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3.
4.
Open Forum Infect Dis ; 6(12): ofz484, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31807607

RESUMO

Objective: Although disseminated nontuberculous mycobacterial infection is attributed to defects in the interleukin (IL)-12/interferon-γ circuit, the immunophenotype of idiopathic pulmonary nontuberculous mycobacterial (PNTM) disease is not well defined. Method: We phenotyped Th1, Th2, Th17, and Treg cytokines and colony-stimulating factor production from patients with idiopathic PNTM disease. Data were compared with healthy donors, cystic fibrosis (CF), and primary ciliary dyskinesia (PCD) patients with PNTM disease. Both supernatant cytokine production and intracellular cytokines expressed by various leukocyte subpopulations following mitogen and antigen stimulation were assayed by electrochemiluminescence-based multiplex immunoassay and flow cytometry, respectively. Results: Regardless of antigen or mitogen stimulation, neither intracellular nor extracellular Th1, Th2, and Treg cytokine levels differed between patients and controls. Th17 cells and IL-17A levels were lower in idiopathic PNTM patients, whereas monocyte granulocyte-macrophage colony-stimulating factor (GM-CSF) expression in response to NTM stimulation was higher compared with healthy donors. Besides, distinct cytokine responses following stimulation by Mycobacterium abscessus and Mycobacterium avium were observed consistently within each group. Conclusions: The IL-12/IFN-γ circuit appeared intact in patients with idiopathic PNTM disease. However, idiopathic PNTM patients had reduced Th17 response and higher mycobacteria-induced monocyte GM-CSF expression.

5.
J Neuroinflammation ; 16(1): 276, 2019 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-31883529

RESUMO

BACKGROUND: Lysosomal storage diseases (LSD) are a large family of inherited disorders characterized by abnormal endolysosomal accumulation of cellular material due to catabolic enzyme and transporter deficiencies. Depending on the affected metabolic pathway, LSD manifest with somatic or central nervous system (CNS) signs and symptoms. Neuroinflammation is a hallmark feature of LSD with CNS involvement such as mucolipidosis type IV, but not of others like Fabry disease. METHODS: We investigated the properties of microglia from LSD with and without major CNS involvement in 2-month-old mucolipidosis type IV (Mcoln1-/-) and Fabry disease (Glay/-) mice, respectively, by using a combination of flow cytometric, RNA sequencing, biochemical, in vitro and immunofluorescence analyses. RESULTS: We characterized microglia activation and transcriptome from mucolipidosis type IV and Fabry disease mice to determine if impaired lysosomal function is sufficient to prime these brain-resident immune cells. Consistent with the neurological pathology observed in mucolipidosis type IV, Mcoln1-/- microglia demonstrated an activation profile with a mixed neuroprotective/neurotoxic expression pattern similar to the one we previously observed in Niemann-Pick disease, type C1, another LSD with significant CNS involvement. In contrast, the Fabry disease microglia transcriptome revealed minimal alterations, consistent with the relative lack of CNS symptoms in this disease. The changes observed in Mcoln1-/- microglia showed significant overlap with alterations previously reported for other common neuroinflammatory disorders including Alzheimer's, Parkinson's, and Huntington's diseases. Indeed, our comparison of microglia transcriptomes from Alzheimer's disease, amyotrophic lateral sclerosis, Niemann-Pick disease, type C1 and mucolipidosis type IV mouse models showed an enrichment in "disease-associated microglia" pattern among these diseases. CONCLUSIONS: The similarities in microglial transcriptomes and features of neuroinflammation and microglial activation in rare monogenic disorders where the primary metabolic disturbance is known may provide novel insights into the immunopathogenesis of other more common neuroinflammatory disorders. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01067742, registered on February 12, 2010.

6.
PLoS One ; 14(10): e0223919, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31671151

RESUMO

Three isoforms of nitric oxide synthase (NOS) occur in mammals. High levels of NO produced by NOS2/iNOS can protect against bacterial and parasitic infections, but the role of NOS in fungal innate immunity is less clear. Compared to wild type mice, Nos3-/- mice showed significantly higher survival of candidemia caused by Candida albicans SC5314. NOS3/eNOS is expressed by endothelial cells in the kidney, and colonization of this organ was decreased during the sub-acute stage of disseminated candidiasis. Nos3-/- mice more rapidly eliminated Candida from the renal cortex and exhibited more balanced local inflammatory reactions, with similar macrophage but less neutrophil infiltration than in infected wild type. Levels of the serum cytokines IL-9, IL-12, IL-17 and chemokines GM-CSF, MIP1α, and MIP1ß were significantly elevated, and IL-15 was significantly lower in infected Nos3-/- mice. Spleens of infected Nos3-/- mice had significantly more Th2 and Th9 but not other CD4+ T cells compared with wild type. Inflammatory genes associated with leukocyte chemotaxis, IL-1 signaling, TLR signaling and Th1 and Th2 cell differentiation pathways were significantly overexpressed in infected Nos3-/- kidneys, with Nos2 being the most strongly induced. Conversely, the general NOS inhibitor NG-nitro-L-arginine methyl ester increased virulence in the mouse candidemia model, suggesting that iNOS contributes to the protective mechanism in infected Nos3-/- mice. By moderating neutrophil infiltration, the absence of eNOS may reduce the collateral damage to kidney cortex, and Th-9 CD4+ cells may enhance clearance of the infection. These data suggest that selective eNOS inhibition could mitigate candidemia by a combination of systemic and local responses that promote a more effective host immune response.

7.
Curr Opin Infect Dis ; 32(6): 531-537, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31567735

RESUMO

PURPOSE OF REVIEW: Invasive fungal infections (IFIs) most often occur secondary to acquired immunodeficiency states such as transplantation, AIDS or immune-modulatory treatment for neoplastic and autoimmune disorders. Apart from these acquired conditions, several primary immunodeficiency disorders (PIDs) can present with IFIs in the absence of iatrogenic immunosuppression. This review highlights recent advances in our understanding of PIDs that cause IFIs, which may help clinicians in the diagnosis and management of such infections. RECENT FINDINGS: A growing number of PIDs that cause varying combinations of invasive infections by commensal Candida, inhaled molds (primarily Aspergillus), Cryptococcus, Pneumocystis, endemic dimorphic fungi, dermatophytes, and/or agents of phaeohyphomycosis has uncovered the organ- and fungus-specific requirements for effective antifungal host defense in humans. Employing certain diagnostic algorithms tailored to the infecting fungus can facilitate the genetic diagnosis of the underlying PID, which has implications for the optimal management of affected patients. SUMMARY: Heightened clinical suspicion is required for the diagnosis of underlying genetic defects in patients who develop IFIs in the absence of acquired immunodeficiency. Early initiation of antifungal therapy followed by long-term secondary prophylaxis is typically needed to achieve remission, but hematopoietic stem-cell transplantation may sometimes be necessary to promote immune restoration and infection control.

8.
Curr Fungal Infect Rep ; 13(3): 86-98, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31555394

RESUMO

Purpose of review: Small molecule kinase inhibitors (SMKIs) have revolutionized the management of malignant and autoimmune disorders. Emerging clinical reports point toward an increased risk for invasive fungal infections (IFIs) in patients treated with certain SMKIs. In this mini-review, we highlight representative examples of SMKIs that have been associated with or are expected to give rise to IFIs. Recent findings: The clinical use of the Bruton's tyrosine kinase inhibitor ibrutinib as well as other FDA-approved SMKIs has been associated with IFIs. The fungal infection susceptibility associated with the clinical use of certain SMKIs underscores their detrimental effects on innate and adaptive antifungal immune responses. Summary: The unprecedented development and clinical use of SMKIs is expected to give rise to an expansion of iatrogenic immunosuppressive factors predisposing to IFIs (and other opportunistic infections). Beyond increased clinical surveillance, better understanding of the pathogenesis of SMKI-associated immune dysregulation should help devising improved risk stratification and prophylaxis strategies in vulnerable patients.

9.
Trends Mol Med ; 25(12): 1080-1093, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31494023

RESUMO

The mammalian immune system has evolved the capacity to detect and destroy tumor cells. Tumors utilize multiple strategies to evade host immune surveillance, including the induction of the checkpoint molecules cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) to suppress antitumor immunity. Pharmacologic blockade of these molecules with checkpoint inhibitors (CPIs) restores T cell function and prolongs survival in patients with various malignancies. Emerging evidence suggests that the same checkpoint pathways may play a crucial role during infections. Indeed, CPIs appear promising as immunotherapeutic agents in infectious diseases, although their efficacy varies depending on pathogen-, cell-, and organ-specific factors. More research will be necessary to clarify the effects and safety of CPIs on clinically relevant outcomes of human infection.

10.
J Infect Dis ; 220(9): 1477-1488, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31401652

RESUMO

BACKGROUND: Candidalysin is a cytolytic peptide toxin secreted by Candida albicans hyphae and has significantly advanced our understanding of fungal pathogenesis. Candidalysin is critical for mucosal C albicans infections and is known to activate epithelial cells to induce downstream innate immune responses that are associated with protection or immunopathology during oral or vaginal infections. Furthermore, candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes. However, the role of candidalysin in driving systemic infections is unknown. METHODS: In this study, using candidalysin-producing and candidalysin-deficient C albicans strains, we show that candidalysin activates mitogen-activated protein kinase (MAPK) signaling and chemokine secretion in endothelial cells in vitro. RESULTS: Candidalysin induces immune activation and neutrophil recruitment in vivo, and it promotes mortality in zebrafish and murine models of systemic fungal infection. CONCLUSIONS: The data demonstrate a key role for candidalysin in neutrophil recruitment and fungal virulence during disseminated systemic C albicans infections.

11.
Open Forum Infect Dis ; 6(2): ofz031, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31312664

RESUMO

The tolerability of long-term posaconazole use remains poorly defined. We present a patient who developed peripheral neuropathy following long-term exposure to the tablet formulation of posaconazole, which was treated with methylprednisolone and magnesium infusions. The potential role of methylprednisolone and magnesium infusions in managing this potentially irreversible triazole-associated complication requires further study.

12.
Cell Rep ; 28(2): 423-433.e5, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31291578

RESUMO

During oropharyngeal candidiasis (OPC), Candida albicans proliferates and invades the superficial oral epithelium. Ephrin type-A receptor 2 (EphA2) functions as an oral epithelial cell ß-glucan receptor that triggers the production of proinflammatory mediators in response to fungal infection. Because EphA2 is also expressed by neutrophils, we investigated its role in neutrophil candidacidal activity during OPC. We found that EphA2 on stromal cells is required for the accumulation of phagocytes in the oral mucosa of mice with OPC. EphA2 on neutrophils is also central to host defense against OPC. The interaction of neutrophil EphA2 with serum-opsonized C. albicans yeast activates the MEK-ERK signaling pathway, leading to NADPH subunit p47phox site-specific phospho-priming. This priming increases intracellular reactive oxygen species production and enhances fungal killing. Thus, in neutrophils, EphA2 serves as a receptor for ß-glucans that augments Fcγ receptor-mediated antifungal activity and controls early fungal proliferation during OPC.

13.
Sci Transl Med ; 11(495)2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31167928

RESUMO

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic disorder caused by AIRE mutations, presents with several autoimmune diseases. Among these, endocrine organ failure is widely recognized, but the prevalence, immunopathogenesis, and treatment of non-endocrine manifestations such as pneumonitis remain poorly characterized. We enrolled 50 patients with APECED in a prospective observational study and comprehensively examined their clinical and radiographic findings, performed pulmonary function tests, and analyzed immunological characteristics in blood, bronchoalveolar lavage fluid, and endobronchial and lung biopsies. Pneumonitis was found in >40% of our patients, presented early in life, was misdiagnosed despite chronic respiratory symptoms and accompanying radiographic and pulmonary function abnormalities, and caused hypoxemic respiratory failure and death. Autoantibodies against BPIFB1 and KCNRG and the homozygous c.967_979del13 AIRE mutation are associated with pneumonitis development. APECED pneumonitis features compartmentalized immunopathology, with accumulation of activated neutrophils in the airways and lymphocytic infiltration in intraepithelial, submucosal, peribronchiolar, and interstitial areas. Beyond APECED, we extend these observations to lung disease seen in other conditions with secondary AIRE deficiency (thymoma and RAG deficiency). Aire-deficient mice had similar compartmentalized cellular immune responses in the airways and lung tissue, which was ameliorated by deficiency of T and B lymphocytes. Accordingly, T and B lymphocyte-directed immunomodulation controlled symptoms and radiographic abnormalities and improved pulmonary function in patients with APECED pneumonitis. Collectively, our findings unveil lung autoimmunity as a common, early, and unrecognized manifestation of APECED and provide insights into the immunopathogenesis and treatment of pulmonary autoimmunity associated with impaired central immune tolerance.

14.
Nat Immunol ; 20(5): 559-570, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30996332

RESUMO

The C-type lectin receptor-Syk (spleen tyrosine kinase) adaptor CARD9 facilitates protective antifungal immunity within the central nervous system (CNS), as human deficiency in CARD9 causes susceptibility to fungus-specific, CNS-targeted infection. CARD9 promotes the recruitment of neutrophils to the fungus-infected CNS, which mediates fungal clearance. In the present study we investigated host and pathogen factors that promote protective neutrophil recruitment during invasion of the CNS by Candida albicans. The cytokine IL-1ß served an essential function in CNS antifungal immunity by driving production of the chemokine CXCL1, which recruited neutrophils expressing the chemokine receptor CXCR2. Neutrophil-recruiting production of IL-1ß and CXCL1 was induced in microglia by the fungus-secreted toxin Candidalysin, in a manner dependent on the kinase p38 and the transcription factor c-Fos. Notably, microglia relied on CARD9 for production of IL-1ß, via both transcriptional regulation of Il1b and inflammasome activation, and of CXCL1 in the fungus-infected CNS. Microglia-specific Card9 deletion impaired the production of IL-1ß and CXCL1 and neutrophil recruitment, and increased fungal proliferation in the CNS. Thus, an intricate network of host-pathogen interactions promotes antifungal immunity in the CNS; this is impaired in human deficiency in CARD9, which leads to fungal disease of the CNS.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/imunologia , Candidíase/imunologia , Quimiocina CXCL1/imunologia , Interleucina-1beta/imunologia , Microglia/imunologia , Neutrófilos/imunologia , Animais , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/microbiologia , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Candida albicans/imunologia , Candida albicans/fisiologia , Candidíase/genética , Candidíase/microbiologia , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Inflamassomos/genética , Inflamassomos/imunologia , Inflamassomos/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Microglia/metabolismo , Microglia/microbiologia , Infiltração de Neutrófilos/genética , Infiltração de Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/microbiologia
15.
Sci Immunol ; 4(34)2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30979797

RESUMO

Autoimmune regulator (AIRE) mutations result in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome characterized by defective central T cell tolerance and the production of many autoantibodies targeting tissue-specific antigens and cytokines. By studying CD3- and AIRE-deficient patients, we found that lack of either T cells or AIRE function resulted in the peripheral accumulation of autoreactive mature naïve B cells. Proteomic arrays and Biacore affinity measurements revealed that unmutated antibodies expressed by these autoreactive naïve B cells recognized soluble molecules and cytokines including insulin, IL-17A, and IL-17F, which are AIRE-dependent thymic peripheral tissue antigens targeted by autoimmune responses in APECED. AIRE-deficient patients also displayed decreased frequencies of regulatory T cells (Tregs) that lacked common TCRß clones found instead in their conventional T cell compartment, thereby suggesting holes in the Treg TCR repertoire of these patients. Hence, AIRE-mediated T cell/Treg selection normally prevents the expansion of autoreactive naïve B cells recognizing peripheral self-antigens.

16.
Pediatr Blood Cancer ; 66(7): e27732, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30900813

RESUMO

Invasive fusariosis (IF) most commonly occurs in patients with hematologic malignancies and severe neutropenia, particularly during concomitant corticosteroid use. Breakthrough infections can occur in high-risk patients despite Aspergillus-active antifungal prophylaxis. We describe a patient with rapid acute lymphoblastic leukemia (ALL) progression who presented with multifocal skin nodules thought to be choloromatous disease. These lesions were ultimately diagnosed as IF and the patient had two simultaneously active disease processes. This case highlights the importance of pathologic diagnosis of new skin lesions in ALL patients, even during leukemia progression, and demonstrates that IF can occur despite normal neutrophil counts and Aspergillus-active prophylaxis.


Assuntos
Fusariose/microbiologia , Fusariose/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/microbiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Adulto , Fusariose/terapia , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia
17.
Methods Mol Biol ; 1952: 219-232, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30825178

RESUMO

Matrigel is extracted from the Engelbreth-Holm-Swarm (EHS) mouse sarcoma in C57BL/6 mice, a tumor rich in extracellular matrix (ECM) proteins. It consists mainly of laminin (approximately 60%), collagen IV (approximately 30%), and nidogen-1/entactin (approximately 8%), while it also contains heparan sulfate proteoglycans, such as perlecan, other ECM proteins, as well as growth factors bound to the ECM. Matrigel mimics the physiological cell matrix and is the most commonly used matrix substrate to study in vitro and in vivo angiogenesis. Here, we describe the in vivo Matrigel plug assay and how it can be used for both qualitative and quantitative assessment of angiogenesis.


Assuntos
Colágeno/química , Células Endoteliais/citologia , Laminina/química , Glicoproteínas de Membrana/química , Neovascularização Fisiológica , Proteoglicanas/química , Animais , Separação Celular/métodos , Combinação de Medicamentos , Citometria de Fluxo/métodos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência/métodos , Microtomia/métodos , Inclusão em Parafina/métodos , Coloração e Rotulagem/métodos
18.
Cell Host Microbe ; 25(3): 347-349, 2019 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-30870617

RESUMO

Candida albicans is a commensal fungus of the human gut, but also causes life-threatening systemic infections. Recent studies published in Cell Host & Microbe (Witchley et al., 2019) and Science (Tso et al., 2018) provide insights into the determinants of C. albicans commensal fitness within the mammalian gut.


Assuntos
Candidíase/microbiologia , Animais , Candida albicans , Humanos , Mamíferos , Simbiose
19.
Blood ; 133(18): 1977-1988, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30723080

RESUMO

Ras-related C3 botulinum toxin substrate 2 (RAC2), through interactions with reduced NAD phosphate oxidase component p67 phox , activates neutrophil superoxide production, whereas interactions with p21-activated kinase are necessary for fMLF-induced actin remodeling. We identified 3 patients with de novo RAC2[E62K] mutations resulting in severe T- and B-cell lymphopenia, myeloid dysfunction, and recurrent respiratory infections. Neutrophils from RAC2[E62K] patients exhibited excessive superoxide production, impaired fMLF-directed chemotaxis, and abnormal macropinocytosis. Cell lines transfected with RAC2[E62K] displayed characteristics of active guanosine triphosphate (GTP)-bound RAC2 including enhanced superoxide production and increased membrane ruffling. Biochemical studies demonstrated that RAC2[E62K] retains intrinsic GTP hydrolysis; however, GTPase-activating protein failed to accelerate hydrolysis resulting in prolonged active GTP-bound RAC2. Rac2+/E62K mice phenocopy the T- and B-cell lymphopenia, increased neutrophil F-actin, and excessive superoxide production seen in patients. This gain-of-function mutation highlights a specific, nonredundant role for RAC2 in hematopoietic cells that discriminates RAC2 from the related, ubiquitous RAC1.


Assuntos
Síndromes de Imunodeficiência/genética , Proteínas rac de Ligação ao GTP/genética , Adolescente , Adulto , Animais , Pré-Escolar , Citoesqueleto/patologia , Feminino , Mutação com Ganho de Função , Humanos , Lactente , Recém-Nascido , Linfopenia/genética , Camundongos , Camundongos Endogâmicos C57BL , Linhagem , Proteínas rac de Ligação ao GTP/imunologia
20.
Semin Cell Dev Biol ; 89: 78-90, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-29366628

RESUMO

Fungal infections remain a significant global health problem in humans. Fungi infect millions of people worldwide and cause from acute superficial infections to life-threatening systemic disease to chronic illnesses. Trying to decipher the complex innate and adaptive immune mechanisms that protect humans from pathogenic fungi is therefore a key research goal that may lead to immune-based therapeutic strategies and improved patient outcomes. In this review, we summarize how the cells and molecules of the innate immune system activate the adaptive immune system to elicit long-term immunity to fungi. We present current knowledge and exciting new advances in the context of organ-specific immunity, outlining the tissue-specific tropisms for the major pathogenic fungi of humans, the antifungal functions of tissue-resident myeloid cells, and the adaptive immune responses required to protect specific organs from fungal challenge.

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