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Rosati D, Valentine M, Bruno M, Pradhan A, Dietschmann A, Jaeger M, Leaves I, van de Veerdonk FL, Joosten LA, Roy S, Stappers MHT, Gow NA, Hube B, Brown AJ, Gresnigt MS, Netea MG. Lactic acid in the vaginal milieu modulates the Candida-host interaction. Virulence 2025; 16:2451165. [PMID: 39843417 PMCID: PMC11760238 DOI: 10.1080/21505594.2025.2451165] [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: 08/19/2024] [Revised: 11/07/2024] [Accepted: 12/28/2024] [Indexed: 01/24/2025] Open
Abstract
Vulvovaginal candidiasis (VVC) is one of the most common infections caused by Candida albicans. VVC is characterized by an inadequate hyperinflammatory response and clinical symptoms associated with Candida colonization of the vaginal mucosa. Compared to other host niches in which C. albicans can cause infection, the vaginal environment is extremely rich in lactic acid that is produced by the vaginal microbiota. We examined how lactic acid abundance in the vaginal niche impacts the interaction between C. albicans and the human immune system using an in vitro culture in vaginal simulative medium (VSM). The presence of lactic acid in VSM (VSM+LA) increased C. albicans proliferation, hyphal length, and its ability to cause damage during subsequent infection of vaginal epithelial cells. The cell wall of C. albicans cells grown in VSM+LA displayed a robust mannan fibrillar structure, β-glucan exposure, and low chitin content. These cell wall changes were associated with altered immune responses and an increased ability of the fungus to induce trained immunity. Neutrophils were compromised in clearing C. albicans grown in VSM+LA conditions, despite mounting stronger oxidative responses. Collectively, we found that fungal adaptation to lactic acid in a vaginal simulative context increases its immunogenicity favouring a pro-inflammatory state. This potentially contributes to the immune response dysregulation and neutrophil recruitment observed during recurrent VVC.
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Affiliation(s)
- Diletta Rosati
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, T
he Netherlands
| | - Marisa Valentine
- Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institute, Jena, Germany
| | - Mariolina Bruno
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, T
he Netherlands
| | - Arnab Pradhan
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Axel Dietschmann
- Junior Research Group Adaptive Pathogenicity Strategies, Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institute, Jena, Germany
| | - Martin Jaeger
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, T
he Netherlands
| | - Ian Leaves
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Frank L. van de Veerdonk
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, T
he Netherlands
| | - Leo A.B. Joosten
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, T
he Netherlands
- Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Sumita Roy
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Mark H. T. Stappers
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Neil A.R. Gow
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Bernhard Hube
- Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institute, Jena, Germany
- Institute of Microbiology, Friedrich-Schiller-University, Jena, Germany
| | - Alistair J.P. Brown
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Mark S. Gresnigt
- Junior Research Group Adaptive Pathogenicity Strategies, Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institute, Jena, Germany
| | - Mihai G. Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, T
he Netherlands
- Department of Immunology and Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
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2
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Shi Y, Yang B, Linghu Y, Liu Y, Li H, Xing Y, Wu B, Gao Y, Liao L, Zheng Y, Pan L, Sun X, Chen Q, Hou Y, Su D, Huang H, Han J, Cheng SC, Zhou D, Chen L. Piezo1 senses hyphae and initiates host defense against pathogenic fungi. Cell Rep 2025; 44:115839. [PMID: 40526468 DOI: 10.1016/j.celrep.2025.115839] [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: 12/13/2024] [Revised: 04/06/2025] [Accepted: 05/22/2025] [Indexed: 06/19/2025] Open
Abstract
Candida albicans metamorphoses from benign yeast to a rigid hyphal, becoming an opportunistic pathogen in immunocompromised patients. The process by which immune cells discern fungal transformations remains elusive. Here, we report that the mechanosensitive ion channel Piezo1 is indispensable for recognizing fungal hyphae and triggering antifungal innate immune responses. Hyphae-triggered Piezo1 activation increased C-type lectin receptor (CLR) expression in innate immune cells by inducing the expression of CCAAT/enhancer-binding protein beta (C/EBPβ) via the Piezo1/Ca2+/calmodulin-dependent kinase (CaMK)/cAMP response element-binding protein (CREB) axis. In addition, Piezo1/CaMK signaling activated kinases nuclear Dbf2-related protein 1/2 (NDR1/2), which augmented NLRP3 inflammasome assembly and promoted hyphae-induced inflammation. Abolishing the yeast-to-hyphae transition dampens CLR expression and NLRP3 activation. Piezo1-deficient mice exhibit compromised clearance of C. albicans infection, whereas Piezo1 agonist amplifies C. albicans clearance. In addition, CaMK, CREB, or NDR1/2 inhibition exacerbates hyphae infections, such as Piezo1 deficiency. Therefore, we ascertain Piezo1-mediated mechanotransduction as vital for immune surveillance and control of hyphal C. albicans, heralding Piezo1 agonist as a potential remedy for fungal infections.
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Affiliation(s)
- Yiran Shi
- State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Bingying Yang
- State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Yueyue Linghu
- State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Yue Liu
- State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Haoran Li
- State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Yunzhi Xing
- State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Binbin Wu
- State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Yuting Gao
- State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Liuqi Liao
- State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Yi Zheng
- State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Lei Pan
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Xiufeng Sun
- State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Qinghua Chen
- State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Yongqiang Hou
- State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Dongxue Su
- State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Hongling Huang
- State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Jiahuai Han
- State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Shih-Chin Cheng
- State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Dawang Zhou
- State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Lanfen Chen
- State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, Fujian 361102, China.
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3
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McFadden MJ, Reynolds MB, Michmerhuizen BC, Ólafsson EB, Marshall SM, Davis FA, Schultz TL, Iwawaki T, Sexton JZ, O'Riordan MXD, O'Meara TR. IRE1α promotes phagosomal calcium flux to enhance macrophage fungicidal activity. Cell Rep 2025; 44:115694. [PMID: 40349346 PMCID: PMC12166542 DOI: 10.1016/j.celrep.2025.115694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 02/03/2025] [Accepted: 04/17/2025] [Indexed: 05/14/2025] Open
Abstract
The mammalian endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1α (IRE1α) is essential for cellular homeostasis and plays key roles in infection responses, including innate immunity and microbicidal activity. While IRE1α functions through the IRE1α-XBP1S axis are known, its XBP1S-independent roles are less well understood, and its functions during fungal infection are still emerging. We demonstrate that Candida albicans activates macrophage IRE1α via C-type lectin receptor signaling independent of protein misfolding, suggesting non-canonical activation. IRE1α enhances macrophage fungicidal activity by promoting phagosome maturation, which is crucial for containing C. albicans hyphae. IRE1α facilitates early phagosomal calcium flux post-phagocytosis, which is required for phagolysosomal fusion. In macrophages lacking the IRE1α endoribonuclease domain, defective calcium flux correlates with fewer ER-early endosome contact sites, suggesting a homeostatic role for IRE1α-promoting membrane contact sites. Overall, our findings illustrate non-canonical IRE1α activation during infection and a function for IRE1α in supporting organelle contact sites to safeguard against rapidly growing microbes.
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Affiliation(s)
- Michael J McFadden
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Mack B Reynolds
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
| | | | - Einar B Ólafsson
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Sofia M Marshall
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Faith Anderson Davis
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Tracey L Schultz
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Takao Iwawaki
- Department of Life Science, Medical Research Institute, Kanazawa Medical University, Ishikawa 920-0293, Japan
| | - Jonathan Z Sexton
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Mary X D O'Riordan
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Teresa R O'Meara
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
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Zegeye FD, Straumfors A, Lei P, Graff P, Samulin Erdem J, Afanou AK. Microbial exposure and diversity in Norwegian shrimp processing plants. JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL HYGIENE 2025:1-14. [PMID: 40324108 DOI: 10.1080/15459624.2025.2491488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2025]
Abstract
Seafood processing workers have a high prevalence of respiratory symptoms and occupational asthma, primarily attributed to allergenic protein exposure. However, exposure to airborne microorganisms from raw materials can also contribute to allergic sensitization and other respiratory ailments. This study aimed to assess microbial exposure in shrimp processing plants and identify susceptible work tasks. Full-shift personal air samples were collected from two Norwegian shrimp processing plants across five distinct work processes: thawing, truck driving, cooking-peeling (technician), packing, and flour production. The samples were analyzed for the presence of endotoxin, Toll-Like Receptor (TLR) activation, bacterial and fungal DNA copies, and microbial composition. Endotoxin levels were generally low, with only one sample (98 EU/m3) exceeding the recommended occupational exposure limit (OEL). A significant TLR2 activation was observed among thawers, indicating the presence of microbial ligands capable of triggering an immune response. The median bacterial (75 × 103 DNA copies/m3) and fungal (3,301 × 103 DNA copies/m3) exposure were highest among the flour production workers, while the lowest bacterial and fungal exposure was among packers (1.5 × 103 DNA copies/m3) and technicians (337 DNA copies/m3), respectively. Several bacterial and fungal species were identified, including ten allergenic and sixteen pathogenic species. Sporobolomyces roseus and Saccharomyces cerevisiae were the two most frequently identified allergenic fungal species. Among the pathogenic bacterial species, Prevotella nigrescens and Roseomonas gilardii were the two most detected species. While the pathogenic species were identified mainly in the packing, truck driving, and flour production work processes, most of the allergenic species were found in all work processes. Altogether, work processes before the cooking of shrimp (thawing and truck driving) had higher endotoxin, bacterial load, and species richness than after cooking, suggesting that these work tasks are susceptible to bacterial exposure and that the cooking process significantly reduces bacterial exposure. By shedding light on microbial exposure and identifying high-exposure work tasks, this study enables the development of targeted interventions and implementation of measures for the prevention of occupational diseases.
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Affiliation(s)
- Fikirte Debebe Zegeye
- National Institute of Occupational Health (STAMI), Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Anne Straumfors
- National Institute of Occupational Health (STAMI), Oslo, Norway
| | - Peng Lei
- National Institute of Occupational Health (STAMI), Oslo, Norway
| | - Pål Graff
- National Institute of Occupational Health (STAMI), Oslo, Norway
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5
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Horn S, Schmid M, Berest I, Piattini F, Zhang J, de Bock K, Devuyst O, Nlandu Khodo S, Kisielow J, Kopf M. IL-1 protects from fatal systemic candidiasis in mice by inhibiting oxidative phosphorylation and hypoxia. Nat Commun 2025; 16:2626. [PMID: 40097388 PMCID: PMC11914259 DOI: 10.1038/s41467-025-57797-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 03/04/2025] [Indexed: 03/19/2025] Open
Abstract
Invasive C. albicans infections result in high mortality rates. While IL-1 is important to combat C. albicans infections, the underlying mechanisms remain unclear. Using global and conditional Il1r1 knockouts in mice, here we show that IL-1R signaling in non-hematopoietic cells in the kidney and brain is crucial for a protective response. In the kidney, endothelial IL-1R contributes to fungal clearance independent of neutrophil recruitment, while IL-1R in hematopoietic cells is dispensable. IL-1R signaling indirectly recruits neutrophils and monocytes in the brain by regulating chemokines and adhesion molecules. Single-nucleus-RNA-sequencing data implicates excessive metabolic activity and oxidative phosphorylation across all cell types in the kidney of Il1r1-deficient mice within a few hours upon infection, with associated, localized hypoxia at infection foci. Lastly, we find that hypoxia promotes fungal growth and pathogenicity. In summary, our results show that IL-1R-signaling in non-hematopoietic cells is required to prevent fatal candidiasis by inhibiting a metabolic shift, including excessive oxidative phosphorylation and hypoxia.
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Affiliation(s)
- Sofia Horn
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
| | - Mareike Schmid
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
| | - Ivan Berest
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
| | - Federica Piattini
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
| | - Jing Zhang
- Department of Health Sciences and Technology, Laboratory of Exercise and Health, ETH Zurich, Zurich, Switzerland
| | - Katrien de Bock
- Department of Health Sciences and Technology, Laboratory of Exercise and Health, ETH Zurich, Zurich, Switzerland
| | - Olivier Devuyst
- Institute of Physiology, University of Zurich, Zurich, Switzerland
| | | | - Jan Kisielow
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
| | - Manfred Kopf
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
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Bilal H, Khan MN, Khan S, Shafiq M, Fang W, Zeng Y, Guo Y, Li X, Zhao B, Lv QL, Xu B. Fungal Influences on Cancer Initiation, Progression, and Response to Treatment. Cancer Res 2025; 85:413-423. [PMID: 39589783 DOI: 10.1158/0008-5472.can-24-1609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 09/13/2024] [Accepted: 11/12/2024] [Indexed: 11/27/2024]
Abstract
Fungal dysbiosis is increasingly recognized as a key factor in cancer, influencing tumor initiation, progression, and treatment outcomes. This review explores the role of fungi in carcinogenesis, with a focus on mechanisms such as immunomodulation, inflammation induction, tumor microenvironment remodeling, and interkingdom interactions. Fungal metabolites are involved in oncogenesis, and antifungals can interact with anticancer drugs, including eliciting potential adverse effects and influencing immune responses. Furthermore, mycobiota profiles have potential as diagnostic and prognostic biomarkers, emphasizing their clinical relevance. The interplay between fungi and cancer therapies can affect drug resistance, therapeutic efficacy, and risk of invasive fungal infections associated with targeted therapies. Finally, emerging strategies for modulating mycobiota in cancer care are promising approaches to improve patient outcomes.
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Affiliation(s)
- Hazrat Bilal
- Jiangxi Key Laboratory of Oncology, JXHC Key Laboratory of Tumor Metastasis, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Institute, Nanchang, China
| | - Muhammad Nadeen Khan
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, China
| | - Sabir Khan
- Department of Dermatology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Muhammad Shafiq
- Department of Pharmacology, Research Institute of Clinical Pharmacy, Shantou University Medical College, Shantou, China
| | - Wenjie Fang
- Department of Dermatology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Yuebin Zeng
- Department of Dermatology, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yangzhong Guo
- Jiangxi Key Laboratory of Oncology, JXHC Key Laboratory of Tumor Metastasis, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Institute, Nanchang, China
| | - Xiaohui Li
- Jiangxi Key Laboratory of Oncology, JXHC Key Laboratory of Tumor Metastasis, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Institute, Nanchang, China
| | - Bing Zhao
- Jiangxi Key Laboratory of Oncology, JXHC Key Laboratory of Tumor Metastasis, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Institute, Nanchang, China
| | - Qiao-Li Lv
- Jiangxi Key Laboratory of Oncology, JXHC Key Laboratory of Tumor Metastasis, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Institute, Nanchang, China
| | - Bin Xu
- Jiangxi Key Laboratory of Oncology, JXHC Key Laboratory of Tumor Metastasis, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Institute, Nanchang, China
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Wahab A, Sanborn D, Vergidis P, Razonable R, Yadav H, Pennington KM. Diagnosis and Prevention of Invasive Fungal Infections in the Immunocompromised Host. Chest 2025; 167:374-386. [PMID: 39245320 DOI: 10.1016/j.chest.2024.08.046] [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: 07/11/2023] [Revised: 08/16/2024] [Accepted: 08/30/2024] [Indexed: 09/10/2024] Open
Abstract
TOPIC IMPORTANCE The prevalence of invasive fungal infections (IFIs) has risen in the past 3 decades, attributed to advancements in immune-modulatory therapies used in transplantation, rheumatology, and oncology. REVIEW FINDINGS Organisms that cause IFI evade the host's natural defenses or at opportunities of immunologic weakness. Infections occur from inhalation of potentially pathogenic organisms, translocation of commensal organisms, or reactivation of latent infection. Organisms that cause IFI in immunocompromised populations include Candida species, Cryptococcus species, environmental molds, and endemic fungi. Diagnosis of these infections is challenging due to slow organism growth and fastidious culture requirements. Moreover, fungal biomarkers tend to be nonspecific and can be negatively impacted by prophylactic antifungals. Antibody-based tests are not sensitive in immunocompromised hosts making antigen-based testing necessary. Prevention of IFI is guided by pathogen avoidance, removal or minimization of immune-suppressing factors, and pharmacologic prophylaxis in select hosts. SUMMARY Understanding the complex interplay between the immune system and opportunistic fungal pathogens plays a key role in early diagnosis and prevention.
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Affiliation(s)
- Abdul Wahab
- Department of Medicine, Mayo Clinic Health Systems, Mankato, MN
| | - David Sanborn
- Divisions of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN
| | - Paschalis Vergidis
- Infectious Disease, Mayo Clinic, Rochester, MN; William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN
| | - Raymund Razonable
- Infectious Disease, Mayo Clinic, Rochester, MN; William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN
| | - Hemang Yadav
- Divisions of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN; William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN
| | - Kelly M Pennington
- Divisions of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN; William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN.
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Liu W, Yang H, Xu Q, Lee J, Sun J, Xue S, Yang X, Sun X, Che C. Role of MYO1F in neutrophil and macrophage recruitment and pro-inflammatory cytokine production in Aspergillus fumigatus keratitis. Int Immunopharmacol 2024; 142:113094. [PMID: 39276460 DOI: 10.1016/j.intimp.2024.113094] [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: 07/15/2024] [Revised: 08/21/2024] [Accepted: 09/03/2024] [Indexed: 09/17/2024]
Abstract
PURPOSE Myosin 1f (Myo1f), an unconventional long-tailed class Ⅰ myosin, plays significant roles in immune cell motility and innate antifungal immunity. This study was aimed to assess the expression and role of Myo1f in Aspergillus fumigatus (AF) keratitis. METHODS Myo1f expression in the corneas of mice afflicted with AF keratitis and in AF keratitis-related cells was assessed using protein mass spectrometry, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunofluorescence. Myo1f expression following pre-treatment with inhibitors of dendritic cell-associated C-type lectin-1 (Dectin-1), Toll-like receptor 4 (TLR-4), and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) was also examined. In AF keratitis mouse models, Myo1f small interfering RNA (siRNA) was administered via subconjunctival injection to observe disease progression, inflammatory cell recruitment, and protein production using slit lamp examination, immunofluorescence, hematoxylin-eosin (HE) staining, and western blotting. RESULTS Myo1f expression was upregulated in both AF keratitis mouse models and AF keratitis-related cells. Dectin-1, TLR-4, and LOX-1 were found to be essential for the production of Myo1f in response to the infection with AF. In mice with AF keratitis, knockdown of Myo1f reduced disease severity, decreased the recruitment of neutrophils alongside macrophages to inflammatory areas, suppressed the myeloid differentiation factor 88 (MyD88)/ nuclear factor-kappaB (NF-κB) signaling pathway, and decreased the production of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, along with IL-6. Additionally, Myo1f was associated with apoptosis and pyroptosis in mice with AF keratitis. CONCLUSIONS These findings demonstrated that Myo1f contributed to the recruitment of neutrophils and macrophages, the production of pro-inflammatory cytokines, and was associated with apoptosis and pyroptosis during AF keratitis.
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Affiliation(s)
- Wenting Liu
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hua Yang
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qiang Xu
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jieun Lee
- Department of Ophthalmology, School of Medicine, Pusan National University, Yangsan, Korea
| | - Jintao Sun
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shasha Xue
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xuejiao Yang
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaoyan Sun
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Chengye Che
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao, China.
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Avina SL, Pawar S, Rivera A, Xue C. Will the Real Immunogens Please Stand Up: Exploiting the Immunogenic Potential of Cryptococcal Cell Antigens in Fungal Vaccine Development. J Fungi (Basel) 2024; 10:840. [PMID: 39728336 PMCID: PMC11676676 DOI: 10.3390/jof10120840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 11/19/2024] [Accepted: 11/30/2024] [Indexed: 12/28/2024] Open
Abstract
Cryptococcus neoformans is an opportunistic fungal pathogen that is a continuous global health concern, especially for immunocompromised populations. The World Health Organization recognized C. neoformans as one of four critical fungal pathogens, thus emphasizing the need for increased research efforts and clinical resource expansion. Currently, there are no fungal vaccines available for clinical use. Exciting new findings in cryptococcal vaccine development have identified whole cell-based and subunit-based vaccinations to help mitigate health risks and make commercialization attainable. Importantly, recent work has focused on how different cryptococcal cell-wall antigens modified in these vaccine candidates allow us to manipulate their immunogenicity to produce a desired long-term protective anti-fungal immune response. In this review, we discuss the different cryptococcal cell immunogens, namely the polysaccharide capsule, glucans, chitin/chitosan, mannoproteins, and extracellular vesicles, and their role in novel cryptococcal vaccination approaches. Additionally, we examine the immunological mechanisms responsible for protection in these vaccine candidates and the similar host response-stimulation pathways induced through different immunogen exposure.
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Affiliation(s)
- Samantha L. Avina
- Graduate School of Biomedical Sciences, Rutgers University, Newark, NJ 07103, USA; (S.L.A.); (S.P.); (A.R.)
- Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
| | - Siddhi Pawar
- Graduate School of Biomedical Sciences, Rutgers University, Newark, NJ 07103, USA; (S.L.A.); (S.P.); (A.R.)
- Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
| | - Amariliz Rivera
- Graduate School of Biomedical Sciences, Rutgers University, Newark, NJ 07103, USA; (S.L.A.); (S.P.); (A.R.)
- Department of Pediatrics and Center for Immunity and Inflammation, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
| | - Chaoyang Xue
- Graduate School of Biomedical Sciences, Rutgers University, Newark, NJ 07103, USA; (S.L.A.); (S.P.); (A.R.)
- Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
- Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
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10
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Zhang X, Hu D, Sun X, Gu Y, Zhou Y, Su C, Liu S, Zhang C, Lu G, Wu Q, Chen A. PHGDH/SYK: a hub integrating anti-fungal immunity and serine metabolism. Cell Death Differ 2024; 31:1664-1678. [PMID: 39256519 PMCID: PMC11618577 DOI: 10.1038/s41418-024-01374-7] [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: 10/10/2023] [Revised: 08/29/2024] [Accepted: 09/02/2024] [Indexed: 09/12/2024] Open
Abstract
Immune cells modify their metabolic pathways in response to fungal infections. Nevertheless, the biochemical underpinnings need to be better understood. This study reports that fungal infection drives a switch from glycolysis to the serine synthesis pathway (SSP) and one-carbon metabolism by inducing the interaction of spleen tyrosine kinase (SYK) and phosphoglycerate dehydrogenase (PHGDH). As a result, PHGDH promotes SYK phosphorylation, leading to the recruitment of SYK to C-type lectin receptors (CLRs). The CLR/SYK complex initiates signaling cascades that lead to transcription factor activation and pro-inflammatory cytokine production. SYK activates SSP and one-carbon metabolism by inducing PHGDH activity. Then, one-carbon metabolism supports S-adenosylmethionine and histone H3 lysine 36 trimethylation to drive the production of pro-inflammatory cytokines and chemokines. These findings reveal the crosstalk between amino acid metabolism, epigenetic modification, and CLR signaling during fungal infection.
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Affiliation(s)
- Xinyong Zhang
- Department of Neurology, The Second People's Hospital of Huai 'an, Huai 'an, 223001, China
| | - Dongdong Hu
- Department of Emergency, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210031, China
| | - Xiaoyan Sun
- School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan, 316022, China
| | - Yichun Gu
- The Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, and Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China
| | - Yong Zhou
- Department of Neurology, The Second People's Hospital of Huai 'an, Huai 'an, 223001, China
| | - Chuanxin Su
- The Key Laboratory of Targeted Intervention of Clinical Disease, University Hospital Essen, University of Duisburg-Essen, Essen, 45122, Germany
| | - Shi Liu
- State Key Laboratory of Virology, Modern Virology Research Center, Frontier Science Center for Immunology and Metabolism, College of Life Sciences, Wuhan University, Wuhan, 430072, China
| | - Caiyan Zhang
- Department of Critical Care Medicine, Children's Hospital of Fudan University, Shanghai, China
| | - Guoping Lu
- Department of Critical Care Medicine, Children's Hospital of Fudan University, Shanghai, China
| | - Qiwen Wu
- Department of Laboratory Medicine, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China.
| | - Aidong Chen
- The Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, and Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
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11
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Liao Y, Gao IH, Kusakabe T, Lin WY, Grier A, Pan X, Morzhanaeva O, Shea TP, Yano H, Karo-Atar D, Olsen KA, Oh JH, Vandegrift KJ, King IL, Cuomo CA, Artis D, Rehermann B, Lipman N, Iliev ID. Fungal symbiont transmitted by free-living mice promotes type 2 immunity. Nature 2024; 636:697-704. [PMID: 39604728 PMCID: PMC11733984 DOI: 10.1038/s41586-024-08213-2] [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: 04/28/2023] [Accepted: 10/14/2024] [Indexed: 11/29/2024]
Abstract
The gut mycobiota is crucial for intestinal homeostasis and immune function1. Yet its variability and inconsistent fungal colonization of laboratory mice hinders the study of the evolutionary and immune processes that underpin commensalism2,3. Here, we show that Kazachstania pintolopesii is a fungal commensal in wild urban and rural mice, with an exceptional ability to colonize the mouse gastrointestinal tract and dominate the gut mycobiome. Kazachstania pintolopesii colonization occurs in a bacteria-independent manner, results in enhanced colonization resistance to other fungi and is shielded from host immune surveillance, allowing commensal presence. Following changes in the mucosal environment, K. pintolopesii colonization triggers a type 2 immune response in mice and induces gastrointestinal eosinophilia. Mechanistically, we determined that K. pintolopesii activates type 2 immunity via the induction of epithelial IL-33 and downstream IL-33-ST2 signalling during mucus fluctuations. Kazachstania pintolopesii-induced type 2 immunity enhanced resistance to helminth infections or aggravated gastrointestinal allergy in a context-dependent manner. Our findings indicate that K. pintolopesii is a mouse commensal and serves as a valuable model organism for studying gut fungal commensalism and immunity in its native host. Its unnoticed presence in mouse facilities highlights the need to evaluate its influence on experimental outcomes and phenotypes.
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Affiliation(s)
- Yun Liao
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Iris H Gao
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Takato Kusakabe
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Woan-Yu Lin
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Alexander Grier
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Xiangyu Pan
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Olga Morzhanaeva
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Terrance P Shea
- Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Hiroshi Yano
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Allen Discovery Center for Neuroimmune Interactions, New York, NY, USA
| | - Danielle Karo-Atar
- Department of Microbiology and Immunology, Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- McGill Centre for Microbiome Research, McGill University, Montreal, Quebec, Canada
| | - Kaitlin A Olsen
- Department of Microbiology and Immunology, Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- McGill Centre for Microbiome Research, McGill University, Montreal, Quebec, Canada
| | - Ji Hoon Oh
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA
| | - Kurt J Vandegrift
- Department of Biology, The Pennsylvania State University, University Park, PA, USA
| | - Irah L King
- Department of Microbiology and Immunology, Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- McGill Centre for Microbiome Research, McGill University, Montreal, Quebec, Canada
| | - Christina A Cuomo
- Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA
| | - David Artis
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Allen Discovery Center for Neuroimmune Interactions, New York, NY, USA
| | - Barbara Rehermann
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA
| | - Neil Lipman
- Center for Comparative Medicine and Pathology, Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York, NY, USA
| | - Iliyan D Iliev
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA.
- The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA.
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, Cornell University, New York, NY, USA.
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA.
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12
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Tan W, Liu J, Yu R, Zhao P, Liu Y, Lu Q, Wang K, Ding H, Liu Y, Lai X, Cao J. Trim72 is a major host factor protecting against lethal Candida albicans infection. PLoS Pathog 2024; 20:e1012747. [PMID: 39585917 PMCID: PMC11627414 DOI: 10.1371/journal.ppat.1012747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 12/09/2024] [Accepted: 11/11/2024] [Indexed: 11/27/2024] Open
Abstract
Candida albicans is the most common aetiologic pathogen of fungal infections associated with high mortality in immunocompromised patients. There is an urgent need to develop new antifungal therapies owing to the poor efficacy and resistance of current antifungals. Here, we report that Trim72 positively regulates antifungal immunity during lethal fungal infection. Trim72 levels are significantly increased after Candida albicans infection. In vivo, Trim72 knockout significantly increases mortality, organ fungal burden and kidney damage in mice after lethal Candida albicans infection. Whereas recombinant Trim72 protein treatment protects mice against invasive candidiasis. Mechanistically, Trim72 facilitates macrophage infiltration and CCL2 production, which mediates Trim72-elicited protection against lethal Candida albicans infection. Furthermore, Trim72 may enhance macrophage migration and CCL2 production via NF-κB and ERK1/2 signaling. Inhibition of NF-κB and ERK1/2 signaling abrogates Trim72-mediated protection against lethal Candida albicans infection. Therefore, these data imply that Trim72 may be developed as a host-directed therapy for treating severe systemic candidiasis.
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Affiliation(s)
- Wang Tan
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jiayu Liu
- Department of Laboratory Medicine, The Seventh People’s Hospital of Chongqing, Central Hospital Affiliated to Chongqing University of Technology, Chongqing, China
| | - Renlin Yu
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ping Zhao
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuhan Liu
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qian Lu
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ke Wang
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hao Ding
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yi Liu
- Department of Surgery, School of Medicine, Stanford University, Stanford, California, United States of America
| | - Xiaofei Lai
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ju Cao
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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13
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Liu J, Gao Y, Zhang X, Hao Z, Zhang H, Gui R, Liu F, Tong C, Wang X. Transcriptome sequencing analysis of bovine mammary epithelial cells induced by lipopolysaccharide. Anim Biotechnol 2024; 35:2290527. [PMID: 38141161 DOI: 10.1080/10495398.2023.2290527] [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] [Indexed: 12/24/2023]
Abstract
Mastitis in cows is caused by the inflammation of the mammary glands due to an infection by external pathogenic bacteria. Mammary gland epithelial cells, which are in direct contact with the external environment, are responsible for the first line of defense of the mammary gland against pathogenic bacteria, playing an essential role in immune defense. To investigate the mechanism of bovine mammary epithelial cells in the inflammatory process, we treated the cells with LPS for 12 hours and analyzed the changes in mRNA by transcriptome sequencing. The results showed that compared to the control group, the LPS treatment group had 121 up-regulated genes and 18 down-regulated genes. GO and KEGG enrichment analysis revealed that these differential genes were mainly enriched in the IL-17 signaling pathway, Legionellosis, Cytokine-cytokine receptor interaction, NF-kappa B signaling pathway, and other signaling pathways. Furthermore, the expression of GRO1 and CXCL3 mRNAs increased significantly after LPS treatment. These findings provide new insights for the treatment of mastitis in cows in the future.
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Affiliation(s)
- Jingjing Liu
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan Province, P. R. China
| | - Yingkui Gao
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan Province, P. R. China
| | - Xing Zhang
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan Province, P. R. China
| | - Zhonghua Hao
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan Province, P. R. China
| | - Huaqiang Zhang
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan Province, P. R. China
| | - Rong Gui
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan Province, P. R. China
| | - Fang Liu
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan Province, P. R. China
| | - Chao Tong
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan Province, P. R. China
- Wuhu Overseas Student Pioneer Park, Wuhu, Anhui, China
| | - Xuebing Wang
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan Province, P. R. China
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14
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Wang H, Kim SJ, Lei Y, Wang S, Wang H, Huang H, Zhang H, Tsung A. Neutrophil extracellular traps in homeostasis and disease. Signal Transduct Target Ther 2024; 9:235. [PMID: 39300084 PMCID: PMC11415080 DOI: 10.1038/s41392-024-01933-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 06/25/2024] [Accepted: 07/16/2024] [Indexed: 09/22/2024] Open
Abstract
Neutrophil extracellular traps (NETs), crucial in immune defense mechanisms, are renowned for their propensity to expel decondensed chromatin embedded with inflammatory proteins. Our comprehension of NETs in pathogen clearance, immune regulation and disease pathogenesis, has grown significantly in recent years. NETs are not only pivotal in the context of infections but also exhibit significant involvement in sterile inflammation. Evidence suggests that excessive accumulation of NETs can result in vessel occlusion, tissue damage, and prolonged inflammatory responses, thereby contributing to the progression and exacerbation of various pathological states. Nevertheless, NETs exhibit dual functionalities in certain pathological contexts. While NETs may act as autoantigens, aggregated NET complexes can function as inflammatory mediators by degrading proinflammatory cytokines and chemokines. The delineation of molecules and signaling pathways governing NET formation aids in refining our appreciation of NETs' role in immune homeostasis, inflammation, autoimmune diseases, metabolic dysregulation, and cancer. In this comprehensive review, we delve into the multifaceted roles of NETs in both homeostasis and disease, whilst discussing their potential as therapeutic targets. Our aim is to enhance the understanding of the intricate functions of NETs across the spectrum from physiology to pathology.
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Affiliation(s)
- Han Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Susan J Kim
- Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, USA
| | - Yu Lei
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shuhui Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hui Wang
- Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hai Huang
- Feinstein Institutes for Medical Research, Manhasset, NY, USA
| | - Hongji Zhang
- Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, USA.
| | - Allan Tsung
- Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, USA.
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15
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Hu D, Li Y, Wang X, Zou H, Li Z, Chen W, Meng Y, Wang Y, Li Q, Liao F, Wu K, Wu J, Li G, Wang W. Palmitoylation of NLRP3 Modulates Inflammasome Activation and Inflammatory Bowel Disease Development. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 213:481-493. [PMID: 38949555 PMCID: PMC11299489 DOI: 10.4049/jimmunol.2300241] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 06/07/2024] [Indexed: 07/02/2024]
Abstract
Aberrant activity of NLRP3 has been shown associations with severe diseases. Palmitoylation is a kind of protein post-translational modification, which has been shown to regulate cancer development and the innate immune system. Here, we showed that NLRP3 is palmitoylated at Cys419 and that palmitoyltransferase ZDHHC17 is the predominant enzyme that mediates NLRP3 palmitoylation and promotes NLRP3 activation by interacting with NLRP3 and facilitating NIMA-related kinase 7 (NEK7)-NLRP3 interactions. Blockade of NLRP3 palmitoylation by a palmitoylation inhibitor, 2-bromopalmitate, effectively inhibited NLRP3 activation in vitro. Also, in a dextran sulfate sodium-induced colitis model in mice, 2-bromopalmitate application could attenuate weight loss, improve the survival rate, and rescue pathological changes in the colon of mice. Overall, our study reveals that palmitoylation of NLPR3 modulates inflammasome activation and inflammatory bowel disease development. We propose that drugs targeting NLRP3 palmitoylation could be promising candidates in the treatment of NLRP3-mediated inflammatory diseases.
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Affiliation(s)
- Dingwen Hu
- Clinical Experimental Center, Jiangmen Central Hospital, Jiangmen, China
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Yuting Li
- Laboratory Animal Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xianyang Wang
- Laboratory Animal Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Haimei Zou
- Laboratory Animal Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zonghui Li
- Laboratory Animal Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Weijie Chen
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, China
| | - Yu Meng
- Laboratory Animal Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yingchong Wang
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Qin Li
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Feng Liao
- Laboratory Animal Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Kailang Wu
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Jianguo Wu
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, China
| | - Geng Li
- Laboratory Animal Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, China
| | - Wenbiao Wang
- Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
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16
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McFadden MJ, Reynolds MB, Michmerhuizen BC, Ólafsson EB, Anderson FM, Schultz TL, O’Riordan MX, O’Meara TR. Non-canonical activation of IRE1α during Candida albicans infection enhances macrophage fungicidal activity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.10.02.560560. [PMID: 37873171 PMCID: PMC10592910 DOI: 10.1101/2023.10.02.560560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
While the canonical function of IRE1α is to detect misfolded proteins and activate the unfolded protein response (UPR) to maintain cellular homeostasis, microbial pathogens can also activate IRE1α, which modulates innate immunity and infection outcomes. However, how infection activates IRE1α and its associated inflammatory functions have not been fully elucidated. Recognition of microbe-associated molecular patterns can activate IRE1α, but it is unclear whether this depends on protein misfolding. Here, we report that a common and deadly fungal pathogen, Candida albicans, activates macrophage IRE1α through C-type lectin receptor signaling, reinforcing a role for IRE1α as a central regulator of host responses to infection by a broad range of pathogens. This activation did not depend on protein misfolding in response to C. albicans infection. Moreover, lipopolysaccharide treatment was also able to activate IRE1α prior to protein misfolding, suggesting that pathogen-mediated activation of IRE1α occurs through non-canonical mechanisms. During C. albicans infection, we observed that IRE1α activity promotes phagolysosomal fusion that supports the fungicidal activity of macrophages. Consequently, macrophages lacking IRE1α activity displayed inefficient phagosome maturation, enabling C. albicans to lyse the phagosome, evade fungal killing, and drive aberrant inflammatory cytokine production. Mechanistically, we show that IRE1α activity supports phagosomal calcium flux after phagocytosis of C. albicans, which is crucial for phagosome maturation. Importantly, deletion of IRE1α activity decreased the fungicidal activity of phagocytes in vivo during systemic C. albicans infection. Together, these data provide mechanistic insight for the non-canonical activation of IRE1α during infection, and reveal central roles for IRE1α in macrophage antifungal responses.
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Affiliation(s)
- Michael J. McFadden
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Mack B. Reynolds
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
| | | | - Einar B. Ólafsson
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Faith M. Anderson
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Tracey L. Schultz
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Mary X.D. O’Riordan
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Teresa R. O’Meara
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
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17
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Nenciarini S, Renzi S, di Paola M, Meriggi N, Cavalieri D. The yeast-human coevolution: Fungal transition from passengers, colonizers, and invaders. WIREs Mech Dis 2024; 16:e1639. [PMID: 38146626 DOI: 10.1002/wsbm.1639] [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: 05/19/2023] [Revised: 12/06/2023] [Accepted: 12/07/2023] [Indexed: 12/27/2023]
Abstract
Fungi are the cause of more than a billion infections in humans every year, although their interactions with the host are still neglected compared to bacteria. Major systemic fungal infections are very unusual in the healthy population, due to the long history of coevolution with the human host. Humans are routinely exposed to environmental fungi and can host a commensal mycobiota, which is increasingly considered as a key player in health and disease. Here, we review the current knowledge on host-fungi coevolution and the factors that regulate their interaction. On one hand, fungi have learned to survive and inhabit the host organisms as a natural ecosystem, on the other hand, the host immune system finely tunes the response toward fungi. In turn, recognition of fungi as commensals or pathogens regulates the host immune balance in health and disease. In the human gut ecosystem, yeasts provide a fingerprint of the transient microbiota. Their status as passengers or colonizers is related to the integrity of the gut barrier and the risk of multiple disorders. Thus, the study of this less known component of the microbiota could unravel the rules of the transition from passengers to colonizers and invaders, as well as their dependence on the innate component of the host's immune response. This article is categorized under: Infectious Diseases > Environmental Factors Immune System Diseases > Environmental Factors Infectious Diseases > Molecular and Cellular Physiology.
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Affiliation(s)
| | - Sonia Renzi
- Department of Biology, University of Florence, Florence, Italy
| | - Monica di Paola
- Department of Biology, University of Florence, Florence, Italy
| | - Niccolò Meriggi
- Department of Biology, University of Florence, Florence, Italy
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Ma M, Jiang W, Zhou R. DAMPs and DAMP-sensing receptors in inflammation and diseases. Immunity 2024; 57:752-771. [PMID: 38599169 DOI: 10.1016/j.immuni.2024.03.002] [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: 12/18/2023] [Revised: 02/17/2024] [Accepted: 03/01/2024] [Indexed: 04/12/2024]
Abstract
Damage-associated molecular patterns (DAMPs) are endogenous danger molecules produced in cellular damage or stress, and they can activate the innate immune system. DAMPs contain multiple types of molecules, including nucleic acids, proteins, ions, glycans, and metabolites. Although these endogenous molecules do not trigger immune response under steady-state condition, they may undergo changes in distribution, physical or chemical property, or concentration upon cellular damage or stress, and then they become DAMPs that can be sensed by innate immune receptors to induce inflammatory response. Thus, DAMPs play an important role in inflammation and inflammatory diseases. In this review, we summarize the conversion of homeostatic molecules into DAMPs; the diverse nature and classification, cellular origin, and sensing of DAMPs; and their role in inflammation and related diseases. Furthermore, we discuss the clinical strategies to treat DAMP-associated diseases via targeting DAMP-sensing receptors.
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Affiliation(s)
- Ming Ma
- Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, Anhui, China
| | - Wei Jiang
- Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, Anhui, China
| | - Rongbin Zhou
- Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, Anhui, China; Department of Geriatrics, Gerontology Institute of Anhui Province, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
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19
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Zhang Z, Li P, Chen Y, Chen Y, Wang X, Shen S, Zhao Y, Zhu Y, Wang T. Mitochondria-mediated ferroptosis induced by CARD9 ablation prevents MDSCs-dependent antifungal immunity. Cell Commun Signal 2024; 22:210. [PMID: 38566195 PMCID: PMC10986078 DOI: 10.1186/s12964-024-01581-2] [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: 12/19/2023] [Accepted: 03/23/2024] [Indexed: 04/04/2024] Open
Abstract
BACKGROUND Caspase Recruitment Domain-containing protein 9 (CARD9) expressed in myeloid cells has been demonstrated to play an antifungal immunity role in protecting against disseminated candidiasis. Hereditary CARD9 ablation leads to fatal disseminated candidiasis. However, the myeloid cell types and molecular mechanisms implicated in CARD9 protecting against disseminated candidiasis remain wholly elusive. METHODS The role of CARD9 ablation in exacerbating disseminated candidiasis was determined in vivo and in vitro. The molecular mechanism by which CARD9 ablation promotes acute kidney injury in disseminated candidiasis was identified by RNA-sequencing analysis. The expression of mitochondrial proteins and ferroptosis-associated proteins were measured by Quantitative real-time PCR and western blot. RESULTS CARD9 ablation resulted in a reduced proportion of myeloid-derived suppressor cells (MDSCs) and a substantially lower expression of solute carrier family 7 member 11 (SLC7A11) in the kidneys, which increased susceptibility to acute kidney injury and renal ferroptosis during disseminated Candida tropicalis (C. tropicalis) infection. Moreover, CARD9-deficient MDSCs were susceptible to ferroptosis upon stimulation with C. tropicalis, which was attributed to augmented mitochondrial oxidative phosphorylation (OXPHOS) caused by reduced SLC7A11 expression. Mechanistically, C-type lectin receptors (CLRs)-mediated recognition of C. tropicalis promoted the expression of SLC7A11 which was transcriptionally manipulated by the Syk-PKCδ-CARD9-FosB signaling axis in MDSCs. FosB enhanced SLC7A11 transcription by binding to the promoter of SLC7A11 in MDSCs stimulated with C. tropicalis. Mitochondrial OXPHOS, which was negatively regulated by SLC7A11, was responsible for inducing ferroptosis of MDSCs upon C. tropicalis stimulation. Finally, pharmacological inhibition of mitochondrial OXPHOS or ferroptosis significantly increased the number of MDSCs in the kidneys to augment host antifungal immunity, thereby attenuating ferroptosis and acute kidney injury exacerbated by CARD9 ablation during disseminated candidiasis. CONCLUSIONS Collectively, our findings show that CARD9 ablation enhances mitochondria-mediated ferroptosis in MDSCs, which negatively regulates antifungal immunity. We also identify mitochondria-mediated ferroptosis in MDSCs as a new molecular mechanism of CARD9 ablation-exacerbated acute kidney injury during disseminated candidiasis, thus targeting mitochondria-mediated ferroptosis is a novel therapeutic strategy for acute kidney injury in disseminated candidiasis.
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Affiliation(s)
- Zhiyong Zhang
- Department of Endodontic, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, 210008, China
- The State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
| | - Pengfei Li
- The State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
| | - Ying Chen
- The State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
| | - Yuxi Chen
- The State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
| | - Xiuzhu Wang
- The State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
| | - Sunan Shen
- The State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
| | - Yue Zhao
- The State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
| | - Yanan Zhu
- Department of Endodontic, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, 210008, China.
| | - Tingting Wang
- The State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China.
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China.
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Purushothaman K, Crawford AD, Rocha SD, Göksu AB, Lange BM, Mydland LT, Vij S, Qingsong L, Øverland M, Press CM. Cyberlindnera jadinii yeast as a functional protein source: Modulation of immunoregulatory pathways in the intestinal proteome of zebrafish ( Danio rerio). Heliyon 2024; 10:e26547. [PMID: 38468924 PMCID: PMC10925985 DOI: 10.1016/j.heliyon.2024.e26547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 02/09/2024] [Accepted: 02/15/2024] [Indexed: 03/13/2024] Open
Abstract
Yeasts contain bioactive components that can enhance fish immune robustness and disease resistance. Our study focused on analyzing intestinal immunoregulatory pathways in zebrafish (Danio rerio) using iTRAQ and 2D LC-MS/MS to quantify intestinal proteins. Zebrafish were fed either control diet (C) or diet supplemented with autolyzed Cyberlindnera jadinii (ACJ). KEGG analysis revealed that ACJ yeast diet induced increased abundance of proteins related to arginine and proline metabolism, phagosome, C-lectin receptor signaling, ribosome and PPAR signaling pathways, which can modulate and enhance innate immune responses. ACJ yeast diet also showed decreased abundance of proteins associated with inflammatory pathways, including apoptosis, necroptosis and ferroptosis. These findings indicate boosted innate immune response and control of inflammation-related pathways in zebrafish intestine. Our findings in the well annotated proteome of zebrafish enabled a detailed investigation of intestinal responses and provide insight into health-beneficial effects of yeast species C. jadinii, which is relevant for aquaculture species.
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Affiliation(s)
- Kathiresan Purushothaman
- Department of Preclinical Sciences and Pathology, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Ås, Norway
| | - Alexander D. Crawford
- Department of Preclinical Sciences and Pathology, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Ås, Norway
| | - Sérgio D.C. Rocha
- Department of Animal and Aquaculture Sciences, Faculty of Biosciences, Norwegian University of Life Sciences, P.O. Box 5003, Ås, Norway
| | - Aleksandar B. Göksu
- Department of Preclinical Sciences and Pathology, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Ås, Norway
| | - Byron Morales Lange
- Department of Animal and Aquaculture Sciences, Faculty of Biosciences, Norwegian University of Life Sciences, P.O. Box 5003, Ås, Norway
| | - Liv Torunn Mydland
- Department of Animal and Aquaculture Sciences, Faculty of Biosciences, Norwegian University of Life Sciences, P.O. Box 5003, Ås, Norway
| | - Shubha Vij
- School of Applied Science, Republic Polytechnic, 9 Woodlands Avenue 9, Singapore 738964, Singapore
- Tropical Futures Institute, James Cook University Singapore, 149 Sims Drive, 387380, Singapore
| | - Lin Qingsong
- Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore
| | - Margareth Øverland
- Department of Animal and Aquaculture Sciences, Faculty of Biosciences, Norwegian University of Life Sciences, P.O. Box 5003, Ås, Norway
| | - Charles McL. Press
- Department of Preclinical Sciences and Pathology, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Ås, Norway
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21
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Chen Y, Jiang Q, Qing F, Xue J, Xiao Q, He W, Sui L, Liu Z. MDA5 Enhances Invasive Candida albicans Infection by Regulating Macrophage Apoptosis and Phagocytosis/Killing Functions. Inflammation 2024; 47:191-208. [PMID: 37740789 DOI: 10.1007/s10753-023-01903-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/24/2023] [Accepted: 09/08/2023] [Indexed: 09/25/2023]
Abstract
Candida albicans is a common opportunistic pathogenic fungus. The innate immune system provides the first-line host defense against fungal infection. Innate immune receptors and downstream molecules have been shown to play various roles during fungal infection. The innate immune receptor MDA5, encoded by the gene Ifih1, enhances host resistance against viral and Aspergillus fumigatus infection by inducing the production of interferons (IFNs). However, the role of MDA5 in C. albicans infection is still unclear. Here, we found that the gene expression levels of IFIH1 were significantly increased in innate immune cells after C. albicans stimulation through human bioinformatics analysis or mouse experiments. Through in vivo study, MDA5 was shown to enhance host susceptibility to C. albicans infection independent of IFN production. Instead, MDA5 exerted its influence on macrophages and kidneys by modulating the expression of Noxa, Bcl2, and Bax, thereby promoting apoptosis. Additionally, MDA5 compromised killing capabilities of macrophage by inhibition iNOS expression. The introduction of the apoptosis inducer PAC1 further impaired macrophage functions, mimicking the enhancing effect of MDA5 on C. albicans infection. Furthermore, the administration of macrophage scavengers increased the susceptibility of Ifih1-/- mice to C. albicans. The founding suggests that MDA5 promote host susceptibility to invasive C. albicans by enhancing cell apoptosis and compromising macrophage functions, making MDA5 a target to treat candidiasis.
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Affiliation(s)
- Yayun Chen
- School of Graduate, China Medical University, Shenyang, Liaoning, China
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Qian Jiang
- School of Graduate, China Medical University, Shenyang, Liaoning, China
- School of Nursing, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Furong Qing
- School of Graduate, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Junxia Xue
- School of Graduate, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Qiuxiang Xiao
- Department of Pathology, The First Affiliated Hospital, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Wenji He
- School of Graduate, China Medical University, Shenyang, Liaoning, China
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Lina Sui
- School of Graduate, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Zhiping Liu
- School of Graduate, China Medical University, Shenyang, Liaoning, China.
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China.
- Center for Scientific Research, Gannan Medical University, Ganzhou, Jiangxi, 341000, China.
- Center for Immunology, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, 341000, China.
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22
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Yin X, Wang L, Niu Y, Xie D, Zhang Q, Xiao J, Dong L, Wang C. Unmasking Chemokine-Inducing Specificity in Oligosaccharide Biomaterial to Promote Hair Growth. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2304655. [PMID: 37567583 DOI: 10.1002/adma.202304655] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 07/23/2023] [Indexed: 08/13/2023]
Abstract
Hair loss affects over 50 million people worldwide with limited therapeutic options. Despite evidence highlighting the vital role of local immune cells in regulating the life cycle of hair follicles (HFs), accurate regulation of immunocytes to directly promote hair growth remains unachieved. Here, inspired by the physiological feedback in the skin immunity to suppress microbe-triggered inflammation, an oligosaccharide biomaterial with "unmasked" specific activity is developed to recruit regulatory T (Treg ) cells around HFs, leading to accelerated hair growth in mice. By processing the glucomannan polysaccharide via controllable enzymatic cleavage, a series of oligosaccharide fractions with more specific chemokine-inducing functions is obtained. Notably, a hexasaccharide-based fraction (OG6) stimulates macrophages to selectively express Treg -chemoattractant C-C Motif Chemokine Ligand 5 (CCL5) through a mannose receptor-mediated endocytosis and NOD1/2-dependent signaling, as evidenced by molecular docking, inhibition assays, and a Foxp3-reporter mouse model. Intradermal delivery of OG6 to the depilated mouse skin promotes Treg mobilization around HFs and stimulates de novo regeneration of robust hairs. This study demonstrates that unmasking precise immunomodulatory functions in oligosaccharides from their parental polysaccharide can potentially solve the long-lasting dilemma with polysaccharide biomaterials that are widely renowned for versatile activities yet high heterogeneity, opening new avenues to designing glycan-based therapeutic tools with improved specificity and safety.
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Affiliation(s)
- Xiaoyu Yin
- State Key Laboratory in Quality Research of Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, 999078, China
- State Key Laboratory in Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Lintao Wang
- State Key Laboratory in Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Yiming Niu
- State Key Laboratory in Quality Research of Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, 999078, China
| | - Daping Xie
- State Key Laboratory in Quality Research of Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, 999078, China
| | - Qingwen Zhang
- State Key Laboratory in Quality Research of Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, 999078, China
| | - Jian Xiao
- Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Lei Dong
- State Key Laboratory in Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
- National Resource Center For Mutant Mice, Nanjing, 210023, China
| | - Chunming Wang
- State Key Laboratory in Quality Research of Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, 999078, China
- Zhuhai UM Science & Technology Research Institute, University of Macau, Hengqin, 519000, China
- Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China
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Wang L, Zheng M, Liu J, Jin Z, Wang C, Gao M, Zhang H, Zhang X, Xia X. LDLa containing C-type lectin mediates phagocytosis of V.anguillarum and regulates immune effector genes in shrimp. FISH & SHELLFISH IMMUNOLOGY 2024; 145:109361. [PMID: 38185393 DOI: 10.1016/j.fsi.2024.109361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 12/29/2023] [Accepted: 01/04/2024] [Indexed: 01/09/2024]
Abstract
C-type lectins (CTLs) function as pattern recognition receptors (PRRs) by recognizing invading microorganisms, thereby triggering downstream immune events against infected pathogens. In this study, a novel CTL containing a low-density lipoprotein receptor class A (LDLa) domain was obtained from Litopenaeus vannamei, designed as LvLDLalec. Stimulation by the bacterial pathogen Vibrio anguillarum (V. anguillarum) resulted in remarkable up-regulation of LvLDLalec, as well as release of LvLDLalec into hemolymph. The rLvLDLalec protein possessed broad-spectrum bacterial binding and agglutinating activities, as well as hemocyte attachment ability. Importantly, LvLDLalec facilitated the bacterial clearance in shrimp hemolymph and protected shrimp from bacterial infection. Further studies revealed that LvLDLalec promoted hemocytes phagocytosis against V. anguillarum and lysosomes were involved in the process. Meanwhile, LvLDLalec participated in humoral immunity through activating and inducing nuclear translocation of Dorsal to regulate phagocytosis-related genes and antimicrobial peptides (AMPs) genes, thereby accelerated the removal of invading pathogens in vivo and improved the survival rate of L. vannamei. These results unveil that LvLDLalec serves as a PRR participate in cellular and humoral immunity exerting opsonin activity to play vital roles in the immune regulatory system of L. vannamei.
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Affiliation(s)
- Liuen Wang
- College of Life Sciences, Henan Normal University, Xinxiang, Henan, 453007, China
| | - Meimei Zheng
- College of Life Sciences, Henan Normal University, Xinxiang, Henan, 453007, China
| | - Jisheng Liu
- College of Life Sciences, Henan Normal University, Xinxiang, Henan, 453007, China
| | - Zeyu Jin
- College of Life Sciences, Henan Normal University, Xinxiang, Henan, 453007, China
| | - Cui Wang
- College of Life Sciences, Henan Normal University, Xinxiang, Henan, 453007, China
| | - Miaomiao Gao
- College of Life Sciences, Henan Normal University, Xinxiang, Henan, 453007, China
| | - Hongwei Zhang
- Department of Nature Resources, Henan Institute of Science and Technology, Xinxiang, Henan, 453003, China
| | - Xiaowen Zhang
- College of Life Sciences, Henan Normal University, Xinxiang, Henan, 453007, China; Henan International Joint Laboratory of Agricultural Microbial Ecology and Technology, Henan Normal University, Xinxiang, 453007, China; The Observation and Research Field Station of Taihang Mountain Forest Ecosystems of Henan Province, Xinxiang, 453007, Henan, China.
| | - Xiaohua Xia
- College of Life Sciences, Henan Normal University, Xinxiang, Henan, 453007, China.
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24
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Hoving JC. Emergomyces africanus poses an emerging threat. Nat Microbiol 2024; 9:4-5. [PMID: 38177299 DOI: 10.1038/s41564-023-01565-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2024]
Affiliation(s)
- Jennifer Claire Hoving
- CMM AFRICA Medical Mycology Research Unit, Institute of Infectious Diseases and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
- MRC Centre for Medical Mycology, University of Exeter, Exeter, UK.
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25
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Li L, Huang X, Chen H. Unveiling the hidden players: exploring the role of gut mycobiome in cancer development and treatment dynamics. Gut Microbes 2024; 16:2328868. [PMID: 38485702 PMCID: PMC10950292 DOI: 10.1080/19490976.2024.2328868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 03/06/2024] [Indexed: 03/19/2024] Open
Abstract
The role of gut fungal species in tumor-related processes remains largely unexplored, with most studies still focusing on fungal infections. This review examines the accumulating evidence suggesting the involvement of commensal and pathogenic fungi in cancer biological process, including oncogenesis, progression, and treatment response. Mechanisms explored include fungal influence on host immunity, secretion of bioactive toxins/metabolites, interaction with bacterial commensals, and migration to other tissues in certain types of cancers. Attempts to utilize fungal molecular signatures for cancer diagnosis and fungal-derived products for treatment are discussed. A few studies highlight fungi's impact on the responsiveness and sensitivity to chemotherapy, radiotherapy, immunotherapy, and fecal microbiota transplant. Given the limited understanding and techniques in fungal research, the studies on gut fungi are still facing great challenges, despite having great potentials.
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Affiliation(s)
- Lingxi Li
- State Key Laboratory of Systems Medicine for Cancer, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Shanghai, China
| | - Xiaowen Huang
- State Key Laboratory of Systems Medicine for Cancer, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Shanghai, China
| | - Haoyan Chen
- State Key Laboratory of Systems Medicine for Cancer, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Shanghai, China
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26
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Dhaliwal M, Muthu V, Sharma A, Raj K, Rudramurthy SM, Agarwal R, Kaur H, Rawat A, Singh S, Chakrabarti A. Immune and metabolic perturbations in COVID-19-associated pulmonary mucormycosis: A transcriptome analysis of innate immune cells. Mycoses 2024; 67:e13679. [PMID: 38214399 DOI: 10.1111/myc.13679] [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: 10/18/2023] [Accepted: 11/23/2023] [Indexed: 01/13/2024]
Abstract
BACKGROUND AND OBJECTIVES The mechanisms underlying COVID-19-associated pulmonary mucormycosis (CAPM) remain unclear. We use a transcriptomic analysis of the innate immune cells to investigate the host immune and metabolic response pathways in patients with CAPM. PATIENTS AND METHODS We enrolled subjects with CAPM (n = 5), pulmonary mucormycosis (PM) without COVID-19 (n = 5), COVID-19 (without mucormycosis, n = 5), healthy controls (n = 5) without comorbid illness and negative for SARS-CoV-2. Peripheral blood samples from cases were collected before initiating antifungal therapy, and neutrophils and monocytes were isolated. RNA sequencing was performed using Illumina HiSeqX from monocytes and neutrophils. Raw reads were aligned with HISAT-2 pipeline and DESeq2 was used for differential gene expression. Gene ontology (GO) and metabolic pathway analysis were performed using Shiny GO application and R packages (ggplot2, Pathview). RESULTS The derangement of core immune and metabolic responses in CAPM patients was noted. Pattern recognition receptors, dectin-2, MCL, FcRγ receptors and CLEC-2, were upregulated, but signalling pathways such as JAK-STAT, IL-17 and CARD-9 were downregulated; mTOR and MAP-kinase signalling were elevated in monocytes from CAPM patients. The complement receptors, NETosis, and pro-inflammatory responses, such as S100A8/A9, lipocalin and MMP9, were elevated. The major metabolic pathways of glucose metabolism-glycolysis/gluconeogenesis, pentose phosphate pathway, HIF signalling and iron metabolism-ferroptosis were also upregulated in CAPM. CONCLUSIONS We identified significant alterations in the metabolic pathways possibly leading to cellular iron overload and a hyperglycaemic state. Immune responses revealed altered recognition, signalling, effector functions and a pro-inflammatory state in monocytes and neutrophils from CAPM patients.
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Affiliation(s)
- Manpreet Dhaliwal
- Department of Paediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Valliappan Muthu
- Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Arunima Sharma
- Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Khem Raj
- Department of Microbiology, Panjab University, Chandigarh, India
| | - Shivaprakash M Rudramurthy
- Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ritesh Agarwal
- Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Harsimran Kaur
- Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Amit Rawat
- Department of Paediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Surjit Singh
- Department of Paediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Arunaloke Chakrabarti
- Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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27
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Zhang D, Zhou G, Thongda W, Li C, Ye Z, Zhao H, Beck BH, Mohammed H, Peatman E. Early divergent responses to virulent and attenuated vaccine isolates of Flavobacterium covae sp. nov. In channel catfish, Ictalurus punctatus. FISH & SHELLFISH IMMUNOLOGY 2024; 144:109248. [PMID: 38030028 DOI: 10.1016/j.fsi.2023.109248] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/14/2023] [Accepted: 11/23/2023] [Indexed: 12/01/2023]
Abstract
Columnaris disease continues to inflict substantial losses among freshwater cultured species since its first description one hundred years ago. The experimental and anecdotal evidence suggests an expanded range and rising virulence of columnaris worldwide due to the warming global climate. The channel catfish (Ictalurus punctatus) are particularly vulnerable to columnaris. A recently developed live attenuated vaccine (17-23) for Flavobacterium columnare (now Flavobacterium covae sp. nov.) demonstrated superior protection for vaccinated catfish against genetically diverse columnaris isolates. In this study, we aimed to elucidate the molecular mechanisms and patterns of immune evasion and host manipulation linked to virulence by comparing gene expression changes in the host after the challenge with a virulent (BGSF-27) or live attenuated F. covae sp. nov. vaccine (17-23). Thirty-day-old fry were accordingly challenged with either virulent or vaccine isolates. Gill tissues were collected at 0 h (control), 1 h, and 2 h post-infection, which are two critical time points in early host-pathogen interactions. Transcriptome profiling of the gill tissues revealed a larger number (518) of differentially expressed genes (DEGs) in vaccine-exposed fish than those exposed to the virulent pathogen (321). Pathway analyses suggested potent suppression of early host immune responses by the virulent isolate through a higher expression of nuclear receptor corepressors (NCoR) responsible for antagonizing macrophage and T-cell signaling. Conversely, in vaccinated fry, we observed induction of Ca2+/calmodulin-dependent protein kinase II (CAMKII), responsible for clearing NCoR, and commensurate up-regulation of transcription factor AP-1 subunits, c-Fos, and c-Jun. As in mammalian systems, AP-1 expression was connected with a broad immune activation in vaccinated fry, including induction of CC chemokines, proteinases, iNOS, and IL-12b. Relatedly, divergent expression patterns of Src tyrosine kinase Lck, CD44, and CD28 indicated a delay or suppression of T-cell adhesion and activation in fry exposed to the virulent isolate. Broader implications of these findings will be discussed. The transcriptomic differences between virulent and attenuated bacteria may offer insights into how the host responds to the vaccination or infection and provide valuable knowledge to understand the early immune mechanisms of columnaris disease in aquaculture.
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Affiliation(s)
- Dongdong Zhang
- Hainan Provincial Key Laboratory for Tropical Hydrobiology and Biotechnology, School of Marine Bilology and Fisheries, Hainan University, Haikou, 570228, PR China; School of Fisheries, Aquaculture, and Aquatic Sciences, Auburn University, Auburn, AL, 36849, USA; College of Breeding and Multiplication (Sanya Institute of Breeding and Multiplication), Hainan University, Sanya, PR China
| | - Gengfu Zhou
- Hainan Provincial Key Laboratory for Tropical Hydrobiology and Biotechnology, School of Marine Bilology and Fisheries, Hainan University, Haikou, 570228, PR China
| | - Wilawan Thongda
- Center of Excellence for Shrimp Molecular Biology and Biotechnology (CENTEX Shrimp), Faculty of Science, Mahidol University, Bangkok, 10400, Thailand; National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani, 12120, Thailand
| | - Chao Li
- School of Fisheries, Aquaculture, and Aquatic Sciences, Auburn University, Auburn, AL, 36849, USA
| | - Zhi Ye
- School of Fisheries, Aquaculture, and Aquatic Sciences, Auburn University, Auburn, AL, 36849, USA
| | - Honggang Zhao
- School of Fisheries, Aquaculture, and Aquatic Sciences, Auburn University, Auburn, AL, 36849, USA
| | - Benjamin H Beck
- United States Department of Agriculture, Agricultural Research Service, Aquatic Animal Health Research Unit, Auburn, AL, 36832, USA
| | - Haitham Mohammed
- School of Fisheries, Aquaculture, and Aquatic Sciences, Auburn University, Auburn, AL, 36849, USA
| | - Eric Peatman
- School of Fisheries, Aquaculture, and Aquatic Sciences, Auburn University, Auburn, AL, 36849, USA.
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28
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Yazdi M, Behnaminia N, Nafari A, Sepahvand A. Genetic Susceptibility to Fungal Infections. Adv Biomed Res 2023; 12:248. [PMID: 38192892 PMCID: PMC10772798 DOI: 10.4103/abr.abr_259_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 08/15/2022] [Accepted: 08/20/2022] [Indexed: 01/10/2024] Open
Abstract
Reports of fungal infections have increased over the past decades, making them a major threat to human health. In this study, we review the effects of genetic defects on susceptibility to fungal diseases. To identify all relevant literature, we searched Google Scholar, PubMed, and Scopus and profiled studies published between 2008 and 2021. The results of several studies conducted on this subject have shown the significant effects of genetic variations such as hyper-IgE syndrome, Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome, dectin-1 deficiency, CARD9 mutations, STAT1 mutations, and IL17 mutationson the host immune system's response, which has an important impact on susceptibility to fungal infections. The underlying immune system-related genetic profile affects the susceptibility of individuals to different fungal infections; therefore, this subject should be further studied for better treatment of fungal diseases.
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Affiliation(s)
- Mohammad Yazdi
- Department of Biochemistry, School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Nima Behnaminia
- Student Research Committee, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Amirhossein Nafari
- Student Research Committee, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Asghar Sepahvand
- Razi Herbal Medicines Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran
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29
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Adnan M, Siddiqui AJ, Ashraf SA, Bardakci F, Alreshidi M, Badraoui R, Noumi E, Tepe B, Sachidanandan M, Patel M. Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation to Elucidate the Molecular Targets and Potential Mechanism of Phoenix dactylifera (Ajwa Dates) against Candidiasis. Pathogens 2023; 12:1369. [PMID: 38003833 PMCID: PMC10674288 DOI: 10.3390/pathogens12111369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 11/13/2023] [Accepted: 11/17/2023] [Indexed: 11/26/2023] Open
Abstract
Candidiasis, caused by opportunistic fungal pathogens of the Candida genus, poses a significant threat to immunocompromised individuals. Natural compounds derived from medicinal plants have gained attention as potential sources of anti-fungal agents. Ajwa dates (Phoenix dactylifera L.) have been recognized for their diverse phytochemical composition and therapeutic potential. In this study, we employed a multi-faceted approach to explore the anti-candidiasis potential of Ajwa dates' phytochemicals. Utilizing network pharmacology, we constructed an interaction network to elucidate the intricate relationships between Ajwa dates phytoconstituents and the Candida-associated molecular targets of humans. Our analysis revealed key nodes in the network (STAT3, IL-2, PTPRC, STAT1, CASP1, ALB, TP53, TLR4, TNF and PPARG), suggesting the potential modulation of several crucial processes (the regulation of the response to a cytokine stimulus, regulation of the inflammatory response, positive regulation of cytokine production, cellular response to external stimulus, etc.) and fungal pathways (Th17 cell differentiation, the Toll-like receptor signaling pathway, the C-type lectin receptor signaling pathway and necroptosis). To validate these findings, molecular docking studies were conducted, revealing the binding affinities of the phytochemicals towards selected Candida protein targets of humans (ALB-rutin (-9.7 kJ/mol), STAT1-rutin (-9.2 kJ/mol), STAT3-isoquercetin (-8.7 kJ/mol), IL2-β-carotene (-8.5 kJ/mol), CASP1-β-carotene (-8.2 kJ/mol), TP53-isoquercetin (-8.8 kJ/mol), PPARG-luteolin (-8.3 kJ/mol), TNF-βcarotene (-7.7 kJ/mol), TLR4-rutin (-7.4 kJ/mol) and PTPRC-rutin (-7.0 kJ/mol)). Furthermore, molecular dynamics simulations of rutin-ALB and rutin-STAT1 complex were performed to gain insights into the stability and dynamics of the identified ligand-target complexes over time. Overall, the results not only contribute to the understanding of the molecular interactions underlying the anti-fungal potential of specific phytochemicals of Ajwa dates in humans but also provide a rational basis for the development of novel therapeutic strategies against candidiasis in humans. This study underscores the significance of network pharmacology, molecular docking and dynamics simulations in accelerating the discovery of natural products as effective anti-fungal agents. However, further experimental validation of the identified compounds is warranted to translate these findings into practical therapeutic applications.
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Affiliation(s)
- Mohd Adnan
- Department of Biology, College of Science, University of Ha’il, Ha’il 55473, Saudi Arabia; (M.A.)
- Medical and Diagnostic Research Centre, University of Ha’il, Ha’il 55473, Saudi Arabia
| | - Arif Jamal Siddiqui
- Department of Biology, College of Science, University of Ha’il, Ha’il 55473, Saudi Arabia; (M.A.)
- Medical and Diagnostic Research Centre, University of Ha’il, Ha’il 55473, Saudi Arabia
| | - Syed Amir Ashraf
- Medical and Diagnostic Research Centre, University of Ha’il, Ha’il 55473, Saudi Arabia
- Department of Clinical Nutrition, College of Applied Medial Sciences, University of Ha’il, Ha’il 55473, Saudi Arabia
| | - Fevzi Bardakci
- Department of Biology, College of Science, University of Ha’il, Ha’il 55473, Saudi Arabia; (M.A.)
- Medical and Diagnostic Research Centre, University of Ha’il, Ha’il 55473, Saudi Arabia
| | - Mousa Alreshidi
- Department of Biology, College of Science, University of Ha’il, Ha’il 55473, Saudi Arabia; (M.A.)
- Medical and Diagnostic Research Centre, University of Ha’il, Ha’il 55473, Saudi Arabia
| | - Riadh Badraoui
- Department of Biology, College of Science, University of Ha’il, Ha’il 55473, Saudi Arabia; (M.A.)
- Medical and Diagnostic Research Centre, University of Ha’il, Ha’il 55473, Saudi Arabia
| | - Emira Noumi
- Department of Biology, College of Science, University of Ha’il, Ha’il 55473, Saudi Arabia; (M.A.)
- Medical and Diagnostic Research Centre, University of Ha’il, Ha’il 55473, Saudi Arabia
| | - Bektas Tepe
- Department of Molecular Biology and Genetics, Faculty of Science and Literature, Kilis 7 Aralik University, Kilis TR-79000, Turkey
| | - Manojkumar Sachidanandan
- Medical and Diagnostic Research Centre, University of Ha’il, Ha’il 55473, Saudi Arabia
- Department of Oral Radiology, College of Dentistry, University of Ha’il, Ha’il 55473, Saudi Arabia
| | - Mitesh Patel
- Department of Biotechnology, Parul Institute of Applied Sciences and Centre of Research for Development, Parul University, Vadodara 391760, India
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30
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Gu Y, Jia XM. STING negatively regulates antifungal immunity. Trends Microbiol 2023; 31:1090-1092. [PMID: 37741789 DOI: 10.1016/j.tim.2023.09.003] [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: 08/04/2023] [Revised: 08/30/2023] [Accepted: 09/11/2023] [Indexed: 09/25/2023]
Abstract
During viral infections, stimulator of interferon genes (STING) exerts a positive protective immune response. Chen et al. now shed light on the distinct role of STING in fungal infections. STING translocates to the phagosome to negatively regulate the immune response against Candida albicans infection through the inhibition of Src-involved Syk phosphorylation.
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Affiliation(s)
- Yebo Gu
- Department of Stomatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Xin-Ming Jia
- Clinical Medicine Scientific and Technical Innovation Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Key Laboratory of Pathogen-Host Interactions of the Ministry of Education of China, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200092, China.
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31
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Generalov E, Yakovenko L. Receptor basis of biological activity of polysaccharides. Biophys Rev 2023; 15:1209-1222. [PMID: 37975017 PMCID: PMC10643635 DOI: 10.1007/s12551-023-01102-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 07/19/2023] [Indexed: 11/19/2023] Open
Abstract
Polysaccharides, the most diverse forms of organic molecules in nature, exhibit a large number of different biological activities, such as immunomodulatory, radioprotective, antioxidant, regenerative, metabolic, signaling, antitumor, and anticoagulant. The reaction of cells to a polysaccharide is determined by its specific interaction with receptors present on the cell surface, the type of cells, and their condition. The effect of many polysaccharides depends non-linearly on their concentration. The same polysaccharide in different conditions can have very different effects on cells and organisms, up to the opposite; therefore, when conducting studies of the biological activity of polysaccharides, both for the purpose of developing new drugs or approaches to the treatment of patients, and in order to clarify the features of intracellular processes, information about already known research results is needed. There is a lot of scattered data on the biological activities of polysaccharides, but there are few reviews that would consider natural polysaccharides from various sources and possible molecular mechanisms of their action. The purpose of this review is to present the main results published at different times in order to facilitate the search for information necessary for conducting relevant studies.
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Affiliation(s)
- Evgenii Generalov
- Faculty of Physics, M.V. Lomonosov Moscow State University, Moscow, 119991 Russia
| | - Leonid Yakovenko
- Faculty of Physics, M.V. Lomonosov Moscow State University, Moscow, 119991 Russia
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32
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Muselius B, Roux-Dalvai F, Droit A, Geddes-McAlister J. Resolving the Temporal Splenic Proteome during Fungal Infection for Discovery of Putative Dual Perspective Biomarker Signatures. JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY 2023; 34:1928-1940. [PMID: 37222660 PMCID: PMC10487597 DOI: 10.1021/jasms.3c00114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/06/2023] [Accepted: 05/09/2023] [Indexed: 05/25/2023]
Abstract
Fungal pathogens are emerging threats to global health with the rise of incidence associated with climate change and increased geographical distribution; factors also influencing host susceptibility to infection. Accurate detection and diagnosis of fungal infections is paramount to offer rapid and effective therapeutic options. For improved diagnostics, the discovery and development of protein biomarkers presents a promising avenue; however, this approach requires a priori knowledge of infection hallmarks. To uncover putative novel biomarkers of disease, profiling of the host immune response and pathogen virulence factor production is indispensable. In this study, we use mass-spectrometry-based proteomics to resolve the temporal proteome of Cryptococcus neoformans infection of the spleen following a murine model of infection. Dual perspective proteome profiling defines global remodeling of the host over a time course of infection, confirming activation of immune associated proteins in response to fungal invasion. Conversely, pathogen proteomes detect well-characterized C. neoformans virulence determinants, along with novel mapped patterns of pathogenesis during the progression of disease. Together, our innovative systematic approach confirms immune protection against fungal pathogens and explores the discovery of putative biomarker signatures from complementary biological systems to monitor the presence and progression of cryptococcal disease.
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Affiliation(s)
- Benjamin Muselius
- Department
of Molecular and Cellular Biology, University
of Guelph, Guelph, Ontario N1G 2W1, Canada
| | - Florence Roux-Dalvai
- Proteomics
platform, CHU de Québec - Université
Laval Research Center, Québec
City, Québec G1
V 4G2, Canada
- Computational
Biology Laboratory, CHU de Québec
- Université Laval Research Center, Québec City, Québec G1 V 4G2, Canada
- Canadian
Proteomics and Artificial Intelligence Consortium, Guelph, Ontario N1G 2W1, Canada
| | - Arnaud Droit
- Proteomics
platform, CHU de Québec - Université
Laval Research Center, Québec
City, Québec G1
V 4G2, Canada
- Computational
Biology Laboratory, CHU de Québec
- Université Laval Research Center, Québec City, Québec G1 V 4G2, Canada
- Canadian
Proteomics and Artificial Intelligence Consortium, Guelph, Ontario N1G 2W1, Canada
| | - Jennifer Geddes-McAlister
- Department
of Molecular and Cellular Biology, University
of Guelph, Guelph, Ontario N1G 2W1, Canada
- Canadian
Proteomics and Artificial Intelligence Consortium, Guelph, Ontario N1G 2W1, Canada
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33
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Abstract
The worldwide prevalence of asthma and allergic disorders (allergic rhinitis, atopic dermatitis, food allergy) has been steadily rising in recent decades. It is now estimated that up to 20% of the global population is afflicted by an allergic disease, with increasing incidence rates in both high- and low-income countries. The World Allergy Organization estimates that the total economic burden of asthma and allergic rhinitis alone is approximately $21 billion per year. While allergic stimuli are a complex and heterogenous class of inputs including parasites, pollens, food antigens, drugs, and metals, it has become clear that fungi are major drivers of allergic disease, with estimates that fungal sensitization occurs in 20-30% of atopic individuals and up to 80% of asthma patients. Fungi are eukaryotic microorganisms that can be found throughout the world in high abundance in both indoor and outdoor environments. Understanding how and why fungi act as triggers of allergic type 2 inflammation will be crucial for combating this important health problem. In recent years, there have been significant advances in our understanding of fungi-induced type 2 immunity, however there is still much we don't understand, including why fungi have a tendency to induce allergic reactions in the first place. Here, we will discuss how fungi trigger type 2 immune responses and posit why this response has been evolutionarily selected for induction during fungal encounter.
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Affiliation(s)
- Yufan Zheng
- Molecular Mycology and Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Eric V. Dang
- Molecular Mycology and Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
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34
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Rapala-Kozik M, Surowiec M, Juszczak M, Wronowska E, Kulig K, Bednarek A, Gonzalez-Gonzalez M, Karkowska-Kuleta J, Zawrotniak M, Satała D, Kozik A. Living together: The role of Candida albicans in the formation of polymicrobial biofilms in the oral cavity. Yeast 2023; 40:303-317. [PMID: 37190878 DOI: 10.1002/yea.3855] [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: 10/31/2022] [Revised: 04/23/2023] [Accepted: 04/26/2023] [Indexed: 05/17/2023] Open
Abstract
The oral cavity of humans is colonized by diversity of microbial community, although dominated by bacteria, it is also constituted by a low number of fungi, often represented by Candida albicans. Although in the vast minority, this usually commensal fungus under certain conditions of the host (e.g., immunosuppression or antibiotic therapy), can transform into an invasive pathogen that adheres to mucous membranes and also to medical or dental devices, causing mucosal infections. This transformation is correlated with changes in cell morphology from yeast-like cells to hyphae and is supported by numerous virulence factors exposed by C. albicans cells at the site of infection, such as multifunctional adhesins, degradative enzymes, or toxin. All of them affect the surrounding host cells or proteins, leading to their destruction. However, at the site of infection, C. albicans can interact with different bacterial species and in its filamentous form may produce biofilms-the elaborated consortia of microorganisms, that present increased ability to host colonization and resistance to antimicrobial agents. In this review, we highlight the modification of the infectious potential of C. albicans in contact with different bacterial species, and also consider the mutual bacterial-fungal relationships, involving cooperation, competition, or antagonism, that lead to an increase in the propagation of oral infection. The mycofilm of C. albicans is an excellent hiding place for bacteria, especially those that prefer low oxygen availability, where microbial cells during mutual co-existence can avoid host recognition or elimination by antimicrobial action. However, these microbial relationships, identified mainly in in vitro studies, are modified depending on the complexity of host conditions and microbial dominance in vivo.
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Affiliation(s)
- Maria Rapala-Kozik
- Department of Comparative Biochemistry and Bioanalytics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Krakow, Poland
| | - Magdalena Surowiec
- Department of Comparative Biochemistry and Bioanalytics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Krakow, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, Kraków, Poland
| | - Magdalena Juszczak
- Department of Comparative Biochemistry and Bioanalytics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Krakow, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, Kraków, Poland
| | - Ewelina Wronowska
- Department of Comparative Biochemistry and Bioanalytics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Krakow, Poland
| | - Kamila Kulig
- Department of Comparative Biochemistry and Bioanalytics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Krakow, Poland
| | - Aneta Bednarek
- Department of Comparative Biochemistry and Bioanalytics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Krakow, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, Kraków, Poland
| | - Miriam Gonzalez-Gonzalez
- Department of Comparative Biochemistry and Bioanalytics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Krakow, Poland
| | - Justyna Karkowska-Kuleta
- Department of Comparative Biochemistry and Bioanalytics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Krakow, Poland
| | - Marcin Zawrotniak
- Department of Comparative Biochemistry and Bioanalytics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Krakow, Poland
| | - Dorota Satała
- Department of Comparative Biochemistry and Bioanalytics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Krakow, Poland
| | - Andrzej Kozik
- Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Krakow, Poland
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35
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Braden LM, Michaud D, Groman D, Byrne P, Hori TS, Fast MD. Rejection of Lepeophtheirus salmonis driven in part by chitin sensing is not impacted by seawater acclimitization in Coho salmon (Oncorhynchus kisutch). Sci Rep 2023; 13:9685. [PMID: 37322246 PMCID: PMC10272145 DOI: 10.1038/s41598-023-36632-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 06/07/2023] [Indexed: 06/17/2023] Open
Abstract
There is tremendous variation in life-history strategies among anadromous salmonids. Species that enter the ocean environment at small sizes (< 20 g) are likely under more physiological pressure from pathogens; however, little data is available on responses at these early stages. With this in mind, we performed salmon louse challenges with Coho salmon either immediately after seawater entry (SW; ca. 10 g) or after 30 days in SW (ca. 20 g). Irrespective of size or time in SW, parasites were rapidly rejected by the host, with > 90% of all parasites lost by 16 days post-infection (dpi). Rejection was concomitant with host epithelial granulomatous infiltrations that initially targeted the embedded frontal filament (4 dpi) and the entire parasite by 10 dpi. Illumina sequencing, followed by functional enrichment analysis, revealed a concerted defense response in the fin within 1 dpi that included multiple innate and adaptive immunity components. Strikingly, early indications of an allergic-type inflammatory response were associated with chitin sensing pathways orchestrated by early overexpression of the IgE-receptor, fcer1g. Additionally, there was profound overexpression of several classes of c-type lectin receptors, including dectin-2, mincle, and dc-sign at 1 dpi onward. These profiles and upregulation of cellular effector markers were corroborated by histopathological evaluation, revealing the simultaneous presence of mast cell/eosinophilic granular cells, sacciform cells, macrophages/histiocytes, and granulocytes in fin. At 10 dpi and concurrent with parasite expulsion, there was evidence of immunoregulation in addition to tissue remodelling pathways. At 16 dpi, the response was effectively abrogated. Simultaneous profiling of the parasite transcriptome revealed early induction of chitin metabolism and immunomodulation, toxin production and ECM degradation; however, after 7 dpi, these were replaced with overexpression of stress and immune defense genes. These data present the first evidence for Coho salmon demonstrating chitin- and sugar moiety-sensing as key drivers of salmon louse rejection.
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Affiliation(s)
- Laura M Braden
- Department of Pathology and Microbiology, Atlantic Veterinary College, Charlottetown, PE, Canada
- Department of Fish Health and Molecular Biology, AquaBounty Canada, Souris, PE, Canada
| | - Dylan Michaud
- Department of Pathology and Microbiology, Atlantic Veterinary College, Charlottetown, PE, Canada
| | - David Groman
- Aquatic Diagnostic Services, Atlantic Veterinary College, Charlottetown, PE, Canada
| | - Phil Byrne
- Department of Fisheries and Oceans Canada, Charlottetown, PE, Canada
| | | | - Mark D Fast
- Department of Pathology and Microbiology, Atlantic Veterinary College, Charlottetown, PE, Canada.
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36
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Cui L, Liu Y, Hu Y, Dong J, Deng Q, Jiao B, Sun Y, Wu Y, Liu T, Wang W, Li C. Shexiang Tongxin Dropping Pill alleviates M1 macrophage polarization-induced inflammation and endothelial dysfunction to reduce coronary microvascular dysfunction via the dectin-1/Syk/IRF5 pathway. JOURNAL OF ETHNOPHARMACOLOGY 2023:116742. [PMID: 37290736 DOI: 10.1016/j.jep.2023.116742] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 06/03/2023] [Accepted: 06/05/2023] [Indexed: 06/10/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Shexiang Tongxin Dropping Pill (STDP), a traditional Chinese medicine compound, is fragrant, invigorates the qi, unblocks pulses, activates the blood circulation, removes blood stasis, and relieves pain. It is used clinically to treat coronary heart disease and angina pectoris. Coronary microvascular dysfunction (CMD) is associated with increased morbidity and mortality from cardiovascular events. Endothelial dysfunction and inflammation have been verified as its underlying causes. STDP can ameliorate CMD, but the mechanism has not been fully elucidated. AIM OF THE STUDY To explore the effects of STDP on M1 macrophage polarization-induced inflammation and endothelial dysfunction as an inhibitor of CMD, and to determine its mechanisms of action. MATERIALS AND METHODS The CMD rat model was established by left anterior descending artery (LAD) ligation. The efficacy of STDP against CMD was evaluated by echocardiography, optical microangiography, Evans blue staining, and histological examination. The OGD/R-induced endothelial injury model, the endothelial injury-induced sterile inflammation model, the Dectin-1 overexpression model, and the Dectin-1-overexpressing RAW264.7 macrophage supernatant-stimulated HUVEC-induced secondary injury of endothelial function model were established to confirm the efficacy of STDP against M1 macrophage polarization-induced inflammation and endothelial dysfunction. RESULTS STDP blunted the deterioration of cardiac function and ameliorated CMD by reducing inflammatory cell infiltration and endothelial dysfunction in CMD rats. Endothelial injury and Dectin-1 overexpression induced M1 macrophage polarization and inflammation. Mechanically, STDP hindered M1 macrophage polarization and inflammation by inhibiting the Dectin-1/Syk/IRF5 pathway both in vivo and in vitro. STDP alleviated endothelial dysfunction induced by Dectin-1 overexpression in macrophages. CONCLUSION STDP can alleviate M1 macrophage polarization-induced inflammation and endothelial dysfunction against CMD via the Dectin-1/Syk/IRF5 pathway. Dectin-1-associated M1 macrophage polarization might be developed as a novel target for ameliorating CMD.
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Affiliation(s)
- Lingwen Cui
- Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yizhou Liu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yueyao Hu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Jianteng Dong
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Qiong Deng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Boyang Jiao
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Ying Sun
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yan Wu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Tianhua Liu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Wei Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China; Key Laboratory of TCM Syndrome and Formula, Beijing University of Chinese Medicine, Ministry of Education, Beijing, 100029, China; Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Chun Li
- Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China; Key Laboratory of TCM Syndrome and Formula, Beijing University of Chinese Medicine, Ministry of Education, Beijing, 100029, China.
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Pan C, Wang L, Zhang M, Li J, Liu J, Liu J. In Situ Polymerization-Mediated Antigen Presentation. J Am Chem Soc 2023. [PMID: 37262440 DOI: 10.1021/jacs.3c02682] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Activating antigen-presenting cells is essential to generate adaptive immunity, while the efficacy of conventional activation strategies remains unsatisfactory due to suboptimal antigen-specific priming. Here, in situ polymerization-mediated antigen presentation (IPAP) is described, in which antigen-loaded nanovaccines are spontaneously formed and efficiently anchored onto the surface of dendritic cells in vivo through co-deposition with dopamine. The resulting chemically bound nanovaccines can promote antigen presentation by elevating macropinocytosis-based cell uptake and reducing lysosome-related antigen degradation. IPAP is able to prolong the duration of antigen reservation in the injection site and enhance subsequent accumulation in the draining lymph nodes, thereby eliciting robust antigen-specific cellular and humoral immune responses. IPAP is also applicable for different antigens and capable of circumventing the disadvantages of complicated preparation and purification. By implementation with ovalbumin, IPAP induces a significant protective immunity against ovalbumin-overexpressing tumor cell challenge in a prophylactic murine model. The use of the SARS-CoV-2 Spike protein S1 subunit also remarkably increases the production of S1-specific immunoglobulin G in mice. IPAP offers a unique strategy for stimulating antigen-presenting cells to boost antigen-specific adaptive responses and proposes a facile yet versatile method for immunization against various diseases.
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Affiliation(s)
- Chao Pan
- Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Institute of Molecular Medicine, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Lu Wang
- Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Institute of Molecular Medicine, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Mengmeng Zhang
- Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Institute of Molecular Medicine, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Juanjuan Li
- Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Institute of Molecular Medicine, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Junqiu Liu
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Key Laboratory of Organosilicon Material Technology, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Jinyao Liu
- Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Institute of Molecular Medicine, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
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Conn BN, Wozniak KL. Innate Pulmonary Phagocytes and Their Interactions with Pathogenic Cryptococcus Species. J Fungi (Basel) 2023; 9:617. [PMID: 37367553 PMCID: PMC10299524 DOI: 10.3390/jof9060617] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 05/23/2023] [Accepted: 05/25/2023] [Indexed: 06/28/2023] Open
Abstract
Cryptococcus neoformans is an opportunistic fungal pathogen that causes over 180,000 annual deaths in HIV/AIDS patients. Innate phagocytes in the lungs, such as dendritic cells (DCs) and macrophages, are the first cells to interact with the pathogen. Neutrophils, another innate phagocyte, are recruited to the lungs during cryptococcal infection. These innate cells are involved in early detection of C. neoformans, as well as the removal and clearance of cryptococcal infections. However, C. neoformans has developed ways to interfere with these processes, allowing for the evasion of the host's innate immune system. Additionally, the innate immune cells have the ability to aid in cryptococcal pathogenesis. This review discusses recent literature on the interactions of innate pulmonary phagocytes with C. neoformans.
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Affiliation(s)
| | - Karen L. Wozniak
- Department of Microbiology and Molecular Genetics, Oklahoma State University, 307 Life Science East, Stillwater, OK 74078, USA;
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Loh JT, Lam KP. Fungal infections: Immune defense, immunotherapies and vaccines. Adv Drug Deliv Rev 2023; 196:114775. [PMID: 36924530 DOI: 10.1016/j.addr.2023.114775] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 03/05/2023] [Accepted: 03/07/2023] [Indexed: 03/17/2023]
Abstract
Invasive fungal infection is an under recognized and emerging global health threat. Recently, the World Health Organization (WHO) released the first ever list of health-threatening fungi to guide research and public health interventions to strengthen global response to fungi infections and antifungal resistance. Currently, antifungal drugs only demonstrate partial success in improving prognosis of infected patients, and this is compounded by the rapid evolution of drug resistance among fungi species. The increased prevalence of fungal infections in individuals with underlying immunological deficiencies reflects the importance of an intact host immune system in controlling mycoses, and further highlights immunomodulation as a potential new avenue for the treatment of disseminated fungal diseases. In this review, we will summarize how host innate immune cells sense invading fungi through their pattern recognition receptors, and subsequently initiate a series of effector mechanisms and adaptive immune responses to mediate fungal clearance. In addition, we will discuss emerging preclinical and clinical data on antifungal immunotherapies and fungal vaccines which can potentially expand our antifungal armamentarium in future.
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Affiliation(s)
- Jia Tong Loh
- Singapore Immunology Network, Agency for Science, Technology and Research, 8A Biomedical Grove, S138648, Republic of Singapore.
| | - Kong-Peng Lam
- Singapore Immunology Network, Agency for Science, Technology and Research, 8A Biomedical Grove, S138648, Republic of Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5, Science Drive 2, S117545, Republic of Singapore; School of Biological Sciences, College of Science, Nanyang Technological University, 60, Nanyang Drive, S637551, Republic of Singapore.
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Xu X, Wei Y, Pang J, Wei Z, Wang L, Chen Q, Wang Z, Zhang Y, Chen K, Peng Y, Zhang Z, Liu J, Zhang Y, Jin ZB, Liang Q. Time-Course Transcriptomic Analysis Reveals the Crucial Roles of PANoptosis in Fungal Keratitis. Invest Ophthalmol Vis Sci 2023; 64:6. [PMID: 36867131 PMCID: PMC9988702 DOI: 10.1167/iovs.64.3.6] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2023] Open
Abstract
Purpose Fungal keratitis (FK) is a serious corneal infection with high morbidity. Host immune responses function as a double-edged sword by eradicating fungal pathogens while also causing corneal damage, dictating the severity, progression, and outcome of FK. However, the underlying immunopathogenesis remains elusive. Methods Time-course transcriptome was performed to illustrate the dynamic immune landscape in a mouse model of FK. Integrated bioinformatic analyses included identification of differentially expressed genes, time series clustering, Gene Ontology enrichment, and inference of infiltrating immune cells. Gene expression was verified by quantitative polymerase chain reaction (qPCR), Western blot, or immunohistochemistry. Results FK mice exhibited dynamic immune responses with concerted trends with clinical score, transcriptional alteration, and immune cell infiltration score peaking at 3 days post infection (dpi). Disrupted substrate metabolism, broad immune activation, and corneal wound healing occurred sequentially in early, middle, and late stages of FK. Meanwhile, dynamics of infiltrating innate and adaptive immune cells displayed distinct characteristics. Proportions of dendritic cells showed overall decreasing trend with fungal infection, whereas that of macrophages, monocytes, and neutrophils rose sharply in early stage and then gradually decreased as inflammation resolved. Activation of adaptive immune cells was also observed in late stage of infection. Furthermore, shared immune responses and activation of AIM2-, pyrin-, and ZBP1-mediated PANoptosis were revealed across different time points. Conclusions Our study profiles the dynamic immune landscape and highlights the crucial roles of PANoptosis in FK pathogenesis. These findings provide novel insights into host responses to fungi and contribute to the development of PANoptosis-targeted therapeutics for patients with FK.
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Affiliation(s)
- Xizhan Xu
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Yuan Wei
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Jinding Pang
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Zhenyu Wei
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Leying Wang
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Qiankun Chen
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Zhiqun Wang
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Yang Zhang
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Kexin Chen
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Yan Peng
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Zijun Zhang
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Jiamin Liu
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Yuheng Zhang
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Zi-Bing Jin
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Qingfeng Liang
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
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Topal J, Panchal N, Barroeta A, Roppelt A, Mudde A, Gaspar HB, Thrasher AJ, Houghton BC, Booth C. Lentiviral Gene Transfer Corrects Immune Abnormalities in XIAP Deficiency. J Clin Immunol 2023; 43:440-451. [PMID: 36329240 PMCID: PMC9892131 DOI: 10.1007/s10875-022-01389-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 10/19/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND X-linked inhibitor of apoptosis protein (XIAP) deficiency is a severe immunodeficiency with clinical features including hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD) due to defective NOD2 responses. Management includes immunomodulatory therapies and hematopoietic stem cell transplant (HSCT). However, this cohort is particularly susceptible to the chemotherapeutic regimens and acutely affected by graft-vs-host disease (GvHD), driving poor long-term survival in transplanted patients. Autologous HSC gene therapy could offer an alternative treatment option and would abrogate the risks of alloreactivity. METHODS Hematopoietic progenitor (Lin-ve) cells from XIAPy/- mice were transduced with a lentiviral vector encoding human XIAP cDNA before transplantation into irradiated XIAP y/- recipients. After 12 weeks animals were challenged with the dectin-1 ligand curdlan and recovery of innate immune function was evaluated though analysis of inflammatory cytokines, body weight, and splenomegaly. XIAP patient-derived CD14+ monocytes were transduced with the same vector and functional recovery was demonstrated using in vitro L18-MDP/NOD2 assays. RESULTS In treated XIAPy/- mice, ~40% engraftment of gene-corrected Lin-ve cells led to significant recovery of weight loss, splenomegaly, and inflammatory cytokine responses to curdlan, comparable to wild-type mice. Serum IL-6, IL-10, MCP-1, and TNF were significantly reduced 2-h post-curdlan administration in non-corrected XIAPy/- mice compared to wild-type and gene-corrected animals. Appropriate reduction of inflammatory responses was observed in gene-corrected mice, whereas non-corrected mice developed an inflammatory profile 9 days post-curdlan challenge. In gene-corrected patient CD14+ monocytes, TNF responses were restored following NOD2 activation with L18-MDP. CONCLUSION Gene correction of HSCs recovers XIAP-dependent immune defects and could offer a treatment option for patients with XIAP deficiency.
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Affiliation(s)
- Joseph Topal
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Neelam Panchal
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Amairelys Barroeta
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Anna Roppelt
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
| | - Annelotte Mudde
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK
| | - H Bobby Gaspar
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK
- Orchard Therapeutics, London, UK
| | - Adrian J Thrasher
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK
- Department of Immunology and Gene Therapy, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK
| | - Benjamin C Houghton
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Claire Booth
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK.
- Department of Immunology and Gene Therapy, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK.
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PU.1-CD23 signaling mediates pulmonary innate immunity against Aspergillus fumigatus infection by driving inflammatory response. BMC Immunol 2023; 24:4. [PMID: 36650424 PMCID: PMC9844028 DOI: 10.1186/s12865-023-00539-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 01/03/2023] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Aspergillosis is a common cause of morbidity and mortality in immunocompromised populations. PU.1 is critical for innate immunity against Aspergillus fumigatus (AF) in macrophages. However, the molecular mechanism underlying PU.1 mediating immunity against AF infection in human alveolar macrophages (AMs) is still unclear. METHODS In this study, we detected the expressions of PU.1, CD23, p-ERK, CCL20 and IL-8 and key inflammatory markers IL-1β, IL-6, TNF-α and IL-12 in human THP-1-derived macrophages (HTMs) or PU.1/CD23-overexpressed immunodeficient mice with AF infection. Moreover, we examined these expressions in PU.1-overexpressed/interfered HTMs. Additionally, we detected the phagocytosis of macrophages against AF infection with altered PU.1 expression. Dual luciferase, ChIP and EMSAs were performed to detect the interaction of PU.1 and CD23. And we invested the histological changes in mouse lung tissues transfected with PU.1/CD23-expressing adenoviruses in AF infection. RESULTS The results showed that the expressions of PU.1, CD23, p-ERK, CCL20, IL-8, IL-1β, IL-6, TNF-α and IL-12 increased significantly with AF infection, and PU.1 regulated the later 8 gene expressions in HTMs. Moreover, CD23 was directly activated by PU.1, and overexpression of CD23 in PU.1-interfered HTMs upregulated IL-1β, IL-6, TNF-α and IL-12 levels which were downregulated by PU.1 interference. PU.1 overexpression strengthened the phagocytosis of the HTMs against AF. And injection of PU.1/CD23-expressing adenoviruses attenuated pathological defects in immunodeficient mouse lung tissues with AF infection. Adenovirus (Ad)-PU.1 increased the CD23, p-ERK, CCL20, IL-8 levels. CONCLUSIONS Our study concluded that PU.1-CD23 signaling mediates innate immunity against AF in lungs through regulating inflammatory response. Therefore, PU.1-CD23 may be a new anti-aspergillosis therapeutic for the treatment of invasive aspergillosis with the deepening of gene therapy and its wide application in the clinic.
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Yu M, Ding H, Gong S, Luo Y, Lin H, Mu Y, Li H, Li X, Zhong M. Fungal dysbiosis facilitates inflammatory bowel disease by enhancing CD4+ T cell glutaminolysis. Front Cell Infect Microbiol 2023; 13:1140757. [PMID: 37124046 PMCID: PMC10140311 DOI: 10.3389/fcimb.2023.1140757] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 03/21/2023] [Indexed: 05/02/2023] Open
Abstract
The fungal microbiota is an important component of the complex multikingdom microbial community colonizing the mammalian gastrointestinal tract and has an important role in immune regulation. However, how fungi regulate inflammatory bowel disease (IBD) is poorly understood. This study found that intestinal fungi regulate immune responses in IBD. Antibiotic-mediated depletion of fungi facilitated the development of IBD. Fungi greatly enhanced oxidative phosphorylation (OXPHOS) by enhancing glutaminolysis. Mechanistically, we found that fungi could activate the dectin-1-Syk- NF-κB signaling pathway to promote the expression of key enzymes and transporters involved in glutaminolysis. In summary, our findings reveal that fungal interactions in the human gut could be a promising therapeutic target for IBD.
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Affiliation(s)
- Minhao Yu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hui Ding
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Institute of Digestive Disease, National Health Commission (NHC) Key Laboratory of Digestive Diseases, Shanghai, China
| | - Shuai Gong
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Institute of Digestive Disease, National Health Commission (NHC) Key Laboratory of Digestive Diseases, Shanghai, China
| | - Yang Luo
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Haiping Lin
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yifei Mu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hao Li
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaobo Li
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Institute of Digestive Disease, National Health Commission (NHC) Key Laboratory of Digestive Diseases, Shanghai, China
- *Correspondence: Ming Zhong, ; Xiaobo Li,
| | - Ming Zhong
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- *Correspondence: Ming Zhong, ; Xiaobo Li,
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Lan Y, Shao R, Zhang J, Liu J, Liao X, Liang S, Mai K, Ai Q, Wan M. Vitamin D 3 enhances the antibacterial ability in head-kidney macrophages of turbot (Scophthalmus maximus L.) through C-type lectin receptors. FISH & SHELLFISH IMMUNOLOGY 2023; 132:108491. [PMID: 36503059 DOI: 10.1016/j.fsi.2022.108491] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 12/06/2022] [Accepted: 12/08/2022] [Indexed: 06/17/2023]
Abstract
It has been known that vitamin D3 (VD3) not only plays an important role in regulating calcium and phosphorus metabolism in animals, but also has extensive effects on immune functions. In this study, the mechanism how VD3 influences bactericidal ability in turbot was explored. The transcriptomic analysis identified that dietary VD3 significantly upregulated the gene expression of C-type lectin receptors (CLRs), including mannose receptors (mrc1, mrc2, pla2r1) and collectins (collectin 11 and collectin 12) in turbot intestine. Further results obtained from in vitro experiments confirmed that the gene expression of mannose receptors and collectins in head-kidney macrophages (HKMs) of turbot was induced after the cells were incubated with different concentrations of VD3 (0, 1, 10 nM) or 1,25(OH)2D3 (0, 10, 100 pM). Meanwhile, both phagocytosis and bactericidal functions of HKMs were significantly improved in VD3 or 1,25(OH)2D3-incubated HKMs. Furthermore, phagocytosis and bacterial killing of HKMs decreased after collectin 11 was knocked down. Moreover, VD3-enhanced antibacterial activities diminished in collectin 11-interfered cells. Interestingly, the evidence was provided in the present study that inactive VD3 could be metabolized into active 1,25(OH)2D3 via hydroxylases encoded by cyp27a1 and cyp27b1 in fish macrophages. In conclusion, VD3 could be metabolized to 1,25(OH)2D3 in HKMs, which promoted the expression of CLRs in macrophages, leading to enhanced bacterial clearance.
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Affiliation(s)
- Yawen Lan
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture & Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao, China
| | - Rui Shao
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture & Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao, China
| | - Jinjin Zhang
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture & Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao, China
| | - Jiayu Liu
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture & Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao, China
| | - Xinmeng Liao
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture & Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao, China
| | - Shufei Liang
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture & Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao, China
| | - Kangsen Mai
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture & Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao, China; Pilot National Laboratory of Marine Science and Technology, Qingdao, China
| | - Qinghui Ai
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture & Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao, China; Pilot National Laboratory of Marine Science and Technology, Qingdao, China
| | - Min Wan
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture & Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao, China; Pilot National Laboratory of Marine Science and Technology, Qingdao, China.
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Lee S, Hao LT, Park J, Oh DX, Hwang DS. Nanochitin and Nanochitosan: Chitin Nanostructure Engineering with Multiscale Properties for Biomedical and Environmental Applications. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2023; 35:e2203325. [PMID: 35639091 DOI: 10.1002/adma.202203325] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/24/2022] [Indexed: 06/15/2023]
Abstract
Nanochitin and nanochitosan (with random-copolymer-based multiscale architectures of glucosamine and N-acetylglucosamine units) have recently attracted immense attention for the development of green, sustainable, and advanced functional materials. Nanochitin and nanochitosan are multiscale materials from small oligomers, rod-shaped nanocrystals, longer nanofibers, to hierarchical assemblies of nanofibers. Various physical properties of chitin and chitosan depend on their molecular- and nanostructures; translational research has utilized them for a wide range of applications (biomedical, industrial, environmental, and so on). Instead of reviewing the entire extensive literature on chitin and chitosan, here, recent developments in multiscale-dependent material properties and their applications are highlighted; immune, medical, reinforcing, adhesive, green electrochemical materials, biological scaffolds, and sustainable food packaging are discussed considering the size, shape, and assembly of chitin nanostructures. In summary, new perspectives for the development of sustainable advanced functional materials based on nanochitin and nanochitosan by understanding and engineering their multiscale properties are described.
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Affiliation(s)
- Suyoung Lee
- Division of Environmental Science and Engineering, Department of Chemical Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Pohang, 37673, Republic of Korea
| | - Lam Tan Hao
- Research Center for Bio-Based Chemistry, Korea Research Institute of Chemical Technology (KRICT), Ulsan, 44429, Republic of Korea
- Advanced Materials and Chemical Engineering, University of Science and Technology (UST), Daejeon, 34113, Republic of Korea
| | - Jeyoung Park
- Division of Environmental Science and Engineering, Department of Chemical Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Pohang, 37673, Republic of Korea
- Research Center for Bio-Based Chemistry, Korea Research Institute of Chemical Technology (KRICT), Ulsan, 44429, Republic of Korea
- Advanced Materials and Chemical Engineering, University of Science and Technology (UST), Daejeon, 34113, Republic of Korea
| | - Dongyeop X Oh
- Research Center for Bio-Based Chemistry, Korea Research Institute of Chemical Technology (KRICT), Ulsan, 44429, Republic of Korea
- Advanced Materials and Chemical Engineering, University of Science and Technology (UST), Daejeon, 34113, Republic of Korea
| | - Dong Soo Hwang
- Division of Environmental Science and Engineering, Department of Chemical Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Pohang, 37673, Republic of Korea
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Inomata M, Amano S, Abe M, Hayashi T, Sakagami H. Innate immune response of human periodontal ligament fibroblasts via the Dectin-1/Syk pathway. J Med Microbiol 2022; 71. [PMID: 36748551 DOI: 10.1099/jmm.0.001627] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Introduction. A diverse microbiota including fungi exists in the subgingival sites of patients with chronic periodontitis. The cell wall of Candida albicans, the most abundant fungal species, contains β-glucan. Dectin-1 binds β-glucan and participates in fungal recognition.Gap statement. Human periodontal ligament fibroblasts (PDLFs) are present in the periodontal ligament and synthesize immunomodulatory cytokines that influence the local response to infections. However, the expression and role of Dectin-1 in PDLFs have not been explored.Aim. This study aimed to determine if PDLFs express Dectin-1 and induce innate immune responses through Dectin-1 and the signalling molecule Syk.Methodology. The expression of Dectin-1 in PDLFs was determined by flow cytometry, western blotting and confocal microscopy. Real-time PCR and Western blotting were used to determine the immune response of PDLFs stimulated with β-glucan-rich zymosan and C. albicans.Results. Dectin-1 was constitutively expressed in PDLFs. Zymosan induced the expression of cytokines, including IL6, IL1B and IL17A, and the chemokine IL8. Zymosan also induced the expression of the antimicrobial peptide β-defensin-1 (DEFB1). Further, the phosphorylation of Syk and NF-κB occurred upon Dectin-1 activation. Notably, heat-killed C. albicans induced the expression of IL6, IL17A, IL8 and DEFB1, and this activation was suppressed by the Syk inhibitor, R406.Conclusion. These findings indicate that the Dectin-1/Syk pathway induces an innate immune response of PDLFs, which may facilitate the control of oral infections such as candidiasis and periodontitis.
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Affiliation(s)
- Megumi Inomata
- Division of Microbiology and Immunology, Department of Oral Biology and Tissue Engineering, Meikai University School of Dentistry, Sakado, Japan
| | - Shigeru Amano
- Research Institute of Odontology (M-RIO), Meikai University School of Dentistry, Sakado, Japan
| | - Masayo Abe
- Division of Microbiology and Immunology, Department of Oral Biology and Tissue Engineering, Meikai University School of Dentistry, Sakado, Japan
| | - Toru Hayashi
- Department of Anatomy Science, School of Allied Health Sciences, Kitasato University, Kitasato, Japan
| | - Hiroshi Sakagami
- Research Institute of Odontology (M-RIO), Meikai University School of Dentistry, Sakado, Japan
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Lopes JP, Lionakis MS. Pathogenesis and virulence of Candida albicans. Virulence 2022; 13:89-121. [PMID: 34964702 PMCID: PMC9728475 DOI: 10.1080/21505594.2021.2019950] [Citation(s) in RCA: 203] [Impact Index Per Article: 67.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 12/08/2021] [Accepted: 12/14/2021] [Indexed: 12/18/2022] Open
Abstract
Candida albicans is a commensal yeast fungus of the human oral, gastrointestinal, and genital mucosal surfaces, and skin. Antibiotic-induced dysbiosis, iatrogenic immunosuppression, and/or medical interventions that impair the integrity of the mucocutaneous barrier and/or perturb protective host defense mechanisms enable C. albicans to become an opportunistic pathogen and cause debilitating mucocutaneous disease and/or life-threatening systemic infections. In this review, we synthesize our current knowledge of the tissue-specific determinants of C. albicans pathogenicity and host immune defense mechanisms.
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Affiliation(s)
- José Pedro Lopes
- From the Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, USA
| | - Michail S. Lionakis
- From the Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, USA
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Zhang Z, Zheng Y, Chen Y, Yin Y, Chen Y, Chen Q, Hou Y, Shen S, Lv M, Wang T. Gut fungi enhances immunosuppressive function of myeloid-derived suppressor cells by activating PKM2-dependent glycolysis to promote colorectal tumorigenesis. Exp Hematol Oncol 2022; 11:88. [DOI: 10.1186/s40164-022-00334-6] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 10/07/2022] [Indexed: 11/09/2022] Open
Abstract
Abstract
Background
Accumulating evidence implicates that gut fungi are associated with the pathogenesis of colorectal cancer (CRC). Our previous study has revealed that Candida tropicalis (C. tropicalis) promotes colorectal tumorigenesis by enhancing immunosuppressive function of myeloid-derived suppressor cells (MDSCs) and increasing accumulation of MDSCs, but the underlying mechanisms remain unestablished.
Methods
Bone marrow–derived MDSCs were stimulated with C. tropicalis. RNA-sequencing analysis was performed to screen the differentially expressed genes. Quantitative real-time PCR and western blot were used to measure the expression of related proteins. Co-culture assay of MDSCs and CD8+ T cells was used to determine the immunosuppressive ability of MDSCs. Metabolomic analysis was conducted to detect metabolic reprogramming of MDSCs. Aerobic glycolysis of MDSCs was assessed by extracellular acidification rate (ECAR), glucose consumption and lactate production. A CAC mouse model was induced by AOM and DSS to determine the therapeutic action of TEPP-46. IHC and immunofluorescence were performed to examine the expression of PKM2, PKM2 (p-Y105) and iNOS in human CRC-infiltrated MDSCs.
Results
C. tropicalis facilitates immunosuppressive function of MDSCs by increasing the expression of iNOS, COX2 and NOX2, production of nitric oxide (NO) and reactive oxygen species (ROS). Mechanistically, C. tropicalis facilitates the immunosuppressive function of MDSCs through the C-type lectin receptors Dectin-3 and Syk. C. tropicalis-enhanced immunosuppressive function of MDSCs is further dependent on aerobic glycolysis. On the one hand, NO produced by MDSCs enhanced aerobic glycolysis in a positive feedback manner. On the other hand, C. tropicalis promotes p-Syk binding to PKM2, which results in PKM2 Tyr105 phosphorylation and PKM2 nuclear translocation in MDSCs. Nuclear PKM2 interacts with HIF-1α and subsequently upregulates the expression of HIF-1α target genes encoding glycolytic enzymes, GLUT1, HK2, PKM2, LDHA and PDK1, which are required for the C. tropicalis-induced aerobic glycolysis of MDSCs. Blockade of PKM2 nuclear translocation attenuates C. tropicalis-mediated colorectal tumorigenesis. The high expression of PKM2, PKM2 (p-Y105) and iNOS in CRC-infiltrated MDSCs correlates with the development of human CRC.
Conclusion
C. tropicalis enhances immunosuppressive function of MDSCs via Syk-PKM2-HIF-1α-glycolysis signaling axis, which drives CRC. Therefore, we identify the Syk-PKM2-HIF-1α-glycolysis signaling axis as a potential therapeutic target for CRC.
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49
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Kumar N, Vyas A, Agnihotri SK, Chattopadhyay N, Sachdev M. Small secretory proteins of immune cells can modulate gynecological cancers. Semin Cancer Biol 2022; 86:513-531. [PMID: 35150864 DOI: 10.1016/j.semcancer.2022.02.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 02/04/2022] [Accepted: 02/05/2022] [Indexed: 01/27/2023]
Abstract
Small secretory proteins of immune cells are mostly Cytokines, which include chemokines, interleukins, interferons, lymphokines and tumor necrosis factors but not hormones or growth factors. These secretory proteins are the molecular messengers and primarily involved in autocrine, paracrine and endocrine signaling as immunomodulating agents. Hence, these proteins actually regulate the cells of immune system to communicate with one another to produce a synchronized, robust, still self-regulated response to a specific antigen. Chemokines are smaller secreted proteins that control overall immune cell movement and location; these chemokines are divided into 4 subgroups, namely, CXC, CC, CX3C and C according to the position of 4 conserved cysteine residues. Complete characterization of cytokines and chemokines can exploit their vast signaling networks to develop cancer treatments. These secretory proteins like IL-6, IL-10, IL-12, TNFα, CCL2, CXCL4 & CXCL8 are predominantly expressed in most of the gynecological cancers, which directly stimulate immune effector cells and stromal cells at the tumor site and augment tumor cell recognition by cytotoxic T-cells. Hence; these secretory proteins are the major regulators, which can actually modulate all kinds of gynecological cancers. Furthermore, advancements in adoptive T-cell treatment have relied on the use of multiple cytokines/chemokines to establish a highly regulated environment for anti-tumor T cell growth. A number of in vitro studies as well as animal models and clinical subjects have also shown that cytokines/chemokines have broad antitumor activity, which has been translated into a number of cancer therapy approaches. This review will focus on the foremost cytokines & chemokines involved in the majority of the gynecological malignancies and discuss their basic biology as well as clinical applications.
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Affiliation(s)
- Niranjan Kumar
- Division of Endocrinology, CSIR- Central Drug Research Institute, Lucknow, 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Sector 19, Kamla Nehru Nagar, Ghaziabad, 201 002, India
| | - Akanksha Vyas
- Division of Endocrinology, CSIR- Central Drug Research Institute, Lucknow, 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Sector 19, Kamla Nehru Nagar, Ghaziabad, 201 002, India
| | | | - Naibedya Chattopadhyay
- Division of Endocrinology, CSIR- Central Drug Research Institute, Lucknow, 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Sector 19, Kamla Nehru Nagar, Ghaziabad, 201 002, India.
| | - Monika Sachdev
- Division of Endocrinology, CSIR- Central Drug Research Institute, Lucknow, 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Sector 19, Kamla Nehru Nagar, Ghaziabad, 201 002, India.
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50
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Avelar GM, Dambuza IM, Ricci L, Yuecel R, Mackenzie K, Childers DS, Bain JM, Pradhan A, Larcombe DE, Netea MG, Erwig LP, Brown GD, Duncan SH, Gow NA, Walker AW, Brown AJ. Impact of changes at the Candida albicans cell surface upon immunogenicity and colonisation in the gastrointestinal tract. CELL SURFACE (AMSTERDAM, NETHERLANDS) 2022; 8:100084. [PMID: 36299406 PMCID: PMC9589014 DOI: 10.1016/j.tcsw.2022.100084] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/13/2022] [Accepted: 10/14/2022] [Indexed: 11/07/2022]
Abstract
The immunogenicity of Candida albicans cells is influenced by changes in the exposure of microbe-associated molecular patterns (MAMPs) on the fungal cell surface. Previously, the degree of exposure on the C. albicans cell surface of the immunoinflammatory MAMP β-(1,3)-glucan was shown to correlate inversely with colonisation levels in the gastrointestinal (GI) tract. This is important because life-threatening systemic candidiasis in critically ill patients often arises from translocation of C. albicans strains present in the patient's GI tract. Therefore, using a murine model, we have examined the impact of gut-related factors upon β-glucan exposure and colonisation levels in the GI tract. The degree of β-glucan exposure was examined by imaging flow cytometry of C. albicans cells taken directly from GI compartments, and compared with colonisation levels. Fungal β-glucan exposure was lower in the cecum than the small intestine, and fungal burdens were correspondingly higher in the cecum. This inverse correlation did not hold for the large intestine. The gut fermentation acid, lactate, triggers β-glucan masking in vitro, leading to attenuated anti-Candida immune responses. Additional fermentation acids are present in the GI tract, including acetate, propionate, and butyrate. We show that these acids also influence β-glucan exposure on C. albicans cells in vitro and, like lactate, they influence β-glucan exposure via Gpr1/Gpa2-mediated signalling. Significantly, C. albicans gpr1Δ gpa2Δ cells displayed elevated β-glucan exposure in the large intestine and a corresponding decrease in fungal burden, consistent with the idea that Gpr1/Gpa2-mediated β-glucan masking influences colonisation of this GI compartment. Finally, extracts from the murine gut and culture supernatants from the mannan grazing gut anaerobe Bacteroides thetaiotaomicron promote β-glucan exposure at the C. albicans cell surface. Therefore, the local microbiota influences β-glucan exposure levels directly (via mannan grazing) and indirectly (via fermentation acids), whilst β-glucan masking appears to promote C. albicans colonisation of the murine large intestine.
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Affiliation(s)
- Gabriela M. Avelar
- Aberdeen Fungal Group, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK
| | - Ivy M. Dambuza
- Aberdeen Fungal Group, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK
- Medical Research Council Centre for Medical Mycology, University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter EX4 4QD, UK
| | - Liviana Ricci
- Microbiome, Food Innovation and Food Security Research Theme, Rowett Institute, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK
| | - Raif Yuecel
- Iain Fraser Cytometry Centre, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK
| | - Kevin Mackenzie
- Microscopy & Histology Facility, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK
| | - Delma S. Childers
- Aberdeen Fungal Group, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK
| | - Judith M. Bain
- Aberdeen Fungal Group, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK
| | - Arnab Pradhan
- Aberdeen Fungal Group, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK
- Medical Research Council Centre for Medical Mycology, University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter EX4 4QD, UK
| | - Daniel E. Larcombe
- Aberdeen Fungal Group, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK
- Medical Research Council Centre for Medical Mycology, University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter EX4 4QD, UK
| | - Mihai G. Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands
- Department for Immunology & Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany
| | - Lars P. Erwig
- Aberdeen Fungal Group, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK
- Johnson-Johnson Innovation, EMEA Innovation Centre, One Chapel Place, London W1G 0BG, UK
| | - Gordon D. Brown
- Aberdeen Fungal Group, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK
- Medical Research Council Centre for Medical Mycology, University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter EX4 4QD, UK
| | - Sylvia H. Duncan
- Microbiome, Food Innovation and Food Security Research Theme, Rowett Institute, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK
| | - Neil A.R. Gow
- Aberdeen Fungal Group, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK
- Medical Research Council Centre for Medical Mycology, University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter EX4 4QD, UK
| | - Alan W. Walker
- Microbiome, Food Innovation and Food Security Research Theme, Rowett Institute, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK
| | - Alistair J.P. Brown
- Aberdeen Fungal Group, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK
- Medical Research Council Centre for Medical Mycology, University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter EX4 4QD, UK
- Corresponding author at: Medical Research Council Centre for Medical Mycology, University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter EX4 4QD, UK.
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