, School of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
| | - Aaron Weinberg
- Department of Biological Sciences, School of Dental Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, United States.,Case Comprehensive Cancer Center, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
| | - Jason Thuener
- Otolaryngology-Head and Neck surgery, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
| | - Quintin Pan
- Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, United States.,Otolaryngology-Head and Neck surgery, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
| | - Pushpa Pandiyan
- Department of Biological Sciences, School of Dental Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, United States.,Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, United States.,Case Comprehensive Cancer Center, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
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24
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Rahabi M, Jacquemin G, Prat M, Meunier E, AlaEddine M, Bertrand B, Lefèvre L, Benmoussa K, Batigne P, Aubouy A, Auwerx J, Kirzin S, Bonnet D, Danjoux M, Pipy B, Alric L, Authier H, Coste A. Divergent Roles for Macrophage C-type Lectin Receptors, Dectin-1 and Mannose Receptors, in the Intestinal Inflammatory Response. Cell Rep 2021; 30:4386-4398.e5. [PMID: 32234475 DOI: 10.1016/j.celrep.2020.03.018] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 12/19/2019] [Accepted: 03/05/2020] [Indexed: 12/17/2022] Open
Abstract
Colonic macrophages are considered to be major effectors of inflammatory bowel diseases (IBDs) and the control of gut inflammation through C-type lectin receptors is an emerging concept. We show that during colitis, the loss of dectin-1 on myeloid cells prevents intestinal inflammation, while the lack of mannose receptor (MR) exacerbates it. A marked increase in dectin-1 expression in dextran sulfate sodium (DSS)-exposed MR-deficient mice supports the critical contribution of dectin-1 to colitis outcome. Dectin-1 is crucial for Ly6ChighCCR2high monocyte population enrichment in the blood and their recruitment to inflamed colon as precursors of inflammatory macrophages. Dectin-1 also promotes inflammasome-dependent interleukin-1β (IL-1β) secretion through leukotriene B4 production. Interestingly, colonic inflammation is associated with a concomitant overexpression of dectin-1/CCL2/LTA4H and downregulation of MR on macrophages from IBD patients. Thus, MR and dectin-1 on macrophages are important mucosal inflammatory regulators that contribute to the intestinal inflammation.
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Affiliation(s)
- Mouna Rahabi
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France
| | | | - Mélissa Prat
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France
| | - Etienne Meunier
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France
| | - Mohamad AlaEddine
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France
| | | | - Lise Lefèvre
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France
| | | | - Philippe Batigne
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France
| | - Agnès Aubouy
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France
| | - Johan Auwerx
- Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausane, Lausane 1015, Switzerland
| | - Sylvain Kirzin
- Department of Surgery and Digestive Diseases, CHU Purpan, Université de Toulouse, Toulouse, France
| | - Delphine Bonnet
- Department of Internal Medicine and Digestive Diseases, CHU Purpan, Toulouse, France; IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
| | - Marie Danjoux
- Department of Pathology, CHU Purpan, Université de Toulouse, Toulouse, France
| | - Bernard Pipy
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France
| | - Laurent Alric
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France; Department of Internal Medicine and Digestive Diseases, CHU Purpan, Toulouse, France
| | - Hélène Authier
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France.
| | - Agnès Coste
- UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France
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25
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Farias e Silva K, Nanini HF, Cascabulho CM, Rosas SLB, Santana PT, Carneiro AJDV, Anaissie E, Nucci M, de Souza HSP. Serum 1,3-beta-D-glucan as a noninvasive test to predict histologic activity in patients with inflammatory bowel disease. World J Gastroenterol 2021; 27:866-885. [PMID: 33727775 PMCID: PMC7941859 DOI: 10.3748/wjg.v27.i9.866] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 01/11/2021] [Accepted: 02/18/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND 1,3-beta-D-glucan (BG) is a ubiquitous cell wall component of gut micro-organisms. We hypothesized that the serum levels of BG could reflect active intestinal inflammation in patients with inflammatory bowel disease.
AIM To determine whether the serum BG concentrations correlate with intestinal inflammation.
METHODS A prospective observational study was performed in a tertiary referral center, from 2016 to 2019, in which serum BG was determined in 115 patients with Crohn’s disease (CD), 51 with ulcerative colitis (UC), and 82 controls using a photometric detection kit. Inflammatory activity was determined by ileocolonoscopy, histopathology, magnetic resonance enterography, and biomarkers, including fecal calprotectin (FC), C-reactive protein, and a panel of cytokines. The ability of BG to detect active vs inactive disease was assessed using the area under the receiver operating characteristic curve. In subgroup analysis, serial BG was used to assess the response to therapeutic interventions.
RESULTS The serum BG levels were higher in CD patients than in controls (P = 0.0001). The BG levels paralleled the endoscopic activity in CD patients and histologic activity and combined endoscopic and histologic activity in both CD and UC patients. The area under the curve (AUC) in receiver operating characteristic analysis to predict endoscopic activity was 0.694 [95% confidence interval (CI): 0.60-0.79; P = 0.001] in CD, and 0.662 (95%CI: 0.51-0.81; P = 0.066) in UC patients. The AUC in receiver operating characteristic analysis to predict histologic activity was 0.860 (95%CI: 0.77-0.95; P < 0.001) in CD, and 0.786 (95%CI: 0.57-0.99; P = 0.015) in UC patients. The cut-off values of BG for both endoscopic and histologic activity were 60 µg/mL in CD, and 40 µg/mL in UC patients. Performance analysis showed that the results based on BG of 40 and 60 µg/mL were more specific for predicting endoscopic activity (71.8% and 87.2% for CD; and 87.5% and 87.5% for UC, respectively) than FC (53.3% and 66.7% for CD; and 20% and 80% for UC, respectively); and also histologic activity (60.5% and 76.3% for CD; and 90.0% and 95.0% for UC, respectively) than FC (41.7% and 50.0% for CD; and 25% and 50% for UC, respectively). Regarding the clinical, endoscopic, and histologic activities, the BG levels were reduced following therapeutic intervention in patients with CD (P < 0.0001) and UC (P = 0.003). Compared with endoscopic (AUC: 0.693; P = 0.002) and histologic (AUC: 0.868; P < 0.001) activity, no significant correlation was found between serum BG and transmural healing based on magnetic resonance enterography (AUC: 0.576; P = 0.192). Positive correlations were detected between BG and IL-17 in the CD (r: 0.737; P = 0.001) and the UC group (r: 0.574; P = 0.005), and between BG and interferon-gamma in the CD group (r: 0.597; P = 0.015).
CONCLUSION Serum BG may represent an important novel noninvasive approach for detecting mucosal inflammation and therapeutically monitoring inflammatory bowel diseases, particularly in CD.
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Affiliation(s)
- Katia Farias e Silva
- Department of Clinical Medicine, School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil
| | - Hayandra F Nanini
- Department of Clinical Medicine, School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil
| | - Cynthia Machado Cascabulho
- Laboratory of Innovations in Therapies, Education and Bioproducts, Instituto Oswaldo Cruz, Rio de Janeiro 21040-360, Brazil
| | - Siane L B Rosas
- Department of Clinical Medicine, School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil
| | - Patricia T Santana
- Department of Clinical Medicine, School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil
| | - Antonio José de V Carneiro
- Department of Clinical Medicine, School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil
| | - Elias Anaissie
- Clinical Trial and Consulting Services, Cincinnati, OH 45267, United States
| | - Marcio Nucci
- Department of Clinical Medicine, School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil
| | - Heitor Siffert Pereira de Souza
- Department of Clinical Medicine, School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil
- Internal Medicine, D'Or Institute for Research and Education (IDOR), Rio de Janeiro 22281-100, Brazil
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Briard B, Malireddi RKS, Kanneganti TD. Role of inflammasomes/pyroptosis and PANoptosis during fungal infection. PLoS Pathog 2021; 17:e1009358. [PMID: 33735255 PMCID: PMC7971547 DOI: 10.1371/journal.ppat.1009358] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Affiliation(s)
- Benoit Briard
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America
| | - R. K. Subbarao Malireddi
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America
| | - Thirumala-Devi Kanneganti
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America
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Cryptococcus neoformans Secretes Small Molecules That Inhibit IL-1 β Inflammasome-Dependent Secretion. Mediators Inflamm 2020; 2020:3412763. [PMID: 33380899 PMCID: PMC7748918 DOI: 10.1155/2020/3412763] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 10/22/2020] [Accepted: 11/04/2020] [Indexed: 01/22/2023] Open
Abstract
Cryptococcus neoformans is an encapsulated yeast that causes disease mainly in immunosuppressed hosts. It is considered a facultative intracellular pathogen because of its capacity to survive and replicate inside phagocytes, especially macrophages. This ability is heavily dependent on various virulence factors, particularly the glucuronoxylomannan (GXM) component of the polysaccharide capsule. Inflammasome activation in phagocytes is usually protective against fungal infections, including cryptococcosis. Nevertheless, recognition of C. neoformans by inflammasome receptors requires specific changes in morphology or the opsonization of the yeast, impairing proper inflammasome function. In this context, we analyzed the impact of molecules secreted by C. neoformans B3501 strain and its acapsular mutant Δcap67 in inflammasome activation in an in vitro model. Our results showed that conditioned media derived from B3501 was capable of inhibiting inflammasome-dependent events (i.e., IL-1β secretion and LDH release via pyroptosis) more strongly than conditioned media from Δcap67, regardless of GXM presence. We also demonstrated that macrophages treated with conditioned media were less responsive against infection with the virulent strain H99, exhibiting lower rates of phagocytosis, increased fungal burdens, and enhanced vomocytosis. Moreover, we showed that the aromatic metabolite DL-Indole-3-lactic acid (ILA) and DL-p-Hydroxyphenyllactic acid (HPLA) were present in B3501's conditioned media and that ILA alone or with HPLA is involved in the regulation of inflammasome activation by C. neoformans. These results were confirmed by in vivo experiments, where exposure to conditioned media led to higher fungal burdens in Acanthamoeba castellanii culture as well as in higher fungal loads in the lungs of infected mice. Overall, the results presented show that conditioned media from a wild-type strain can inhibit a vital recognition pathway and subsequent fungicidal functions of macrophages, contributing to fungal survival in vitro and in vivo and suggesting that secretion of aromatic metabolites, such as ILA, during cryptococcal infections fundamentally impacts pathogenesis.
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Lenardon MD, Sood P, Dorfmueller HC, Brown AJ, Gow NA. Scalar nanostructure of the Candida albicans cell wall; a molecular, cellular and ultrastructural analysis and interpretation. Cell Surf 2020; 6:100047. [PMID: 33294751 PMCID: PMC7691183 DOI: 10.1016/j.tcsw.2020.100047] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 11/02/2020] [Accepted: 11/03/2020] [Indexed: 12/16/2022] Open
Abstract
Despite the importance of fungal cell walls as the principle determinant of fungal morphology and the defining element determining fungal interactions with other cells, few scalar models have been developed that reconcile chemical and microscopic attributes of its structure. The cell wall of the fungal pathogen Candida albicans is comprised of an amorphous inner skeletal layer of β(1,3)- and β(1,6)-glucan and chitin and an outer fibrillar layer thought to be dominated by highly mannosylated cell wall proteins. The architecture of these two layers can be resolved at the electron microscopy level, but the visualised structure of the wall has not yet been defined precisely in chemical terms. We have therefore examined the precise structure, location and molecular sizes of the cell wall components using transmission electron microscopy and tomography and tested predictions of the cell wall models using mutants and agents that perturb the normal cell wall structure. We demonstrate that the fibrils are comprised of a frond of N-linked outer chain mannans linked to a basal layer of GPI-proteins concentrated in the mid-wall region and that the non-elastic chitin microfibrils are cantilevered with sufficient lengths of non-fibrillar chitin and/or β-glucan to enable the chitin-glucan cage to flex, e.g. during morphogenesis and osmotic swelling. We present the first three-dimensional nano-scalar model of the C. albicans cell wall which can be used to test hypotheses relating to the structure-function relationships that underpin the pathobiology of this fungal pathogen.
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Key Words
- 2D, two dimensions
- 2°, secondary
- 3D, three dimensions
- 3°, tertiary
- 6xHis, hexahistidine tag
- AFM, atomic force microscopy
- BSA, bovine serum albumin
- CWPs, cell wall proteins
- Cell wall proteins
- ChBD, chitin binding domain
- Chitin
- EndoH, endoglycosidase H
- Fc-dectin-1, soluble chimeric form of dectin-1
- Fungal cell wall ultrastructure
- GPI, glycosylphosphatidylinositol
- HPF/FS, high pressure freezing/freeze substitution
- HuCκ, human kappa light chain
- N-mannan
- NMR, nuclear magnetic resonance
- OD600, optical density at 600 nm
- PAMPs, pathogen associated molecular patterns
- PBS, phosphate buffered saline
- PRRs, pattern recognition receptors
- SEM, scanning electron microscopy
- TEM, transmission electron microscopy
- WGA, wheat germ agglutinin
- rpm, revolutions per minute
- scAb, single chain antibody
- β-glucan
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Affiliation(s)
- Megan D. Lenardon
- Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK
| | - Prashant Sood
- Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK
| | - Helge C. Dorfmueller
- Molecular Microbiology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK
| | - Alistair J.P. Brown
- Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK
| | - Neil A.R. Gow
- Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK
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Bhaskaran N, Faddoul F, Paes da Silva A, Jayaraman S, Schneider E, Mamileti P, Weinberg A, Pandiyan P. IL-1β-MyD88-mTOR Axis Promotes Immune-Protective IL-17A +Foxp3 + Cells During Mucosal Infection and Is Dysregulated With Aging. Front Immunol 2020; 11:595936. [PMID: 33240286 PMCID: PMC7677307 DOI: 10.3389/fimmu.2020.595936] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 10/08/2020] [Indexed: 12/22/2022] Open
Abstract
CD4+Foxp3+Tregs maintain immune homeostasis, but distinct mechanisms underlying their functional heterogeneity during infections are driven by specific cytokine milieu. Here we show that MyD88 deletion in Foxp3+ cells altered their function and resulted in increased fungal burden and immunopathology during oral Candida albicans (CA) challenge. Excessive inflammation due to the absence of MyD88 in Tregs coincided with a reduction of the unique population of IL-17A expressing Foxp3+ cells (Treg17) and an increase in dysfunctional IFN-γ+/Foxp3+ cells (TregIFN-γ) in infected mice. Failure of MyD88-/- Tregs to regulate effector CD4+ T cell functions correlated with heightened levels of IFN-γ in CD4+ T cells, as well as increased infiltration of inflammatory monocytes and neutrophils in oral mucosa in vivo. Mechanistically, IL-1β/MyD88 signaling was required for the activation of IRAK-4, Akt, and mTOR, which led to the induction and proliferation of Treg17 cells. In the absence of IL-1 receptor signaling, Treg17 cells were reduced, but IL-6-driven expansion of TregIFN-γ cells was increased. This mechanism was physiologically relevant during Candida infection in aged mice, as they exhibited IL-1 receptor/MyD88 defect in Foxp3+ cells, loss of p-mTORhighTreg17 cells and reduced levels of IL-1β in oral mucosa, which coincided with persistent tongue inflammation. Concurrent with Treg dysfunction, aging was associated with increased CD4+ T cell hyperactivation and heightened levels of IL-6 in mice and humans in oral mucosa in vivo. Taken together, our data identify IL-1β/MyD88/Treg axis as a new component that modulates inflammatory responses in oral mucosa. Also, dysregulation of this axis in an aging immune system may skew host defense towards an immunopathological response in mucosal compartments.
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Affiliation(s)
- Natarajan Bhaskaran
- Department of Biological Sciences, Case Western Reserve University, Cleveland, OH, United States
| | - Fady Faddoul
- Advanced Education in General Dentistry, Case Western Reserve University, Cleveland, OH, United States
| | - Andre Paes da Silva
- Department of Periodontics, School of Dental Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Sangeetha Jayaraman
- Department of Biological Sciences, Case Western Reserve University, Cleveland, OH, United States
| | - Elizabeth Schneider
- Department of Biological Sciences, Case Western Reserve University, Cleveland, OH, United States
| | - Prerna Mamileti
- Department of Biological Sciences, Case Western Reserve University, Cleveland, OH, United States
| | - Aaron Weinberg
- Department of Biological Sciences, Case Western Reserve University, Cleveland, OH, United States
| | - Pushpa Pandiyan
- Department of Biological Sciences, Case Western Reserve University, Cleveland, OH, United States.,Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
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Camilli G, Griffiths JS, Ho J, Richardson JP, Naglik JR. Some like it hot: Candida activation of inflammasomes. PLoS Pathog 2020; 16:e1008975. [PMID: 33119702 PMCID: PMC7595283 DOI: 10.1371/journal.ppat.1008975] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Affiliation(s)
- Giorgio Camilli
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London, United Kingdom
- * E-mail:
| | - James S. Griffiths
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London, United Kingdom
| | - Jemima Ho
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London, United Kingdom
| | - Jonathan P. Richardson
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London, United Kingdom
| | - Julian R. Naglik
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London, United Kingdom
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31
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Tucey TM, Verma J, Olivier FAB, Lo TL, Robertson AAB, Naderer T, Traven A. Metabolic competition between host and pathogen dictates inflammasome responses to fungal infection. PLoS Pathog 2020; 16:e1008695. [PMID: 32750090 PMCID: PMC7433900 DOI: 10.1371/journal.ppat.1008695] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Revised: 08/18/2020] [Accepted: 06/07/2020] [Indexed: 12/11/2022] Open
Abstract
The NLRP3 inflammasome has emerged as a central immune regulator that senses virulence factors expressed by microbial pathogens for triggering inflammation. Inflammation can be harmful and therefore this response must be tightly controlled. The mechanisms by which immune cells, such as macrophages, discriminate benign from pathogenic microbes to control the NLRP3 inflammasome remain poorly defined. Here we used live cell imaging coupled with a compendium of diverse clinical isolates to define how macrophages respond and activate NLRP3 when faced with the human yeast commensal and pathogen Candida albicans. We show that metabolic competition by C. albicans, rather than virulence traits such as hyphal formation, activates NLRP3 in macrophages. Inflammasome activation is triggered by glucose starvation in macrophages, which occurs when fungal load increases sufficiently to outcompete macrophages for glucose. Consistently, reducing Candida’s ability to compete for glucose and increasing glucose availability for macrophages tames inflammatory responses. We define the mechanistic requirements for glucose starvation-dependent inflammasome activation by Candida and show that it leads to inflammatory cytokine production, but it does not trigger pyroptotic macrophage death. Pyroptosis occurs only with some Candida isolates and only under specific experimental conditions, whereas inflammasome activation by glucose starvation is broadly relevant. In conclusion, macrophages use their metabolic status, specifically glucose metabolism, to sense fungal metabolic activity and activate NLRP3 when microbial load increases. Therefore, a major consequence of Candida-induced glucose starvation in macrophages is activation of inflammatory responses, with implications for understanding how metabolism modulates inflammation in fungal infections. Activation of the immune regulator NLRP3 inflammasome by microbial pathogens has been shown to play both protective and destructive roles in infection, underscoring the importance of tight control over NLRP3-driven inflammation to ensure host health. A key microbe recognised by NLRP3 is the human yeast commensal and pathogen Candida albicans, which is responsible for mucosal and invasive infections. We demonstrate that innate immune cells sense their metabolic status to trigger NLRP3 activation only when microbial numbers have reached dangerous levels. This regulation is a consequence of metabolic competition between C. albicans and macrophages for an essential nutrient–glucose. The NLRP3 inflammasome is activated when increased fungal load in the infection microenvironment drives down glucose levels, thereby causing glucose starvation in macrophages. Restoring glucose homeostasis in macrophages reduced NLRP3 activation and production of the proinflammatory cytokine IL-1β, suggesting that metabolism regulates NLRP3 inflammasome activity in fungal infections.
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Affiliation(s)
- Timothy M. Tucey
- Infection and Immunity Program and the Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Jiyoti Verma
- Infection and Immunity Program and the Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Françios A. B. Olivier
- Infection and Immunity Program and the Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Tricia L. Lo
- Infection and Immunity Program and the Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Avril A. B. Robertson
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Australia
| | - Thomas Naderer
- Infection and Immunity Program and the Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Ana Traven
- Infection and Immunity Program and the Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
- * E-mail:
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32
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Inflammatory bowel diseases, the hygiene hypothesis and the other side of the microbiota: Parasites and fungi. Pharmacol Res 2020; 159:104962. [PMID: 32480001 DOI: 10.1016/j.phrs.2020.104962] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/22/2020] [Accepted: 05/22/2020] [Indexed: 12/26/2022]
Abstract
This review tackles the concept of the evolutionary mismatch, in relation with the reduction of the prevalence of the so-called "dirty old friends". These formed the variegated community of parasites and microorganisms, either prokaryotic or eukaryotic, that, over long evolutionary times, co-evolved with humans and their ancestors, inhabiting their digestive tracts, and other body districts. This community of microbial symbionts and metazoan parasites is thought to have evolved a complex network of inter-independence with the host, in particular in relation with their immune stimulating capacity, and with the consequent adaptation of the host immune response to this chronic stimulation. Strictly related to this evolutionary mismatch, the hygiene hypothesis, proposed by David Strachan in 1989, foresees that the increase in the incidence of inflammatory and autoimmune disorders during the twentieth century has been caused by the reduced exposure to parasites and microorganisms, especially in industrialized countries. Among these pathologies, inflammatory bowel diseases (IBDs) occupy a prominent role. From these premises, this review summarizes current knowledge on how variations in the composition of the gut bacterial microbiota, as well as its interactions with fungal communities, influence the overall immune balance, favouring or counteracting gut inflammation in IBDs. Additionally, the effect of worm parasites, either directly on the immune balance, or indirectly, through the modulation of bacterial and fungal microbiota, will be addressed. Finally, we will review a series of studies related to the use of molecules derived from parasitic worms and fungi, which hold the potential to be developed as postbiotics for the treatment of IBDs.
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33
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Gómez-Gaviria M, Lozoya-Pérez NE, Staniszewska M, Franco B, Niño-Vega GA, Mora-Montes HM. Loss of Kex2 Affects the Candida albicans Cell Wall and Interaction with Innate Immune Cells. J Fungi (Basel) 2020; 6:jof6020057. [PMID: 32365492 PMCID: PMC7344602 DOI: 10.3390/jof6020057] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 04/27/2020] [Accepted: 04/28/2020] [Indexed: 12/18/2022] Open
Abstract
The secretory pathway in Candida albicans involves the protein translocation into the lumen of the endoplasmic reticulum and transport to the Golgi complex, where proteins undergo posttranslational modifications, including glycosylation and proteolysis. The Golgi-resident Kex2 protease is involved in such processing and disruption of its encoding gene affected virulence and dimorphism. These previous studies were performed using cells without URA3 or with URA3 ectopically placed into the KEX2 locus. Since these conditions are known to affect the cellular fitness and the host-fungus interaction, here we generated a kex2Δ null mutant strain with URA3 placed into the neutral locus RPS1. The characterization of this strain showed defects in the cell wall composition, with a reduction in the N-linked mannan content, and the increment in the levels of O-linked mannans, chitin, and β-glucans. The defects in the mannan content are likely linked to changes in Golgi-resident enzymes, as the α-1,2-mannosyltransferase and α-1,6-mannosyltransferase activities were incremented and reduced, respectively. The mutant cells also showed reduced ability to stimulate cytokine production and phagocytosis by human mononuclear cells and macrophages, respectively. Collectively, these data showed that loss of Kex2 affected the cell wall composition, the protein glycosylation pathways, and interaction with innate immune cells.
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Affiliation(s)
- Manuela Gómez-Gaviria
- Departamento de Biología, División de Ciencias Naturales y Exactas, Campus Guanajuato, Universidad de Guanajuato, Guanajuato Gto 36050, Mexico; (M.G.-G.); (N.E.L.-P.); (B.F.); (G.A.N.-V.)
| | - Nancy E. Lozoya-Pérez
- Departamento de Biología, División de Ciencias Naturales y Exactas, Campus Guanajuato, Universidad de Guanajuato, Guanajuato Gto 36050, Mexico; (M.G.-G.); (N.E.L.-P.); (B.F.); (G.A.N.-V.)
| | - Monika Staniszewska
- Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland;
| | - Bernardo Franco
- Departamento de Biología, División de Ciencias Naturales y Exactas, Campus Guanajuato, Universidad de Guanajuato, Guanajuato Gto 36050, Mexico; (M.G.-G.); (N.E.L.-P.); (B.F.); (G.A.N.-V.)
| | - Gustavo A. Niño-Vega
- Departamento de Biología, División de Ciencias Naturales y Exactas, Campus Guanajuato, Universidad de Guanajuato, Guanajuato Gto 36050, Mexico; (M.G.-G.); (N.E.L.-P.); (B.F.); (G.A.N.-V.)
| | - Hector M. Mora-Montes
- Departamento de Biología, División de Ciencias Naturales y Exactas, Campus Guanajuato, Universidad de Guanajuato, Guanajuato Gto 36050, Mexico; (M.G.-G.); (N.E.L.-P.); (B.F.); (G.A.N.-V.)
- Correspondence: ; Tel.: +52-473-732-0006 (ext. 8193)
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Pellon A, Sadeghi Nasab SD, Moyes DL. New Insights in Candida albicans Innate Immunity at the Mucosa: Toxins, Epithelium, Metabolism, and Beyond. Front Cell Infect Microbiol 2020; 10:81. [PMID: 32195196 PMCID: PMC7062647 DOI: 10.3389/fcimb.2020.00081] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 02/18/2020] [Indexed: 12/16/2022] Open
Abstract
The mucosal surfaces of the human body are challenged by millions of microbes on a daily basis. Co-evolution with these microbes has led to the development of plastic mechanisms in both host and microorganisms that regulate the balance between preserving beneficial microbes and clearing pathogens. Candida albicans is a fungal pathobiont present in most healthy individuals that, under certain circumstances, can become pathogenic and cause everything from mild mucosal infections to life-threatening systemic diseases. As an essential part of the innate immunity in mucosae, epithelial cells elaborate complex immune responses that discriminate between commensal and pathogenic microbes, including C. albicans. Recently, several significant advances have been made identifying new pieces in the puzzle of host-microbe interactions. This review will summarize these advances in the context of our current knowledge of anti-Candida mucosal immunity, and their impact on epithelial immune responses to this fungal pathogen.
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Affiliation(s)
- Aize Pellon
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, United Kingdom
| | - Shervin Dokht Sadeghi Nasab
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, United Kingdom
| | - David L Moyes
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, United Kingdom
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Borriello F, Zanoni I, Granucci F. Cellular and molecular mechanisms of antifungal innate immunity at epithelial barriers: The role of C-type lectin receptors. Eur J Immunol 2020; 50:317-325. [PMID: 31986556 PMCID: PMC10668919 DOI: 10.1002/eji.201848054] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 10/29/2019] [Accepted: 01/24/2020] [Indexed: 12/26/2022]
Abstract
Humans are constantly exposed to fungi, either in the form of commensals at epithelial barriers or as inhaled spores. Innate immune cells play a pivotal role in maintaining commensal relationships and preventing skin, mucosal, or systemic fungal infections due to the expression of pattern recognition receptors that recognize fungal cell wall components and modulate both their activation status and the ensuing adaptive immune response. Commensal fungi also play a critical role in the modulation of homeostasis and disease susceptibility at epithelial barriers. This review will outline cellular and molecular mechanisms of anti-fungal innate immunity focusing on C-type lectin receptors and their relevance in the context of host-fungi interactions at skin and mucosal surfaces in murine experimental models as well as patients susceptible to fungal infections.
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Affiliation(s)
- Francesco Borriello
- Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
- WAO Center of Excellence, Naples, Italy
| | - Ivan Zanoni
- Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
| | - Francesca Granucci
- Department of Biotechnology and Biosciences, University of Milano - Bicocca, Milan, Italy
- INGM-National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi,", Milan, Italy
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36
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Merkhofer RM, Klein BS. Advances in Understanding Human Genetic Variations That Influence Innate Immunity to Fungi. Front Cell Infect Microbiol 2020; 10:69. [PMID: 32185141 PMCID: PMC7058545 DOI: 10.3389/fcimb.2020.00069] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 02/12/2020] [Indexed: 12/30/2022] Open
Abstract
Fungi are ubiquitous. Yet, despite our frequent exposure to commensal fungi of the normal mammalian microbiota and environmental fungi, serious, systemic fungal infections are rare in the general population. Few, if any, fungi are obligate pathogens that rely on infection of mammalian hosts to complete their lifecycle; however, many fungal species are able to cause disease under select conditions. The distinction between fungal saprophyte, commensal, and pathogen is artificial and heavily determined by the ability of an individual host's immune system to limit infection. Dramatic examples of commensal fungi acting as opportunistic pathogens are seen in hosts that are immune compromised due to congenital or acquired immune deficiency. Genetic variants that lead to immunological susceptibility to fungi have long been sought and recognized. Decreased myeloperoxidase activity in neutrophils was first reported as a mechanism for susceptibility to Candida infection in 1969. The ability to detect genetic variants and mutations that lead to rare or subtle susceptibilities has improved with techniques such as single nucleotide polymorphism (SNP) microarrays, whole exome sequencing (WES), and whole genome sequencing (WGS). Still, these approaches have been limited by logistical considerations and cost, and they have been applied primarily to Mendelian impairments in anti-fungal responses. For example, loss-of-function mutations in CARD9 were discovered by studying an extended family with a history of fungal infection. While discovery of such mutations furthers the understanding of human antifungal immunity, major Mendelian susceptibility loci are unlikely to explain genetic disparities in the rate or severity of fungal infection on the population level. Recent work using unbiased techniques has revealed, for example, polygenic mechanisms contributing to candidiasis. Understanding the genetic underpinnings of susceptibility to fungal infections will be a powerful tool in the age of personalized medicine. Future application of this knowledge may enable targeted health interventions for susceptible individuals, and guide clinical decision making based on a patient's individual susceptibility profile.
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Affiliation(s)
- Richard M Merkhofer
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
| | - Bruce S Klein
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.,Department of Pediatrics, University of Wisconsin-Madison, Madison, WI, United States.,Department of Medicine, University of Wisconsin-Madison, Madison, WI, United States.,Department of Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, United States
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37
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Hernández-Chávez MJ, Clavijo-Giraldo DM, Novák Á, Lozoya-Pérez NE, Martínez-Álvarez JA, Salinas-Marín R, Hernández NV, Martínez-Duncker I, Gácser A, Mora-Montes HM. Role of Protein Mannosylation in the Candida tropicalis-Host Interaction. Front Microbiol 2019; 10:2743. [PMID: 31849889 PMCID: PMC6892782 DOI: 10.3389/fmicb.2019.02743] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 11/11/2019] [Indexed: 12/12/2022] Open
Abstract
Mannans are components of the fungal wall attached to proteins via N- or O-linkages. In Candida albicans, Och1 is an α1,6-mannosyltransferase that adds the first mannose unit to the N-linked mannan outer chain; whereas Pmr1 is an ion pump that imports Mn2+ into the Golgi lumen. This cation is the cofactor of Golgi-resident mannosyltransferases, and thus Pmr1 is involved in the synthesis of both N- and O-linked mannans. Since we currently have limited information about the genetic network behind the Candida tropicalis protein mannosylation machinery, we disrupted OCH1 and PMR1 in this organism. The C. tropicalis pmr1Δ and och1Δ mutants showed increased doubling times, aberrant colony and cellular morphology, reduction in the wall mannan content, and increased susceptibility to wall perturbing agents. These changes were accompanied by increased exposure of both β1,3-glucan and chitin at the wall surface of both mutant strains. Our results showed that O-linked mannans are dispensable for cytokine production by human mononuclear cells, but N-linked mannans and β1,3-glucan are key ligands to trigger cytokine production in a co-stimulatory pathway involving dectin-1 and mannose receptor. Moreover, we found that the N-linked mannan core found on the surface of C. tropicalis och1Δ null mutant was capable of inducing cytokine production; and that a mannan-independent pathway for IL-10 production is present in the C. tropicalis-mononuclear cell interaction. Both mutant strains showed virulence attenuation in the Galleria mellonella and the mouse model of systemic candidiasis. Therefore, mannans are relevant for cell wall composition and organization, and for the C. tropicalis-host interaction.
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Affiliation(s)
- Marco J Hernández-Chávez
- Departamento de Biología, División de Ciencias Naturales y Exactas, Campus Guanajuato, Universidad de Guanajuato, Guanajuato, Mexico
| | - Diana M Clavijo-Giraldo
- Departamento de Biología, División de Ciencias Naturales y Exactas, Campus Guanajuato, Universidad de Guanajuato, Guanajuato, Mexico
| | - Ádám Novák
- Department of Microbiology, University of Szeged, Szeged, Hungary
| | - Nancy E Lozoya-Pérez
- Departamento de Biología, División de Ciencias Naturales y Exactas, Campus Guanajuato, Universidad de Guanajuato, Guanajuato, Mexico
| | - José A Martínez-Álvarez
- Departamento de Biología, División de Ciencias Naturales y Exactas, Campus Guanajuato, Universidad de Guanajuato, Guanajuato, Mexico
| | - Roberta Salinas-Marín
- Laboratorio de Glicobiología Humana y Diagnóstico Molecular, Universidad Autónoma del Estado de Morelos, Cuernavaca, Mexico
| | - Nahúm V Hernández
- Departamento de Biología, División de Ciencias Naturales y Exactas, Campus Guanajuato, Universidad de Guanajuato, Guanajuato, Mexico
| | - Iván Martínez-Duncker
- Laboratorio de Glicobiología Humana y Diagnóstico Molecular, Universidad Autónoma del Estado de Morelos, Cuernavaca, Mexico
| | - Attila Gácser
- Department of Microbiology, University of Szeged, Szeged, Hungary.,MTA-SZTE "Lendület" Mycobiome Research Group, University of Szeged, Szeged, Hungary
| | - Héctor M Mora-Montes
- Departamento de Biología, División de Ciencias Naturales y Exactas, Campus Guanajuato, Universidad de Guanajuato, Guanajuato, Mexico
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Thwe PM, Fritz DI, Snyder JP, Smith PR, Curtis KD, O'Donnell A, Galasso NA, Sepaniac LA, Adamik BJ, Hoyt LR, Rodriguez PD, Hogan TC, Schmidt AF, Poynter ME, Amiel E. Syk-dependent glycolytic reprogramming in dendritic cells regulates IL-1β production to β-glucan ligands in a TLR-independent manner. J Leukoc Biol 2019; 106:1325-1335. [PMID: 31509298 PMCID: PMC6883127 DOI: 10.1002/jlb.3a0819-207rr] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 08/23/2019] [Accepted: 08/23/2019] [Indexed: 11/12/2022] Open
Abstract
Dendritic cells (DCs) activated via TLR ligation experience metabolic reprogramming, in which the cells are heavily dependent on glucose and glycolysis for the synthesis of molecular building blocks essential for maturation, cytokine production, and the ability to stimulate T cells. Although the TLR-driven metabolic reprogramming events are well documented, fungal-mediated metabolic regulation via C-type lectin receptors such as Dectin-1 and Dectin-2 is not clearly understood. Here, we show that activation of DCs with fungal-associated β-glucan ligands induces acute glycolytic reprogramming that supports the production of IL-1β and its secretion subsequent to NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. This acute glycolytic induction in response to β-glucan ligands requires spleen tyrosine kinase signaling in a TLR-independent manner, suggesting now that different classes of innate immune receptors functionally induce conserved metabolic responses to support immune cell activation. These studies provide new insight into the complexities of metabolic regulation of DCs immune effector function regarding cellular activation associated with protection against fungal microbes.
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Affiliation(s)
- Phyu M Thwe
- Cellular, Molecular, and Biomedical (CMB) Sciences Graduate Program, University of Vermont, Burlington, Vermont, USA
| | | | - Julia P Snyder
- Cellular, Molecular, and Biomedical (CMB) Sciences Graduate Program, University of Vermont, Burlington, Vermont, USA
| | | | | | | | | | - Leslie A Sepaniac
- Cellular, Molecular, and Biomedical (CMB) Sciences Graduate Program, University of Vermont, Burlington, Vermont, USA
| | | | | | - Princess D Rodriguez
- Cellular, Molecular, and Biomedical (CMB) Sciences Graduate Program, University of Vermont, Burlington, Vermont, USA
| | | | | | - Matthew E Poynter
- Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Eyal Amiel
- Department of Biomedical and Health Sciences, University of Vermont, Burlington, Vermont, USA
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Gabaldón T. Recent trends in molecular diagnostics of yeast infections: from PCR to NGS. FEMS Microbiol Rev 2019; 43:517-547. [PMID: 31158289 PMCID: PMC8038933 DOI: 10.1093/femsre/fuz015] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 05/31/2019] [Indexed: 12/29/2022] Open
Abstract
The incidence of opportunistic yeast infections in humans has been increasing over recent years. These infections are difficult to treat and diagnose, in part due to the large number and broad diversity of species that can underlie the infection. In addition, resistance to one or several antifungal drugs in infecting strains is increasingly being reported, severely limiting therapeutic options and showcasing the need for rapid detection of the infecting agent and its drug susceptibility profile. Current methods for species and resistance identification lack satisfactory sensitivity and specificity, and often require prior culturing of the infecting agent, which delays diagnosis. Recently developed high-throughput technologies such as next generation sequencing or proteomics are opening completely new avenues for more sensitive, accurate and fast diagnosis of yeast pathogens. These approaches are the focus of intensive research, but translation into the clinics requires overcoming important challenges. In this review, we provide an overview of existing and recently emerged approaches that can be used in the identification of yeast pathogens and their drug resistance profiles. Throughout the text we highlight the advantages and disadvantages of each methodology and discuss the most promising developments in their path from bench to bedside.
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Affiliation(s)
- Toni Gabaldón
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr Aiguader 88, Barcelona 08003, Spain
- Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain
- ICREA, Pg Lluís Companys 23, 08010 Barcelona, Spain
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40
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Wang C, Li Q, Ren J. Microbiota-Immune Interaction in the Pathogenesis of Gut-Derived Infection. Front Immunol 2019; 10:1873. [PMID: 31456801 PMCID: PMC6698791 DOI: 10.3389/fimmu.2019.01873] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 07/24/2019] [Indexed: 12/12/2022] Open
Abstract
Gut-derived infection is among the most common complications in patients who underwent severe trauma, serious burn, major surgery, hemorrhagic shock or severe acute pancreatitis (SAP). It could cause sepsis and multiple organ dysfunction syndrome (MODS), which are regarded as a leading cause of mortality in these cases. Gut-derived infection is commonly caused by pathological translocation of intestinal bacteria or endotoxins, resulting from the dysfunction of the gut barrier. In the last decades, the studies regarding to the pathogenesis of gut-derived infection mainly focused on the breakdown of intestinal epithelial tight junction and increased permeability. Limited information is available on the roles of intestinal microbial barrier in the development of gut-derived infection. Recently, advances of next-generation DNA sequencing techniques and its utilization has revolutionized the gut microecology, leading to novel views into the composition of the intestinal microbiota and its connections with multiple diseases. Here, we reviewed the recent progress in the research field of intestinal barrier disruption and gut-derived infection, mainly through the perspectives of the dysbiosis of intestinal microbiota and its interaction with intestinal mucosal immune cells. This review presents novel insights into how the gut microbiota collaborates with mucosal immune cells to involve the development of pathological bacterial translocation. The data might have important implication to better understand the mechanism underlying pathological bacterial translocation, contributing us to develop new strategies for prevention and treatment of gut-derived sepsis.
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Affiliation(s)
| | - Qiurong Li
- Research Institute of General Surgery, Jinling Hospital, Medical School, Nanjing University, Nanjing, China
| | - Jianan Ren
- Research Institute of General Surgery, Jinling Hospital, Medical School, Nanjing University, Nanjing, China
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Ferrante C, Recinella L, Ronci M, Orlando G, Di Simone S, Brunetti L, Chiavaroli A, Leone S, Politi M, Tirillini B, Angelini P, Covino S, Venanzoni R, Vladimir-Knežević S, Menghini L. Protective effects induced by alcoholic Phlomis fruticosa and Phlomis herba-venti extracts in isolated rat colon: Focus on antioxidant, anti-inflammatory, and antimicrobial activities in vitro. Phytother Res 2019; 33:2387-2400. [PMID: 31322313 DOI: 10.1002/ptr.6429] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 06/05/2019] [Accepted: 06/10/2019] [Indexed: 12/14/2022]
Abstract
Phlomis fruticosa L. and P. herba-venti are species belonging to the Lamiaceae family, which have been traditionally used to prepare tonic and digestive drinks. Multiple studies also demonstrated the inhibitory effects of P. fruticosa extracts and essential oil against oxidative/proinflammatory pathways and bacterial strains deeply involved in ulcerative colitis. Considering these findings, the present study evaluated the effects of alcoholic P. fruticosa and P. herba-venti leaf extracts in isolated rat colon challenged with Escherichia coli lipopolysaccharide (LPS), an ex vivo experimental paradigm of ulcerative colitis. In this context, we assayed colon levels of pro-oxidant and proinflammatory biomarkers, including nitrites, malondialdehyde (MDA), lactate dehydrogenase (LDH), and serotonin (5-HT). Additionally, the extracts have been tested in order to evaluate possible inhibitory effects on specific bacterial and fungal strains involved in ulcerative colitis. Alcoholic P. fruticosa and P. herba-venti extracts were able to blunt LPS-induced nitrite, MDA, 5-HT, and LDH levels in isolated rat colon. The same extracts also inhibited the growth of Pseudomonas aeruginosa, E. coli, Staphylococcus aureus, Candida albicans and Candida tropicalis. In conclusion, our findings show a potential role exerted by alcoholic P. fruticosa and P. herba-venti in managing the clinical symptoms related to ulcerative colitis.
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Affiliation(s)
- Claudio Ferrante
- Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Chieti, 66100, Italy
| | - Lucia Recinella
- Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Chieti, 66100, Italy
| | - Maurizio Ronci
- Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio" of Chieti-Pescara, Chieti, 66100, Italy
| | - Giustino Orlando
- Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Chieti, 66100, Italy
| | - Simonetta Di Simone
- Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Chieti, 66100, Italy
| | - Luigi Brunetti
- Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Chieti, 66100, Italy
| | - Annalisa Chiavaroli
- Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Chieti, 66100, Italy
| | - Sheila Leone
- Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Chieti, 66100, Italy
| | - Matteo Politi
- Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Chieti, 66100, Italy
| | - Bruno Tirillini
- Department of Biomolecular Sciences, University of Urbino, Urbino, Italy
| | - Paola Angelini
- Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy
| | - Stefano Covino
- Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy
| | - Roberto Venanzoni
- Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy
| | - Sanda Vladimir-Knežević
- Department of Pharmacognosy, Faculty of Pharmacy and Biochemistry, University of Zagreb, Marulićev trg 20/II, 10000, Zagreb, Croatia
| | - Luigi Menghini
- Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Chieti, 66100, Italy
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42
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Thompson A, Davies LC, Liao CT, da Fonseca DM, Griffiths JS, Andrews R, Jones AV, Clement M, Brown GD, Humphreys IR, Taylor PR, Orr SJ. The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors. PLoS Pathog 2019; 15:e1007850. [PMID: 31242262 PMCID: PMC6594653 DOI: 10.1371/journal.ppat.1007850] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Accepted: 05/20/2019] [Indexed: 12/20/2022] Open
Abstract
Invasive candidiasis, mainly caused by Candida albicans, is a serious healthcare problem with high mortality rates, particularly in immunocompromised patients. Innate immune cells express pathogen recognition receptors (PRRs) including C-type lectin-like receptors (CLRs) that bind C. albicans to initiate an immune response. Multiple CLRs including Dectin-1, Dectin-2 and Mincle have been proposed individually to contribute to the immune response to C. albicans. However how these receptors collaborate to clear a fungal infection is unknown. Herein, we used novel multi-CLR knockout (KO) mice to decipher the individual, collaborative and collective roles of Dectin-1, Dectin-2 and Mincle during systemic C. albicans infection. These studies revealed an unappreciated and profound role for CLR co-operation in anti-fungal immunity. The protective effect of multiple CLRs was markedly greater than any single receptor, and was mediated through inflammatory monocytes via recognition and phagocytosis of C. albicans, and production of C. albicans-induced cytokines and chemokines. These CLRs were dispensable for mediating similar responses from neutrophils, likely due to lower expression of these CLRs on neutrophils compared to inflammatory monocytes. Concurrent deletion of Dectin-1 and Dectin-2, or all three CLRs, resulted in dramatically increased susceptibility to systemic C. albicans infection compared to mice lacking a single CLR. Multi-CLR KO mice were unable to control fungal growth due to an inadequate early inflammatory monocyte-mediated response. In response to excessive fungal growth, the multi-CLR KO mice mounted a hyper-inflammatory response, likely leading to multiple organ failure. Thus, these data reveal a critical role for CLR co-operation in the effective control of C. albicans and maintenance of organ function during infection. Fungal infections including invasive candidiasis are a serious healthcare problem particularly for immunocompromised patients. Mortality rates for invasive candidiasis are very high and complex anti-fungal immune responses are poorly understood, hindering the development of novel immunotherapies. Dectin-1, Dectin-2 and Mincle are three cell surface receptors that are proposed to be involved in the immune response to fungal pathogens. However, if or how these receptors work together during infection is currently unknown. Here we demonstrate that these receptors, in particular Dectin-1 and Dectin-2, work together to promote fungal clearance by a group of innate immune cells called inflammatory monocytes. Furthermore, we found that mice lacking these three receptors are dramatically susceptible to systemic Candida albicans infection due to defective early innate immune responses. These mice develop hyper-inflammation to try to control excessive fungal growth likely resulting in multi-organ failure. Our work helps explain how these receptors work together to clear/control invasive candidiasis. Our improved knowledge of the interactions between these receptors could be used to help design novel anti-fungal immunotherapies.
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Affiliation(s)
- Aiysha Thompson
- Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, Wales
- UK Dementia Research Institute at Cardiff, Cardiff, Wales
| | - Luke C. Davies
- Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, Wales
| | - Chia-Te Liao
- Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, Wales
| | - Diogo M. da Fonseca
- Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, Wales
| | - James S. Griffiths
- Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, Wales
| | - Robert Andrews
- Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, Wales
| | - Adam V. Jones
- University Dental Hospital, Cardiff and Vale University Health Board, Cardiff, Wales United Kingdom
| | - Mathew Clement
- Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, Wales
| | - Gordon D. Brown
- Medical Research Council Centre for Medical Mycology at the University of Aberdeen, Aberdeen Fungal Group, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom
| | - Ian R. Humphreys
- Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, Wales
| | - Philip R. Taylor
- Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, Wales
- UK Dementia Research Institute at Cardiff, Cardiff, Wales
| | - Selinda J. Orr
- Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, Wales
- * E-mail:
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Pandiyan P, Bhaskaran N, Zou M, Schneider E, Jayaraman S, Huehn J. Microbiome Dependent Regulation of T regs and Th17 Cells in Mucosa. Front Immunol 2019; 10:426. [PMID: 30906299 PMCID: PMC6419713 DOI: 10.3389/fimmu.2019.00426] [Citation(s) in RCA: 168] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Accepted: 02/18/2019] [Indexed: 12/19/2022] Open
Abstract
Mammals co-exist with resident microbial ecosystem that is composed of an incredible number and diversity of bacteria, viruses and fungi. Owing to direct contact between resident microbes and mucosal surfaces, both parties are in continuous and complex interactions resulting in important functional consequences. These interactions govern immune homeostasis, host response to infection, vaccination and cancer, as well as predisposition to metabolic, inflammatory and neurological disorders. Here, we discuss recent studies on direct and indirect effects of resident microbiota on regulatory T cells (Tregs) and Th17 cells at the cellular and molecular level. We review mechanisms by which commensal microbes influence mucosa in the context of bioactive molecules derived from resident bacteria, immune senescence, chronic inflammation and cancer. Lastly, we discuss potential therapeutic applications of microbiota alterations and microbial derivatives, for improving resilience of mucosal immunity and combating immunopathology.
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Affiliation(s)
- Pushpa Pandiyan
- Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Natarajan Bhaskaran
- Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Mangge Zou
- Experimental Immunology, Helmholtz Centre for Infection Research, Hamburg, Germany.,Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Elizabeth Schneider
- Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Sangeetha Jayaraman
- Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Jochen Huehn
- Experimental Immunology, Helmholtz Centre for Infection Research, Hamburg, Germany.,Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
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Chen SM, Zou Z, Qiu XR, Hou WT, Zhang Y, Fang W, Chen YL, Wang YD, Jiang YY, Shen H, An MM. The critical role of Dectin-1 in host controlling systemic Candida krusei infection. Am J Transl Res 2019; 11:721-732. [PMID: 30899374 PMCID: PMC6413270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 01/25/2019] [Indexed: 06/09/2023]
Abstract
There are increasing invasive fungal infections associated with non-albicans, which causes mortal infections in immune deficiency population. Candida krusei is a major non-albicans that exhibits intrinsic resistance to fluconazole and makes clinical treatment difficult. Previous studies revealed that C-type lectin receptors (CLRs) Dectin-1 plays critical roles in host defense against C. albicans infections. C. krusei and C. albicans are phylogenetically different although in the same genus. Whether Dectin-1 contributes to host immune response against C. krusei infection is still unknown. In the present study, we explored the potential roles of the Dectin-1 in host defense against C. krusei. We found that Dectin-1 ligand β-(1,3)-glucan markedly exposed on the cell surface of C. krusei, while β-(1,3)-glucan of C. albicans is masked. Dectin-1 is required for host myeloid cells recognition, killing of C. krusei, and development of subsequent Th1 and Th17 cell-mediated adaptive immune response. Furthermore, Dectin-1-deficient mice (Dectin-1-/- ) are more susceptible to C. krusei infection. Together, we confirmed the important roles of Dectin-1 in host defense against C. krusei infection, demonstrating a previously unknown mechanism for C. krusei infection. Our study, therefore, provides a further understanding of host immune response against C. krusei.
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Affiliation(s)
- Si Min Chen
- Department of Pharmacology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineShanghai 200092, P. R. China
| | - Zui Zou
- Department of Anesthesiology, Changzheng Hospital, Second Military Medical UniversityShanghai 200433, P. R. China
| | - Xi Ran Qiu
- Department of Pharmacology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineShanghai 200092, P. R. China
| | - Wei Tong Hou
- Department of Pharmacology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineShanghai 200092, P. R. China
| | - Yu Zhang
- Department of Pharmacology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineShanghai 200092, P. R. China
| | - Wei Fang
- Department of Pharmacology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineShanghai 200092, P. R. China
| | - Yuan Li Chen
- Department of Pharmacology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineShanghai 200092, P. R. China
| | - Yi Da Wang
- Department of Pharmacology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineShanghai 200092, P. R. China
| | - Yuan Ying Jiang
- Department of Pharmacology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineShanghai 200092, P. R. China
| | - Hui Shen
- Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of MedicineShanghai 200120, P. R. China
| | - Mao Mao An
- Department of Pharmacology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineShanghai 200092, P. R. China
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De Zuani M, Paolicelli G, Zelante T, Renga G, Romani L, Arzese A, Pucillo CEM, Frossi B. Mast Cells Respond to Candida albicans Infections and Modulate Macrophages Phagocytosis of the Fungus. Front Immunol 2018; 9:2829. [PMID: 30555491 PMCID: PMC6284040 DOI: 10.3389/fimmu.2018.02829] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 11/16/2018] [Indexed: 12/12/2022] Open
Abstract
Mast cells (MCs) are long-lived immune cells widely distributed at mucosal surfaces and are among the first immune cell type that can get in contact with the external environment. This study aims to unravel the mechanisms of reciprocal influence between mucosal MCs and Candida albicans as commensal/opportunistic pathogen species in humans. Stimulation of bone marrow-derived mast cells (BMMCs) with live forms of C. albicans induced the release of TNF-α, IL-6, IL-13, and IL-4. Quite interestingly, BMMCs were able to engulf C. albicans hyphae, rearranging their α-tubulin cytoskeleton and accumulating LAMP1+ vesicles at the phagocytic synapse with the fungus. Candida-infected MCs increased macrophage crawling ability and promoted their chemotaxis against the infection. On the other side, resting MCs inhibited macrophage phagocytosis of C. albicans in a contact-dependent manner. Taken together, these results indicate that MCs play a key role in the maintenance of the equilibrium between the host and the commensal fungus C. albicans, limiting pathological fungal growth and modulating the response of resident macrophages during infections.
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Affiliation(s)
- Marco De Zuani
- International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czechia
- Department of Medicine, University of Udine, Udine, Italy
| | | | - Teresa Zelante
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - Giorgia Renga
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - Luigina Romani
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | | | | | - Barbara Frossi
- Department of Medicine, University of Udine, Udine, Italy
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High-Throughput Screening Identifies Genes Required for Candida albicans Induction of Macrophage Pyroptosis. mBio 2018; 9:mBio.01581-18. [PMID: 30131363 PMCID: PMC6106084 DOI: 10.1128/mbio.01581-18] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
The innate immune system is the first line of defense against invasive fungal infections. As a consequence, many successful fungal pathogens have evolved elegant strategies to interact with host immune cells. For example, Candida albicans undergoes a morphogenetic switch coupled to cell wall remodeling upon phagocytosis by macrophages and then induces macrophage pyroptosis, an inflammatory cell death program. To elucidate the genetic circuitry through which C. albicans orchestrates this host response, we performed the first large-scale analysis of C. albicans interactions with mammalian immune cells. We identified 98 C. albicans genes that enable macrophage pyroptosis without influencing fungal cell morphology in the macrophage, including specific determinants of cell wall biogenesis and the Hog1 signaling cascade. Using these mutated genes, we discovered that defects in the activation of pyroptosis affect immune cell recruitment during infection. Examining host circuitry required for pyroptosis in response to C. albicans infection, we discovered that inflammasome priming and activation can be decoupled. Finally, we observed that apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization can occur prior to phagolysosomal rupture by C. albicans hyphae, demonstrating that phagolysosomal rupture is not the inflammasome activating signal. Taking the data together, this work defines genes that enable fungal cell wall remodeling and activation of macrophage pyroptosis independently of effects on morphogenesis and identifies macrophage signaling components that are required for pyroptosis in response to C. albicans infection. Candida albicans is a natural member of the human mucosal microbiota that can also cause superficial infections and life-threatening systemic infections, both of which are characterized by inflammation. Host defense relies mainly on the ingestion and destruction of C. albicans by innate immune cells, such as macrophages and neutrophils. Although some C. albicans cells are killed by macrophages, most undergo a morphological change and escape by inducing macrophage pyroptosis. Here, we investigated the C. albicans genes and host factors that promote macrophage pyroptosis in response to intracellular fungi. This work provides a foundation for understanding how host immune cells interact with C. albicans and may lead to effective strategies to modulate inflammation induced by fungal infections.
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Miyoshi J, Sofia MA, Pierre JF. The evidence for fungus in Crohn's disease pathogenesis. Clin J Gastroenterol 2018; 11:449-456. [PMID: 30027368 DOI: 10.1007/s12328-018-0886-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 07/11/2018] [Indexed: 02/07/2023]
Abstract
Current evidence suggests the etiology of inflammatory bowel diseases (IBD) involves the confluence of host genetic, environmental, and microbial factors that lead to chronic, and often refractory, disease in susceptible individuals. The involvement of microbial triggers in IBD, including Crohn's disease (CD), is increasingly evident with supporting data provided with advancements in metagenomic sequencing that have identified perturbations in microbial structure and function-broadly termed dysbiosis-in CD patients compared with healthy subjects. This concept is supported by the finding germ-free animals with CD genetic susceptibility fail to develop disease; demonstrating microorganisms are necessary but not sufficient for CD. The vast majority of CD microbiome research has focused on the complex bacterial communities and microbiome dysbiosis in the gut with 16S metagenomic sequencing. However, emerging data capturing eukaryotes suggest fungal opportunistic pathogens are also associated with IBD pathogenesis and chronicity. This hypothesis is further supported by historical observations that CD patient populations display elevated antibodies against fungal targets, even evident before disease diagnosis. This review discusses the current findings in the field, followed by historical and metagenomic evidence for fungal pathogens in the development and recurrence of CD in adult and pediatric populations.
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Affiliation(s)
- Jun Miyoshi
- Section of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, The University of Chicago, Chicago, USA
| | - Mark Anthony Sofia
- Section of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, The University of Chicago, Chicago, USA
| | - Joseph Francis Pierre
- Department of Pediatrics, The University of Tennessee Health Science Center, 425 Translational Research Building, 71 South Manassas, Memphis, TN, 38163, USA.
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Goyal S, Castrillón-Betancur JC, Klaile E, Slevogt H. The Interaction of Human Pathogenic Fungi With C-Type Lectin Receptors. Front Immunol 2018; 9:1261. [PMID: 29915598 PMCID: PMC5994417 DOI: 10.3389/fimmu.2018.01261] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 05/18/2018] [Indexed: 01/19/2023] Open
Abstract
Fungi, usually present as commensals, are a major cause of opportunistic infections in immunocompromised patients. Such infections, if not diagnosed or treated properly, can prove fatal. However, in most cases healthy individuals are able to avert the fungal attacks by mounting proper antifungal immune responses. Among the pattern recognition receptors (PRRs), C-type lectin receptors (CLRs) are the major players in antifungal immunity. CLRs can recognize carbohydrate ligands, such as β-glucans and mannans, which are mainly found on fungal cell surfaces. They induce proinflammatory immune reactions, including phagocytosis, oxidative burst, cytokine, and chemokine production from innate effector cells, as well as activation of adaptive immunity via Th17 responses. CLRs such as Dectin-1, Dectin-2, Mincle, mannose receptor (MR), and DC-SIGN can recognize many disease-causing fungi and also collaborate with each other as well as other PRRs in mounting a fungi-specific immune response. Mutations in these receptors affect the host response and have been linked to a higher risk in contracting fungal infections. This review focuses on how CLRs on various immune cells orchestrate the antifungal response and on the contribution of single nucleotide polymorphisms in these receptors toward the risk of developing such infections.
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Affiliation(s)
- Surabhi Goyal
- Institute for Microbiology and Hygiene, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Septomics Research Center, Jena University Hospital, Jena, Germany
| | - Juan Camilo Castrillón-Betancur
- Septomics Research Center, Jena University Hospital, Jena, Germany.,International Leibniz Research School for Microbial and Biomolecular Interactions, Leibniz Institute for Natural Product Research and Infection Biology/Hans Knöll Institute, Jena, Germany
| | - Esther Klaile
- Septomics Research Center, Jena University Hospital, Jena, Germany
| | - Hortense Slevogt
- Septomics Research Center, Jena University Hospital, Jena, Germany
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Hasebe A, Saeki A, Yoshida Y, Shibata KI. Differences in interleukin-1β release-inducing activity of Candida albicans toward dendritic cells and macrophages. Arch Oral Biol 2018; 93:115-125. [PMID: 29894908 DOI: 10.1016/j.archoralbio.2018.06.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 06/01/2018] [Accepted: 06/02/2018] [Indexed: 10/14/2022]
Abstract
OBJECTIVE The purpose of this study is to elucidate differences in the mechanism of the IL-1β release-inducing activity of Candida albicans toward dendritic cells and macrophages because IL-1β is one of the proinflammatory cytokines which is crucial in host defense against candidiasis. DESIGN Two C. albicans strains were used in this study. One strain is uridine-auxotrophic (CAI4) that needs uridine to grow and form hyphae, and another is a strain without any specific auxotrophy (pACT1-GFP), which forms hyphae naturally by culturing with serum components. Murine macrophage and dendritic cell lines were primed with LPS and then stimulated with C. albicans CAI4 or pACT1-GFP. RESULTS Both strains of C. albicans induced IL-1β release from dendritic cells, and C. albicans pACT1-GFP induced IL-1β release but CAI4 induced little amounts in macrophages. These differences were suggested to be due to the difference in the amount of extracellular ATP released in the cell culture supernatants induced by C. albicans CAI4 or pACT1-GFP. For induction of IL-1β release from both macrophages and dendritic cells by C. albicans, direct contacts of the microbes with cells were required. In addition, macrophages required morphological change of C. albicans from yeast to hyphae for induction of IL-1β release, whereas dendritic cells did not require it. Dead C. albicans could induce IL-1β release from dendritic cells, but could not from macrophages. CONCLUSIONS There are different mechanisms by which C. albicans induces IL-1β release from dendritic cells and macrophages.
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Affiliation(s)
- Akira Hasebe
- Departments of Oral Molecular Microbiology, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Kita 13, Nishi 7, Kita-ku, Sapporo 060-8586, Japan
| | - Ayumi Saeki
- Departments of Oral Molecular Microbiology, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Kita 13, Nishi 7, Kita-ku, Sapporo 060-8586, Japan
| | - Yasuhiro Yoshida
- Departments of Biomaterials and Bioengineering, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Kita 13, Nishi 7, Kita-ku, Sapporo 060-8586, Japan
| | - Ken-Ichiro Shibata
- Departments of Oral Molecular Microbiology, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Kita 13, Nishi 7, Kita-ku, Sapporo 060-8586, Japan.
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Abstract
Over the last decade, invasive fungal infections have emerged as a growing threat to human health worldwide and novel treatment strategies are urgently needed. In this context, investigations into host-pathogen interactions represent an important and promising field of research. Antigen presenting cells such as macrophages and dendritic cells are strategically located at the frontline of defence against potential invaders. Importantly, these cells express germline encoded pattern recognition receptors (PRRs), which sense conserved entities from pathogens and orchestrate innate immune responses. Herein, we review the latest findings regarding the biology and functions of the different classes of PRRs involved in pathogenic fungal recognition. We also discuss recent literature on PRR collaboration/crosstalk and the mechanisms involved in inhibiting/regulating PRR signalling. Finally, we discuss how the accumulated knowledge on PRR biology, especially Dectin-1, has been used for the design of new immunotherapies against fungal infections.
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Affiliation(s)
- Emmanuel C Patin
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, United Kingdom
| | - Aiysha Thompson
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, United Kingdom
| | - Selinda J Orr
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, United Kingdom.
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