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1.
Nat Immunol ; 24(11): 1879-1889, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37872315

RESUMO

Gastrointestinal fungal dysbiosis is a hallmark of several diseases marked by systemic immune activation. Whether persistent pathobiont colonization during immune alterations and impaired gut barrier function has a durable impact on host immunity is unknown. We found that elevated levels of Candida albicans immunoglobulin G (IgG) antibodies marked patients with severe COVID-19 (sCOVID-19) who had intestinal Candida overgrowth, mycobiota dysbiosis and systemic neutrophilia. Analysis of hematopoietic stem cell progenitors in sCOVID-19 revealed transcriptional changes in antifungal immunity pathways and reprogramming of granulocyte myeloid progenitors (GMPs) for up to a year. Mice colonized with C. albicans patient isolates experienced increased lung neutrophilia and pulmonary NETosis during severe acute respiratory syndrome coronavirus-2 infection, which were partially resolved with antifungal treatment or by interleukin-6 receptor blockade. sCOVID-19 patients treated with tocilizumab experienced sustained reductions in C. albicans IgG antibodies titers and GMP transcriptional changes. These findings suggest that gut fungal pathobionts may contribute to immune activation during inflammatory diseases, offering potential mycobiota-immune therapeutic strategies for sCOVID-19 with prolonged symptoms.


Assuntos
COVID-19 , Micobioma , Humanos , Animais , Camundongos , Antifúngicos , Disbiose , Neutrófilos , Candida albicans , Imunoglobulina G
2.
Immunity ; 54(1): 68-83.e6, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33238133

RESUMO

While antibiotics are intended to specifically target bacteria, most are known to affect host cell physiology. In addition, some antibiotic classes are reported as immunosuppressive for reasons that remain unclear. Here, we show that Linezolid, a ribosomal-targeting antibiotic (RAbo), effectively blocked the course of a T cell-mediated autoimmune disease. Linezolid and other RAbos were strong inhibitors of T helper-17 cell effector function in vitro, showing that this effect was independent of their antibiotic activity. Perturbing mitochondrial translation in differentiating T cells, either with RAbos or through the inhibition of mitochondrial elongation factor G1 (mEF-G1) progressively compromised the integrity of the electron transport chain. Ultimately, this led to deficient oxidative phosphorylation, diminishing nicotinamide adenine dinucleotide concentrations and impairing cytokine production in differentiating T cells. In accordance, mice lacking mEF-G1 in T cells were protected from experimental autoimmune encephalomyelitis, demonstrating that this pathway is crucial in maintaining T cell function and pathogenicity.


Assuntos
Antibacterianos/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Linezolida/uso terapêutico , Mitocôndrias/metabolismo , Peptídeos Cíclicos/uso terapêutico , Ribossomos/metabolismo , Células Th17/fisiologia , Animais , Autoimunidade/efeitos dos fármacos , Diferenciação Celular , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/genética , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Terapia de Alvo Molecular , Esclerose Múltipla/tratamento farmacológico , NAD/metabolismo , Fosforilação Oxidativa , Fator G para Elongação de Peptídeos/genética , Fator G para Elongação de Peptídeos/metabolismo
3.
Nature ; 603(7902): 672-678, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35296857

RESUMO

The fungal microbiota (mycobiota) is an integral part of the complex multikingdom microbial community colonizing the mammalian gastrointestinal tract and has an important role in immune regulation1-6. Although aberrant changes in the mycobiota have been linked to several diseases, including inflammatory bowel disease3-9, it is currently unknown whether fungal species captured by deep sequencing represent living organisms and whether specific fungi have functional consequences for disease development in affected individuals. Here we developed a translational platform for the functional analysis of the mycobiome at the fungal-strain- and patient-specific level. Combining high-resolution mycobiota sequencing, fungal culturomics and genomics, a CRISPR-Cas9-based fungal strain editing system, in vitro functional immunoreactivity assays and in vivo models, this platform enables the examination of host-fungal crosstalk in the human gut. We discovered a rich genetic diversity of opportunistic Candida albicans strains that dominate the colonic mucosa of patients with inflammatory bowel disease. Among these human-gut-derived isolates, strains with high immune-cell-damaging capacity (HD strains) reflect the disease features of individual patients with ulcerative colitis and aggravated intestinal inflammation in vivo through IL-1ß-dependent mechanisms. Niche-specific inflammatory immunity and interleukin-17A-producing T helper cell (TH17 cell) antifungal responses by HD strains in the gut were dependent on the C. albicans-secreted peptide toxin candidalysin during the transition from a benign commensal to a pathobiont state. These findings reveal the strain-specific nature of host-fungal interactions in the human gut and highlight new diagnostic and therapeutic targets for diseases of inflammatory origin.


Assuntos
Fungos , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Microbiota , Micobioma , Animais , Sistemas CRISPR-Cas , Candida albicans , Fungos/genética , Fungos/patogenicidade , Variação Genética , Humanos , Imunidade , Inflamação , Mamíferos
5.
J Allergy Clin Immunol ; 148(1): 16-32, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33966898

RESUMO

The progression through different steps of T-cell development, activation, and effector function is tightly bound to specific cellular metabolic processes. Previous studies established that T-effector cells have a metabolic bias toward aerobic glycolysis, whereas naive and regulatory T cells mainly rely on oxidative phosphorylation. More recently, the field of immunometabolism has drifted away from the notion that mitochondrial metabolism holds little importance in T-cell activation and function. Of note, T cells possess metabolic promiscuity, which allows them to adapt their nutritional requirements according to the tissue environment. Altogether, the integration of these metabolic pathways culminates in the generation of not only energy but also intermediates, which can regulate epigenetic programs, leading to changes in T-cell fate. In this review, we discuss the recent literature on how glycolysis, amino acid catabolism, and fatty acid oxidation work together with the tricarboxylic acid cycle in the mitochondrion. We also emphasize the importance of the electron transport chain for T-cell immunity. We also discuss novel findings highlighting the role of key enzymes, accessory pathways, and posttranslational protein modifications that distinctively regulate T-cell function and might represent prominent candidates for therapeutic purposes.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Ácidos Graxos/imunologia , Glicólise/imunologia , Mitocôndrias/imunologia , NAD/imunologia , Poliaminas/imunologia , Animais , Humanos
6.
J Allergy Clin Immunol ; 147(1): 335-348.e11, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32407834

RESUMO

BACKGROUND: The cross-talk between the host and its microbiota plays a key role in the promotion of health. The production of metabolites such as polyamines by intestinal-resident bacteria is part of this symbiosis shaping host immunity. The polyamines putrescine, spermine, and spermidine are abundant within the gastrointestinal tract and might substantially contribute to gut immunity. OBJECTIVE: We aimed to characterize the polyamine spermidine as a modulator of T-cell differentiation and function. METHODS: Naive T cells were isolated from wild-type mice or cord blood from healthy donors and submitted to polarizing cytokines, with and without spermidine treatment, to evaluate CD4+ T-cell differentiation in vitro. Moreover, mice were subjected to oral supplementation of spermidine, or its precursor l-arginine, to assess the frequency and total numbers of regulatory T (Treg) cells in vivo. RESULTS: Spermidine modulates CD4+ T-cell differentiation in vitro, preferentially committing naive T cells to a regulatory phenotype. After spermidine treatment, activated T cells lacking the autophagy gene Atg5 fail to upregulate Foxp3 to the same extent as wild-type cells. These results indicate that spermidine's polarizing effect requires an intact autophagic machinery. Furthermore, dietary supplementation with spermidine promotes homeostatic differentiation of Treg cells within the gut and reduces pathology in a model of T-cell transfer-induced colitis. CONCLUSION: Altogether, our results highlight the beneficial effects of spermidine, or l-arginine, on gut immunity by promoting Treg cell development.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Colite/imunologia , Imunidade nas Mucosas/efeitos dos fármacos , Espermidina/farmacologia , Linfócitos T Reguladores/imunologia , Animais , Diferenciação Celular/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout
7.
Glia ; 65(9): 1439-1451, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28617991

RESUMO

Pattern recognition receptors, such as toll-like receptors (TLRs), perceive tissue alterations and initiate local innate immune responses. Microglia, the resident macrophages of the brain, encode TLRs which primary role is to protect the tissue integrity. However, deregulated activation of TLRs in microglia may lead to chronic neurodegeneration. This double role of microglial responses is often reported in immune-driven neurologic diseases, as in multiple sclerosis (MS). Consequently, strategies to manipulate microglia inflammatory responses may help to ameliorate disease progression. In this context, the anti-inflammatory cytokine interleukin (IL)-10 appears as an attractive target. In this study, we investigated how activation of microglia by TLRs with distinct roles in MS impacts on IL-10 production. We found that activation of TLR2, TLR4, and TLR9 induced the production of IL-10 to a greater extent than activation of TLR3. This was surprising as both TLR3 and IL-10 play protective roles in animal models of MS. Interestingly, combination of TLR3 triggering with the other TLRs, enhanced IL-10 through the modulation of its transcription, via interferon (IFN)-ß, but independently of IL-27. Thus, in addition to the modulation of inflammatory responses of the periphery described for the axis TLR3/IFN-ß, we now report a direct modulation of microglial responses. We further show that the presence of IFN-γ in the microenvironment abrogated the modulation of IL-10 by TLR3, whereas that of IL-17 had no effect. Considering the therapeutic application of IFN-ß in MS, our study bears important implications for the understanding of the cytokine network regulating microglia responses in this setting.


Assuntos
Interferon beta/metabolismo , Interleucina-10/metabolismo , Microglia/imunologia , Receptores Toll-Like/metabolismo , Animais , Células Cultivadas , Interleucina-10/genética , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Esclerose Múltipla/imunologia , Estabilidade de RNA , RNA Mensageiro/metabolismo , Receptores Toll-Like/agonistas
8.
J Neuroinflammation ; 13(1): 297, 2016 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-27881137

RESUMO

BACKGROUND: The inflammatory response is critical to fight insults, such as pathogen invasion or tissue damage, but if not resolved often becomes detrimental to the host. A growing body of evidence places non-resolved inflammation at the core of various pathologies, from cancer to neurodegenerative diseases. It is therefore not surprising that the immune system has evolved several regulatory mechanisms to achieve maximum protection in the absence of pathology. MAIN BODY: The production of the anti-inflammatory cytokine interleukin (IL)-10 is one of the most important mechanisms evolved by many immune cells to counteract damage driven by excessive inflammation. Innate immune cells of the central nervous system, notably microglia, are no exception and produce IL-10 downstream of pattern recognition receptors activation. However, whereas the molecular mechanisms regulating IL-10 expression by innate and acquired immune cells of the periphery have been extensively addressed, our knowledge on the modulation of IL-10 expression by central nervous cells is much scattered. This review addresses the current understanding on the molecular mechanisms regulating IL-10 expression by innate immune cells of the brain and the implications of IL-10 modulation in neurodegenerative disorders. CONCLUSION: The regulation of IL-10 production by central nervous cells remains a challenging field. Answering the many remaining outstanding questions will contribute to the design of targeted approaches aiming at controlling deleterious inflammation in the brain.


Assuntos
Encéfalo/citologia , Encéfalo/imunologia , Encefalite/imunologia , Encefalite/fisiopatologia , Imunidade Inata/fisiologia , Interleucina-10/metabolismo , Animais , Encefalite/patologia , Humanos , Microglia/metabolismo
9.
Front Immunol ; 9: 400, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29545807

RESUMO

Inflammatory bowel disease encompasses a group of chronic-inflammatory conditions of the colon and small intestine. These conditions are characterized by exacerbated inflammation of the organ that greatly affects the quality of life of patients. Molecular mechanisms counteracting this hyperinflammatory status of the gut offer strategies for therapeutic intervention. Among these regulatory molecules is the anti-inflammatory cytokine interleukin (IL)-10, as shown in mice and humans. Indeed, IL-10 signaling, particularly in macrophages, is essential for intestinal homeostasis. We sought to investigate the temporal profile of IL-10-mediated protection during chemical colitis and which were the underlying mechanisms. Using a novel mouse model of inducible IL-10 overexpression (pMT-10), described here, we show that mice preconditioned with IL-10 for 8 days before dextran sulfate sodium (DSS) administration developed a milder colitic phenotype. In IL-10-induced colitic mice, Ly6C cells isolated from the lamina propria showed a decreased inflammatory profile. Because our mouse model leads to transcription of the IL-10 transgene in the bone marrow and elevated seric IL-10 concentration, we investigated whether IL-10 could imprint immune cells in a long-lasting way, thus conferring sustained protection to colitis. We show that this was not the case, as IL-10-afforded protection was only observed if IL-10 induction immediately preceded DSS-mediated colitis. Thus, despite the protection afforded by IL-10 in colitis, novel strategies are required, specifically to achieve long-lasting protection.


Assuntos
Colite/imunologia , Doenças Inflamatórias Intestinais/imunologia , Interleucina-10/metabolismo , Animais , Colite/induzido quimicamente , Sulfato de Dextrana , Modelos Animais de Doenças , Feminino , Humanos , Interleucina-10/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores de Interleucina-10/genética , Transdução de Sinais , Transgenes/genética
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