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1.
J Infect Dis ; 230(3): 768-777, 2024 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-38446996

RESUMEN

The interaction between the Candida albicans cell wall and pattern recognition receptors is crucial for the initiation of host immune responses, which, ultimately, contribute to the clearance of this pathogenic fungus. In the present study, we investigate the ability of C. albicans mannans to modulate immune response and induce innate immune memory (also termed trained immunity). Using mutants of C. albicans that are defective in or lack mannosyl residues, we show that alterations in the mannosylation of the C. albicans cell wall affect the innate cytokine response and strongly reduce the secretion of T-cell-derived cytokines. Subsequently, we demonstrate that the branching of N-linked mannan, but not O-linked mannan, is essential to potentiate the induction of trained immunity, a process mediated by dectin 2. In conclusion, N-linked mannan is needed, in addition to ß-glucans, for an effective induction of trained immunity by C. albicans.


Asunto(s)
Candida albicans , Citocinas , Inmunidad Innata , Lectinas Tipo C , Mananos , Candida albicans/inmunología , Lectinas Tipo C/metabolismo , Lectinas Tipo C/inmunología , Mananos/inmunología , Animales , Ratones , Citocinas/metabolismo , Pared Celular/inmunología , beta-Glucanos/inmunología , Ratones Endogámicos C57BL , Inmunidad Entrenada
2.
Mycopathologia ; 189(2): 24, 2024 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-38407673

RESUMEN

OBJECTIVES: Invasive aspergillosis (IA) is a major cause of mortality in immunocompromised patients and it is difficult to diagnose because of the lack of reliable highly sensitive diagnostics. We aimed to identify circulating immunological markers that could be useful for an early diagnosis of IA. METHODS: We collected longitudinally serum samples from 33 cases with probable/proven IA and two matched control cohorts without IA (one with microbiological and clinical evidence of bacterial or viral non-fungal pneumonia and one without evidence of infection, all matched for neutropenia, primary underlying disease, and receipt of corticosteroids/other immunosuppressants) at a tertiary university hospital. In addition, samples from an independent cohort (n = 20 cases of proven/probable IA and 20 matched controls without infection) were obtained. A panel of 92 circulating proteins involved in inflammation was measured by proximity extension assay. A random forest model was used to predict the development of IA using biomarkers measured before diagnosis. RESULTS: While no significant differences were observed between IA cases and infected controls, concentrations of 30 inflammatory biomarkers were different between cases and non-infected controls, of which nine were independently replicated: PD-L1, MMP-10, Interleukin(IL)-10, IL-15RA, IL-18, IL-18R1, CDCP1, CCL19 and IL-17C. From the differential abundance analysis of serum samples collected more than 10 days before diagnosis and at diagnosis, increased IL-17C concentrations in IA patients were replicated in the independent cohort. CONCLUSIONS: An increased circulating concentration of IL-17C was detected both in the discovery and independent cohort, both at the time of diagnosis and in samples 10 days before the diagnosis of IA, suggesting it should be evaluated further as potential (early) biomarker of infection.


Asunto(s)
Aspergilosis , Neoplasias Hematológicas , Humanos , Interleucina-17 , Neoplasias Hematológicas/complicaciones , Aspergilosis/diagnóstico , Bioensayo , Hospitales Universitarios , Antígenos de Neoplasias , Moléculas de Adhesión Celular
3.
J Clin Immunol ; 43(8): 2033-2048, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37714974

RESUMEN

Both innate errors of immunity, such as familial Mediterranean fever (FMF) and chronic granulomatous disease (CGD), and the common inflammatory disease gout are characterized by episodes of sterile inflammatory attacks in the absence of an infection. While these disorders encompass distinct pathologies due to differentially affected metabolic pathways and inflammasome activation mechanisms, their common features are the excessive production of interleukin (IL)-1ß and innate immune cell hyperreactivity. On the other hand, the role of T cells and innate-like lymphocytes such as gamma delta (γδ) T cells in these pathologies is ill-defined. In order to widen our understanding of T cell involvement in CGD, FMF and gout pathology, we developed multicolour immunophenotyping panels for flow cytometry to characterize γδ T cells as well as CD4 and CD8 T cell populations in terms of their cytokine production, activation status, memory or naive phenotypes, exhaustion status, homing receptor expression, and cytotoxic activity. Our study is the first deep immunophenotyping analysis of T cell populations in CGD, FMF, and gout patients. We found that CGD affects the frequencies and activation status of T cells, while gout impairs the cytokine production capacity of Vδ2 T cells. FMF was characterized by decreased percentages of regulatory T cells in circulation and attenuated IFN-γ production capacity by Vδ2 T cells. Autoinflammatory syndromes and congenital defects of phagocyte differentially affect T cell compartments. Future studies are warranted to assess whether these phenotypical changes are relevant for disease pathology.


Asunto(s)
Fiebre Mediterránea Familiar , Gota , Enfermedad Granulomatosa Crónica , Humanos , Enfermedad Granulomatosa Crónica/diagnóstico , Linfocitos T CD8-positivos , Citocinas
4.
J Infect Dis ; 225(10): 1796-1806, 2022 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-32702099

RESUMEN

BACKGROUND: Recurrent vulvovaginal candidiasis (RVVC) affects up to 8% of women. The immunopathogenesis is poorly understood but it has been suggested that RVVC might be due to dysregulated innate immune response. The aim of this study was to compare cytokine profiles in stimulated primary mononuclear cells (PBMCs) from RVVC and healthy individuals. METHODS: PBMCs isolated from RVVC patients (n = 24) and healthy volunteers (n = 30) were stimulated with unspecific and pathogen-specific antigens. Cytokine production was assessed after 24 hours, 48 hours, and 7 days using ELISA. RESULTS: No significant differences in cytokine production were found in T helper 1 (Th1), Th2, and Th17 immunity in response to both unspecific and pathogen-specific stimulations. Tumor necrosis factor-α (TNF-α) production in response to C. albicans hyphae was significantly higher in patients than controls and within the patient group, a significant positive correlation was found between interleukin-1ß (IL-1ß) and both TNF-α and IL-6. Both IL-1ß/IL-1Ra and TNF-α/IL-10 ratios in Candida hyphae-stimulated PBMCs were significantly higher in patients than controls. CONCLUSIONS: Women affected by RVVC showed increased monocytes-derived cytokine production, which might contribute to an exaggerated vaginal immune response to Candida hyphae. RVVC patients show no defective Th-dependent adaptive immune response upon Candida stimulation.


Asunto(s)
Candidiasis Vulvovaginal , Candida , Candida albicans/fisiología , Citocinas , Femenino , Humanos , Hifa , Monocitos , Factor de Necrosis Tumoral alfa
5.
Med Mycol ; 60(10)2022 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-36195329

RESUMEN

Candida africana is a fungal pathogen that rarely causes invasive infections, but is mainly isolated from patients with vaginal infections. Vulvovaginal candidiasis is associated with dysregulated inflammatory responses of the host, however, the innate immune responses against C. africana are currently unknown. In this study, we explored the cytokine production of human peripheral blood mononuclear cells (PBMCs) in response to different C. africana isolates (intra-species diversity), and compared it with that induced by other yeasts belonging to the C. albicans species complex such as C. dubliniensis and C. albicans. Candida africana isolates induced both pro- and anti-inflammatory cytokines broadly similar to other Candida species. Candida africana-stimulated PBMCs tended to produce lower Interleukin (IL)-17 and IL-22 levels in comparison with C. albicans, whereas the induction of trained immunity was similar between C. africana and other Candida species. Overall, our results demonstrate that C. africana induces similar innate immune responses as the other Candida species. Therefore, its propensity to cause vulvovaginal infections is not due to an increased capacity to induce cytokine-related immune pathology. Nor is the infrequent occurrence of invasive infection by C. africana explained by a quantitatively different cytokine induction.


Candida africana has been reported to cause vulvovaginal candidiasis. This study shows that C. africana induces broadly similar cytokine production and trained immunity as other Candida species. Its propensity to cause vaginal infections is not due to an enhanced capacity to cause immune dysregulation.


Asunto(s)
Candidiasis Vulvovaginal , Citocinas , Animales , Candida , Candida albicans , Candidiasis Vulvovaginal/microbiología , Candidiasis Vulvovaginal/veterinaria , Femenino , Humanos , Leucocitos Mononucleares
6.
J Infect Dis ; 224(7): 1219-1224, 2021 10 13.
Artículo en Inglés | MEDLINE | ID: mdl-33733279

RESUMEN

Immunocompromised patients are highly susceptible to invasive aspergillosis. Herein, we identified a homozygous deletion mutation (507 del C) resulting in a frameshift (N170I) and early stop codon in the fungal binding Dectin-2 receptor, in an immunocompromised patient. The mutated form of Dectin-2 was weakly expressed, did not form clusters at/near the cell surface and was functionally defective. Peripheral blood mononuclear cells from this patient were unable to mount a cytokine (tumor necrosis factor, interleukin 6) response to Aspergillus fumigatus, and this first identified Dectin-2-deficient patient died of complications of invasive aspergillosis.


Asunto(s)
Aspergilosis/diagnóstico , Aspergillus fumigatus/aislamiento & purificación , Infecciones Fúngicas Invasoras , Lectinas Tipo C/genética , Eliminación de Secuencia/genética , Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Resultado Fatal , Interacciones Huésped-Patógeno , Humanos , Huésped Inmunocomprometido , Infecciones Fúngicas Invasoras/diagnóstico , Infecciones Fúngicas Invasoras/tratamiento farmacológico
7.
Infect Immun ; 89(8): e0000521, 2021 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-34031131

RESUMEN

Infectious diseases are a leading cause of morbidity and mortality worldwide, and human pathogens have long been recognized as one of the main sources of evolutionary pressure, resulting in a high variable genetic background in immune-related genes. The study of the genetic contribution to infectious diseases has undergone tremendous advances over the last decades. Here, focusing on genetic predisposition to fungal diseases, we provide an overview of the available approaches for studying human genetic susceptibility to infections, reviewing current methodological and practical limitations. We describe how the classical methods available, such as family-based studies and candidate gene studies, have contributed to the discovery of crucial susceptibility factors for fungal infections. We will also discuss the contribution of novel unbiased approaches to the field, highlighting their success but also their limitations for the fungal immunology field. Finally, we show how a systems genomics approach can overcome those limitations and can lead to efficient prioritization and identification of genes and pathways with a critical role in susceptibility to fungal diseases. This knowledge will help to stratify at-risk patient groups and, subsequently, develop early appropriate prophylactic and treatment strategies.


Asunto(s)
Hongos/fisiología , Predisposición Genética a la Enfermedad , Interacciones Huésped-Patógeno/genética , Micosis/genética , Micosis/microbiología , Susceptibilidad a Enfermedades/inmunología , Antecedentes Genéticos , Genoma , Genómica/métodos , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad , Micosis/inmunología
8.
J Nephrol ; 2024 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-39352607

RESUMEN

BACKGROUND: Paraneoplastic minimal change disease (MCD) has been associated with hematological malignancies, whereas solid malignancies are commonly associated with membranous glomerulonephritis. In this systematic review of the literature, we describe the clinical features, treatment and outcome of MCD associated with solid neoplasms. METHODS: We performed a systematic review of the MEDLINE, COCHRANE, EMBASE and SCOPUS databases, including case reports of adult patients with biopsy-proven MCD and solid malignancy, without language or time restrictions. RESULTS: Sixty-seven papers were included, presenting 86 cases with a mean age of 57.8 ± 14.7 years; 41.0% were women. Nephrotic syndrome was the initial presentation in 96.2% of patients; 67.2% had kidney function impairment, and 21.2% required kidney replacement therapy. The most frequent malignancies were malignant thymoma (34.9%), kidney (14.0%), lung (12.8%), and gastrointestinal tumors (12.8%). In 40.7% of cases, the neoplasm diagnosis preceded MCD by 33.8 ± 46.1 months, while in 31.4%, it followed diagnosis of MCD by 12.4 ± 22.6 months. In 27.9%, the neoplasm and kidney disease were diagnosed simultaneously. Immunosuppressive therapy was started in 79.1% of cases and tumor-specific treatment in 83.7%. Remission of MCD was achieved in 80.2% of patients: 38.2% responded to immunosuppressive treatment alone and 29.6% to oncological treatment alone. CONCLUSIONS: The association between MCD and solid neoplasms is well-documented. Immunosuppressive therapy alone induced nephrotic syndrome remission in over one-third of cases; most others responded to tumor-specific treatment. Solid tumor screening should be considered in MCD independently of the steroid response, though more data on solid tumor-associated MCD prevalence are needed for a definitive statement. PROSPERO TRIAL REGISTRATION NUMBER: CRD42024521854.

9.
J Fungi (Basel) ; 10(9)2024 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-39330398

RESUMEN

Vulvovaginal candidiasis (VVC) affects up to 75% of women at least once during their lifetime, and up to 8% of women suffer from frequent recurrent episodes of VVC (RVVC). A lack of a protective host response underlies vaginal Candida infections, while a dysregulated hyperinflammatory response may drive RVVC. This study aimed to investigate the systemic inflammatory protein profile in women with RVVC in an African population, considering the potential influence of hormonal contraceptive use on systemic inflammation. Using multiplex Proximity Extension Assay technology, we measured 92 circulatory inflammatory proteins in plasma samples from 158 RVVC patients and 92 asymptomatic women (controls). Hormonal contraceptive use was not found to have a statistically significant correlation with a systemic inflammatory protein profile in either RVVC patients or the asymptomatic women. RVVC women had lower circulating Fibroblast Growth Factor 21 (FGF-21) concentrations compared with healthy controls (adjusted p value = 0.028). Reduced concentrations of FGF-21 may be linked to the immune pathology observed in RVVC cases through IL-1ß. This study may help to identify new biomarkers for the diagnosis and future development of novel immunomodulatory treatments for RVVC.

10.
iScience ; 27(4): 109356, 2024 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-38510149

RESUMEN

Familial Mediterranean fever (FMF) is a periodic fever syndrome caused by variation in MEFV. FMF is known for IL-1ß dysregulation, but the innate immune landscape of this disease has not been comprehensively described. Therefore, we studied circulating inflammatory proteins, and the function of monocytes and (albeit less extensively) neutrophils in treated FMF patients in remission. We found that monocyte IL-1ß and IL-6 production was enhanced upon stimulation, in concordance with alterations in the plasma inflammatory proteome. We did not observe changes in neutrophil functional assays. Subtle differences in chromatin accessibility and transcriptomics in our small patient cohort further argued for monocyte dysregulation. Together, these observations suggest that the MEFV-mutation-mediated primary immune dysregulation in monocytes leads to chronic inflammation that is subsequently associated with counterregulatory epigenetic/transcriptional changes reminiscent of tolerance. These data increase our understanding of the innate immune changes in FMF, aiding future management of chronic inflammation in these patients.

11.
Chem Sci ; 14(27): 7559-7563, 2023 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-37449061

RESUMEN

Candida auris (C. auris) is an emerging multidrug-resistant fungal pathogen that represents a significant public health challenge as it can spread rapidly and result in high mortality rates. The mannans on the C. auris cell surface are potent immunogens and attractive targets for developing a glycoconjugate vaccine. We synthesized the oligosaccharides resembling cell surface mannans of C. auris and printed them onto microarray slides that were used to screen plasma from mice infected with C. auris. IgM antibodies in mouse plasma recognize the ß-1,2 linkage present in C. auris surface mannans. Disaccharide 19 emerged from glycan array screening as a lead for developing a vaccine against C. auris, as the majority of patient plasma samples showed antibodies against this glycan. The synthetic oligosaccharides can be used for the early detection of C. auris infections.

12.
Cell Host Microbe ; 31(11): 1776-1791, 2023 11 08.
Artículo en Inglés | MEDLINE | ID: mdl-37944491

RESUMEN

Trained immunity is a de facto memory for innate immune responses, leading to long-term functional reprogramming of innate immune cells. In physiological conditions, trained immunity leads to adaptive states that enhance resistance against pathogens and contributes to immunosurveillance. Dysregulated trained immunity can however lead either to defective innate immune responses in severe infections or cancer or to inflammatory and autoimmune diseases if trained immunity is inappropriately activated. Here, we review the immunological and molecular mechanisms that mediate trained immunity induction and propose that trained immunity represents an important target for prophylactic and therapeutic approaches in human diseases. On the one hand, we argue that novel approaches that induce trained immunity may enhance vaccine efficacy. On the other hand, induction of trained immunity in cancer, and inhibition of exaggerated induction of trained immunity in inflammatory disorders, are viable targets amenable for new therapeutic approaches.


Asunto(s)
Enfermedades Autoinmunes , Neoplasias , Humanos , Memoria Inmunológica , Inmunidad Entrenada , Inmunidad Innata , Enfermedades Autoinmunes/terapia , Neoplasias/terapia , Inmunidad Adaptativa
13.
Cell Rep ; 42(6): 112658, 2023 06 27.
Artículo en Inglés | MEDLINE | ID: mdl-37330914

RESUMEN

Itaconate is an immunomodulatory metabolite produced by immune cells under microbial stimulation and certain pro-inflammatory conditions and triggers antioxidant and anti-inflammatory responses. We show that dimethyl itaconate, a derivative of itaconate previously linked to suppression of inflammation and widely employed as an alternative to the endogenous metabolite, can induce long-term transcriptional, epigenomic, and metabolic changes, characteristic of trained immunity. Dimethyl itaconate alters glycolytic and mitochondrial energetic metabolism, ultimately leading to increased responsiveness to microbial ligand stimulation. Subsequently, mice treated with dimethyl itaconate present increased survival to infection with Staphylococcus aureus. Additionally, itaconate levels in human plasma correlate with enhanced ex vivo pro-inflammatory cytokine production. Collectively, these findings demonstrate that dimethyl itaconate displays short-term anti-inflammatory characteristics and the capacity to induce long-term trained immunity. This pro-and anti-inflammatory dichotomy of dimethyl itaconate is likely to induce complex immune responses and should be contemplated when considering itaconate derivatives in a therapeutic context.


Asunto(s)
Inmunidad Innata , Macrófagos , Ratones , Humanos , Animales , Macrófagos/metabolismo , Antiinflamatorios/metabolismo
14.
J Invest Dermatol ; 142(11): 2929-2939.e8, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35662644

RESUMEN

Biologics that block the T helper (Th) 17 pathway are very effective in the treatment of psoriasis and other inflammatory diseases. However, IL-17 is also crucial for antifungal host defense, and clinical trial data suggest an increase in the incidence of Candida infections during IL-17 inhibitor (IL-17i) therapy. We investigated the innate and adaptive immune responses of patients with psoriasis with a history of skin and/or mucosal candidiasis during IL-17i or IL-12/23 inhibitor therapy, comparing those responses with those of healthy controls. Patients with psoriasis with IL-17i showed significantly lower CD4+Th1-like (CCR6‒CXCR3+CCR4‒) and Th1 Th17-like (CD4+CCR6+CXCR3+CCR4‒) cell percentages. Patient cells stimulated with Candida albicans produced significantly lower IL-6 in the IL-12/23 inhibitor group and IL-1ß in the IL-17i group, whereas the release of TNF-α and ROS was similar between patients and controls. IFN-γ and IL-10 production in response to several stimuli after 7 days was particularly decreased in patients receiving IL-17i therapy. Finally, after stimulation with the polarizing cytokines IL-1ß and IL-23, the Th17 cytokine response was significantly lower in the IL-17i patient group. These innate and adaptive immune response defects can diminish antifungal host immune response and thereby increase susceptibility to candidiasis in patients treated with IL-17i or IL-12/23 inhibitor.


Asunto(s)
Productos Biológicos , Candidiasis , Psoriasis , Humanos , Factor de Necrosis Tumoral alfa , Interleucina-6 , Antifúngicos/uso terapéutico , Interleucina-10 , Especies Reactivas de Oxígeno , Candidiasis/tratamiento farmacológico , Psoriasis/tratamiento farmacológico , Citocinas , Interleucina-23 , Interleucina-12 , Productos Biológicos/uso terapéutico
15.
Lancet Reg Health Eur ; 13: 100266, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34950923

RESUMEN

BACKGROUND: Biologics directed against the T-helper (Th)-17 pathway have been approved for several inflammatory diseases. Interleukin (IL)-17 is involved in anti- Candida host defense, and clinical trials suggested increased candidiasis incidence during IL-17 inhibitor therapy. We describe the worldwide epidemiology of candidiasis during Th17 inhibitor therapy, and immunological mechanisms involved in candidiasis susceptibility. METHODS: A comprehensive analysis of multiple independent sources reporting Candida adverse events during biologics inhibiting the Th17 pathway was performed. Association between Th17 inhibitors and candidiasis was assessed using safety reports of (1) WHO and (2) EMA, (3) a population-based prescriptions registry, and (4) a psoriasis cohort. In a cohort of psoriasis patients experiencing candidiasis during Th17 inhibitors, Candida killing by immune cells and serum inflammatory proteome were analyzed. FINDINGS: A strong association between IL-17 inhibitors and candidiasis (ROR 10·20) was found in the WHO database, particularly for cutaneous (ROR 12·28), oropharyngeal (ROR 19·18), and esophageal candidiasis (ROR 21·20). Risk was higher relative to TNF-α inhibitors (4-10-fold, depending on candidiasis type), confirmed by EMA reports (16-33-fold), prescriptions registry (2-42-fold), and a psoriasis cohort (3-25-fold). After start of IL-17 inhibitors, patients' risk of candidiasis requiring antifungals increased 2-16 fold. In the psoriasis cohort, 58% of IL-17 treatment episodes were associated with candidiasis. In Th17 inhibitor recipients, proteins involved in anti- Candida immunity and Candida killing by mononuclear leukocytes were impaired. INTERPRETATION: IL-17 inhibitors are associated with an increased risk of oropharyngeal, esophageal, and cutaneous candidiasis, posing a significant disease burden for IL-17 inhibitor recipients. FUNDING: RadboudUMC.

16.
Data Brief ; 35: 106928, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33850980

RESUMEN

Using a comparative RNA-Sequencing based transcriptional profiling approach, responses of primary human peripheral blood mononuclear cells (PBMCs) to common human pathogenic fungi have been characterized (Bruno et al. Computational and Structural Biology Journal). Primary human PBMCs were stimulated in vitro with the fungi A. fumigatus, C. albicans, and R. oryzae after which RNA was isolated and sequenced. From raw sequencing reads differential expressed genes in response to the different fungi where calculated by comparison with unstimulated cells. By overlapping differentially expressed genes in response to the pathogenic fungi A. fumigatus, C. albicans, and R. oryzae a dataset was generated that encompasses a common response to these three distinct fungi as well as species-specific responses. Here we present datasets on these common and species-specific responses that complement the original study (Bruno et al. Computational and Structural Biology Journal). These data serve to facilitate further fundamental research on the immune response to opportunistic pathogenic fungi such as A. fumigatus, C. albicans, and R. oryzae.

17.
Curr Opin Microbiol ; 62: 21-27, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34034082

RESUMEN

The occurrence of invasive pulmonary aspergillosis (IPA) in critically ill patients with viral pneumonitis has increasingly been reported in recent years. Influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) are the two most common forms of this fungal infection. These diseases cause high mortality in patients, most of whom were previously immunocompetent. The pathogenesis of IAPA and CAPA is still not fully understood, but involves viral, fungal and host factors. In this article, we discuss several aspects regarding IAPA and CAPA, including their possible pathogenesis, the use of immunotherapy, and future challenges.


Asunto(s)
COVID-19/complicaciones , Gripe Humana/complicaciones , Aspergilosis Pulmonar Invasiva/etiología , Neumonía Viral/complicaciones , COVID-19/inmunología , Enfermedad Crítica , Humanos , Inmunoterapia , Gripe Humana/inmunología , Aspergilosis Pulmonar Invasiva/inmunología , Aspergilosis Pulmonar Invasiva/patología , Aspergilosis Pulmonar Invasiva/terapia , Neumonía Viral/inmunología
18.
Comput Struct Biotechnol J ; 19: 647-663, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33510868

RESUMEN

Candidiasis, aspergillosis, and mucormycosis cause the majority of nosocomial fungal infections in immunocompromised patients. Using an unbiased transcriptional profiling in PBMCs exposed to the fungal species causing these infections, we found a core host response in healthy individuals that may govern effective fungal clearance: it consists of 156 transcripts, involving canonical and non-canonical immune pathways. Systematic investigation of key steps in antifungal host defense revealed fungal-specific signatures. As previously demonstrated, Candida albicans induced type I and Type II interferon-related pathways. In contrast, central pattern recognition receptor, reactive oxygen species production, and host glycolytic pathways were down-regulated in response to Rhizopus oryzae, which was associated with an ER-stress response. TLR5 was identified to be uniquely regulated by Aspergillus fumigatus and to control cytokine release in response to this fungus. In conclusion, our data reveals the transcriptional profiles induced by C. albicans, A. fumigatus, and R. oryzae, and describes both the common and specific antifungal host responses that could be exploited for novel therapeutic strategies.

19.
Clin Transl Immunology ; 10(2): e1253, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33708384

RESUMEN

OBJECTIVES: Histone methyltransferase G9a, also known as Euchromatic Histone Lysine Methyltransferase 2 (EHMT2), mediates H3K9 methylation which is associated with transcriptional repression. It possesses immunomodulatory effects and is overexpressed in multiple types of cancer. In this study, we investigated the role of G9a in the induction of trained immunity, a de facto innate immune memory, and its effects in non-muscle-invasive bladder cancer (NMIBC) patients treated with intravesical Bacillus Calmette-Guérin (BCG). METHODS: EHMT2 expression was assessed upon induction of trained immunity by RNA sequencing and Western blotting. G9a inhibitor BIX-01294 was used to investigate the effect on trained immunity responses in vitro. Subsequent cytokine production was measured by ELISA, epigenetic modifications were measured by ChIP-qPCR, Seahorse technology was used to measure metabolic changes, and a luminescence assay was used to measure ROS release. RNA sequencing was performed on BIX-01294-treated monocytes ex vivo. RESULTS: The expression of EHMT2 mRNA and protein decreased in monocytes during induction of trained immunity. G9a inhibition by BIX-01294 induced trained immunity and amplified trained immunity responses evoked by various microbial ligands in vitro. This was accompanied by decreased H3K9me2 at the promoters of pro-inflammatory genes. G9a inhibition was also associated with amplified ex vivo trained immunity responses in circulating monocytes of NMIBC patients. Additionally, altered RNA expression of inflammatory genes in monocytes of NMIBC patients was observed upon ex vivo G9a inhibition. Furthermore, intravesical BCG therapy decreased H3K9me2 at the promoter of pro-inflammatory genes. CONCLUSION: Inhibition of G9a is important in the induction of trained immunity, and G9a may represent a novel therapeutic target in NMIBC patients.

20.
STAR Protoc ; 2(1): 100365, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33718890

RESUMEN

A growing number of studies show that innate immune cells can undergo functional reprogramming, facilitating a faster and enhanced response to heterologous secondary stimuli. This concept has been termed "trained immunity." We outline here a protocol to recapitulate this in vitro using adherent monocytes from consecutive isolation of peripheral blood mononuclear cells. The induction of trained immunity and the associated functional reprogramming of monocytes is described in detail using ß-glucan (from Candida albicans) and Bacillus Calmette-Guérin as examples. For complete details on the use and execution of this protocol, please refer to Repnik et al. (2003) and Bekkering et al. (2016).


Asunto(s)
Técnicas de Reprogramación Celular/métodos , Inmunidad Innata/inmunología , Reprogramación Celular/fisiología , Citocinas/inmunología , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/fisiología , Monocitos/fisiología , Mycobacterium bovis/fisiología , beta-Glucanos/farmacología
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