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1.
Cell Surf ; 11: 100125, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38799511

ABSTRACT

Non-tuberculosis mycobacteria (NTM) can form biofilms on diverse artificial surfaces. In the present study, we induced NTM biofilm formation on materials used in various medical devices, evaluated the total amount of biofilm, and observed the ultrastructure by scanning electron microscopy.

2.
Genes Cells ; 29(4): 316-327, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38385597

ABSTRACT

Dectin-1 is a well-characterized C-type lectin receptor involved in anti-fungal immunity through the recognition of polysaccharides; however, molecular mechanisms and outcomes initiated through self-recognition have not been fully understood. Here, we purified a water-soluble fraction from mouse liver that acts as a Dectin-1 agonist. To address the physiological relevance of this recognition, we utilized sterile liver inflammation models. The CCl4-induced hepatitis model showed that Dectin-1 deficiency led to reduced inflammation through decreased inflammatory cell infiltration and lower pro-inflammatory cytokine levels. Moreover, in a NASH model induced by streptozotocin and a high-fat diet, hepatic inflammation and fibrosis were ameliorated in Dectin-1-deficient mice. The Dectin-1 agonist activity was increased in the water-soluble fraction from NASH mice, suggesting a potential pathogenic cycle between Dectin-1 activation and hepatitis progression. In vivo administration of the fraction into mice induced hepatic inflammation. These results highlight a role of self-recognition through Dectin-1 that triggers hepatic innate immune responses and contributes to the exacerbation of inflammation in pathogenic settings. Thus, the blockade of this axis may provide a therapeutic option for liver inflammatory diseases.


Subject(s)
Hepatitis , Lectins, C-Type , Non-alcoholic Fatty Liver Disease , Animals , Mice , Inflammation/metabolism , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/immunology , Non-alcoholic Fatty Liver Disease/metabolism , Water
3.
J Innate Immun ; 15(1): 397-411, 2023.
Article in English | MEDLINE | ID: mdl-36657412

ABSTRACT

Aspergillus fumigatus is a ubiquitous, yet potentially pathogenic, mold. The immune system employs innate receptors, such as dectin-1, to recognize fungal pathogens, but the immunological networks that afford protection are poorly explored. Here, we investigated the role of dectin-1 in anti-A. fumigatus response in an experimental model of acute invasive aspergillosis. Mice lacking dectin-1 presented enhanced signs of inflammation, with increased production of inflammatory cytokines and neutrophil infiltration, quickly succumbing to the infection. Curiously, resistance did not require T/B lymphocytes or IL-17. Instead, the main effector function of dectin-1 was the preservation of the NK cell population in the kidneys by the provision of the cytokine IL-15. While the depletion of NK cells impaired host defense in wild-type mice, IL-15 administration restored antifungal responses in dectin-1-deficient mice. Our results uncover a new effector mechanism for dectin-1 in anti-Aspergillus defense, adding an alternative approach to understand the pathophysiology of this infection.


Subject(s)
Aspergillosis , Aspergillus fumigatus , Animals , Mice , Interleukin-15 , Lectins, C-Type/metabolism , Cytokines , Killer Cells, Natural
4.
Tuberculosis (Edinb) ; 138: 102294, 2023 01.
Article in English | MEDLINE | ID: mdl-36542980

ABSTRACT

Mycobacteria often cause chronic infection. To establish persistence in the host, mycobacteria need to evade host immune responses. However, the molecular mechanisms underlying the evasion strategy are not fully understood. Here, we demonstrate that mycobacterial cell wall lipids trigger an inhibitory receptor to suppress host immune responses. Mycolic acids are major cell wall components and are essential for survival of mycobacteria. By screening inhibitory receptors that react with mycobacterial lipids, we found that mycolic acids from various mycobacterial species bind to mouse Clec12A, and more potently to human Clec12A. Clec12A is a conserved inhibitory C-type lectin receptor containing immunoreceptor tyrosine-based inhibitory motif (ITIM). Innate immune responses, such as MCP-1 production, and PPD-specific recall T cell responses were augmented in Clec12A-deficient mice after infection. In contrast, human Clec12A transgenic mice were susceptible to infection with M. tuberculosis. These results suggest that mycobacteria dampen host immune responses by hijacking an inhibitory host receptor through their specific and essential lipids, mycolic acids. The blockade of this interaction might provide a therapeutic option for the treatment or prevention of mycobacterial infection.


Subject(s)
Mycobacterium Infections , Mycobacterium tuberculosis , Animals , Humans , Mice , Cell Wall/metabolism , Immunity, Innate , Lectins, C-Type/genetics , Lectins, C-Type/metabolism , Mycolic Acids/metabolism , Receptors, Mitogen/metabolism
5.
Int Immunol ; 33(12): 847-851, 2021 11 25.
Article in English | MEDLINE | ID: mdl-34599808

ABSTRACT

Our bodies are continuously assaulted by infection and tissue damage; most of these injurious insults are primarily sensed by immune receptors to maintain tissue homeostasis. Although immune recognition of proteins or nucleic acids has been well characterized, the molecular mechanisms by which immune receptors discriminate lipids to elicit suitable immune responses remain elusive. Recent studies have demonstrated that the C-type lectin receptor family functions as immune sensors for adjuvant lipids derived from pathogens and damaged tissues, thereby promoting innate/acquired immunity. In this review, we will discuss how these receptors recognize lipid components to initiate appropriate, but sometimes deleterious, immune responses against environmental stimuli. We will also discuss an aspect of inhibitory C-type lectin receptors; their ligands might reflect normal self which silences the immune response regarded as "silence"-associated molecular patterns or may be associated with escape strategies of pathogens as "evasion"-associated molecular patterns.


Subject(s)
Immunity, Innate/immunology , Lectins, C-Type/immunology , Animals , Humans , Lipids/immunology
6.
Org Biomol Chem ; 18(19): 3659-3663, 2020 05 21.
Article in English | MEDLINE | ID: mdl-32356529

ABSTRACT

Ac1PIM1 is a potential biosynthetic intermediate for phosphatidylinositol mannosides (PIMs) from Mycobacterium tuberculosis. We achieved the first synthesis of Ac1PIM1 by utilizing an allyl-type protecting group strategy and regioselective phosphorylation of inositol. A very potent agonist of an innate immune receptor DCAR, which is better than previously known agonists, is demonstrated.


Subject(s)
Immunomodulation/drug effects , Lectins, C-Type/agonists , Mycobacterium tuberculosis/chemistry , Phosphatidylinositols/pharmacology , Receptors, Immunologic/agonists , Animals , Cytokines/biosynthesis , Lectins, C-Type/immunology , Mice , Mycobacterium tuberculosis/immunology , Phosphatidylinositols/chemical synthesis , Phosphatidylinositols/chemistry , Phosphorylation , RAW 264.7 Cells , Receptors, Immunologic/immunology
7.
Immunity ; 45(6): 1245-1257, 2016 12 20.
Article in English | MEDLINE | ID: mdl-27887882

ABSTRACT

Phosphatidyl-inositol mannosides (PIM) are glycolipids unique to mycobacteria and other related bacteria that stimulate host immune responses and are implicated in mycobacteria pathogenicity. Here, we found that the FcRγ-coupled C-type lectin receptor DCAR (dendritic cell immunoactivating receptor; gene symbol Clec4b1) is a direct receptor for PIM. Mycobacteria activated reporter cells expressing DCAR, and delipidation of mycobacteria abolished this activity. Acylated PIMs purified from mycobacteria were identified as ligands for DCAR. DCAR was predominantly expressed in small peritoneal macrophages and monocyte-derived inflammatory cells in lungs and spleen. These cells produced monocyte chemoattractant protein-1 (MCP-1) upon PIM treatment, and absence of DCAR or FcRγ abrogated MCP-1 production. Upon mycobacterial infection, Clec4b1-deficient mice showed reduced numbers of monocyte-derived inflammatory cells at the infection site, impaired IFNγ production by T cells, and an increased bacterial load. Thus, DCAR is a critical receptor for PIM that functions to promote T cell responses against mycobacteria.


Subject(s)
Bacterial Proteins/immunology , Lectins, C-Type/immunology , Phosphatidylinositols/immunology , Receptors, Immunologic/immunology , Th1 Cells/immunology , Animals , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mycobacterium/immunology , Mycobacterium Infections/immunology
8.
Chem Commun (Camb) ; 51(81): 15027-30, 2015 Oct 18.
Article in English | MEDLINE | ID: mdl-26310657

ABSTRACT

Mycobacterium tuberculosis H37Ra produces a range of immunogenic ß-gentiobiosyl diacylglycerides. We report the total synthesis of several candidate structures and show that these compounds signal weakly through mouse, but not human, Mincle. Structure-activity relationships reveal a striking dependence upon acyl chain length for gentiobiosyl diacylglyceride signalling through Mincle. Significantly, a truncated ß-glucosyl diglyceride was shown to provide potent signalling through both human and mouse Mincle and could activate murine bone marrow derived dendritic cells.


Subject(s)
Diglycerides/chemical synthesis , Diglycerides/pharmacology , Mycobacterium tuberculosis/chemistry , Receptors, Pattern Recognition/metabolism , Signal Transduction/drug effects , Animals , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Diglycerides/chemistry , Humans , Mice , Molecular Structure , Mycobacterium tuberculosis/isolation & purification , Structure-Activity Relationship
9.
Chem Commun (Camb) ; 51(24): 5100-3, 2015 Mar 25.
Article in English | MEDLINE | ID: mdl-25714652

ABSTRACT

An enantioselective synthesis of (+)-corynomycolic acid, and its elaboration to esters of trehalose, glucose and glycerol, is described. Trehalose dicorynomycolate and trehalose monocorynomycolate activate human and mouse Mincle as effectively as trehalose dicorynomycolate (cord factor). Glucose monomycolate is revealed to be a potent activator of both mouse and human Mincle. Glycerol monocorynomycolate signals through human Mincle, with the activity predominantly residing in the 2'S-isomer.


Subject(s)
Glycolipids/chemistry , Glycolipids/pharmacology , Lectins, C-Type/metabolism , Membrane Proteins/metabolism , Mycolic Acids/chemistry , Receptors, Immunologic/metabolism , Signal Transduction/drug effects , Animals , Cell Line , Humans , Mice , Molecular Conformation , Stereoisomerism , Structure-Activity Relationship
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