RESUMEN
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.
Asunto(s)
Proteínas Adaptadoras de Señalización CARD/inmunología , Candidiasis/inmunología , Quimiocina CXCL1/inmunología , Interleucina-1beta/inmunología , Microglía/inmunología , Neutrófilos/inmunología , Animales , Encéfalo/inmunología , Encéfalo/metabolismo , Encéfalo/microbiología , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Adaptadoras de Señalización CARD/metabolismo , Candida albicans/inmunología , Candida albicans/fisiología , Candidiasis/genética , Candidiasis/microbiología , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Citocinas/genética , Citocinas/inmunología , Citocinas/metabolismo , Interacciones Huésped-Patógeno/inmunología , Inflamasomas/genética , Inflamasomas/inmunología , Inflamasomas/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Ratones Noqueados , Ratones Transgénicos , Microglía/metabolismo , Microglía/microbiología , Infiltración Neutrófila/genética , Infiltración Neutrófila/inmunología , Neutrófilos/metabolismo , Neutrófilos/microbiologíaRESUMEN
Immunity to fungal infections of the central nervous system (CNS) is one of the most poorly understood subjects within the field of medical mycology. Yet, the majority of deaths from invasive fungal infections are caused by brain-tropic fungi. In recent years, there have been several significant discoveries in the regulation of neuroinflammation and the role of the immune system in tissue homeostasis within the CNS. In this review, I highlight five important advances in the neuroimmunology field over the last decade and discuss how we should capitalise on these discoveries to better understand the pathogenesis of fungal CNS infections. In addition, the latest insights into fungal invasion tactics, microglia-astrocyte crosstalk and regulation of antifungal adaptive immune responses are summarised in the context of our contemporary understanding of CNS-specific immunity.
Asunto(s)
Infecciones del Sistema Nervioso Central , Micosis , Humanos , Sistema Nervioso Central , Microglía , InmunidadRESUMEN
Mucosal sites such as the intestine, oral cavity, nasopharynx, and vagina all have associated commensal flora. The surface of the eye is also a mucosal site, but proof of a living, resident ocular microbiome remains elusive. Here, we used a mouse model of ocular surface disease to reveal that commensals were present in the ocular mucosa and had functional immunological consequences. We isolated one such candidate commensal, Corynebacterium mastitidis, and showed that this organism elicited a commensal-specific interleukin-17 response from γδ T cells in the ocular mucosa that was central to local immunity. The commensal-specific response drove neutrophil recruitment and the release of antimicrobials into the tears and protected the eye from pathogenic Candida albicans or Pseudomonas aeruginosa infection. Our findings provide direct evidence that a resident commensal microbiome exists on the ocular surface and identify the cellular mechanisms underlying its effects on ocular immune homeostasis and host defense.
Asunto(s)
Candida albicans/inmunología , Candidiasis/inmunología , Córnea/inmunología , Infecciones por Corynebacterium/inmunología , Corynebacterium/inmunología , Infecciones del Ojo/inmunología , Inmunidad Mucosa , Interleucina-17/metabolismo , Microbiota/inmunología , Neutrófilos/inmunología , Infecciones por Pseudomonas/inmunología , Pseudomonas aeruginosa/inmunología , Linfocitos T/inmunología , Lágrimas/inmunología , Animales , Candidiasis/microbiología , Córnea/microbiología , Infecciones por Corynebacterium/microbiología , Modelos Animales de Enfermedad , Infecciones del Ojo/microbiología , Interacciones Huésped-Patógeno , Humanos , Interleucina-17/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infiltración Neutrófila , Neutrófilos/microbiología , Infecciones por Pseudomonas/microbiología , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismoRESUMEN
Candida albicans is a dimorphic fungus responsible for chronic mucocutaneous and systemic infections. Mucocutaneous immunity to C. albicans requires T helper 17 (Th17) cell differentiation that is thought to depend on recognition of filamentous C. albicans. Systemic immunity is considered T cell independent. Using a murine skin infection model, we compared T helper cell responses to yeast and filamentous C. albicans. We found that only yeast induced Th17 cell responses through a mechanism that required Dectin-1-mediated expression of interleukin-6 (IL-6) by Langerhans cells. Filamentous forms induced Th1 without Th17 cell responses due to the absence of Dectin-1 ligation. Notably, Th17 cell responses provided protection against cutaneous infection while Th1 cell responses provided protection against systemic infection. Thus, C. albicans morphology drives distinct T helper cell responses that provide tissue-specific protection. These findings provide insight into compartmentalization of Th cell responses and C. albicans pathogenesis and have critical implications for vaccine strategies.
Asunto(s)
Candidiasis Mucocutánea Crónica/inmunología , Diferenciación Celular/inmunología , Células Dendríticas/inmunología , Células Th17/citología , Células Th17/inmunología , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Candida albicans/inmunología , Candidiasis Mucocutánea Crónica/microbiología , Interleucina-6/biosíntesis , Interleucina-6/genética , Interleucina-6/inmunología , Células de Langerhans/inmunología , Lectinas Tipo C/genética , Lectinas Tipo C/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Represoras/genética , Piel/inmunología , Piel/microbiología , Células TH1/citología , Células TH1/inmunologíaRESUMEN
Patients with liver dysfunction have increased susceptibility to fungal infections. A recently published article (Sun et al.) describes the potential mechanism underlying this association, which maps to the antifungal activity of liver-resident Kupffer cells. This research highlights the importance of understanding tissue-specific immune responses in disease pathogenesis.
Asunto(s)
Macrófagos del Hígado , Hepatopatías , Antifúngicos , Humanos , Inmunidad , HígadoRESUMEN
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.
Asunto(s)
Inmunidad Adaptativa/inmunología , Antifúngicos/uso terapéutico , Inmunidad Innata/inmunología , Micosis/inmunología , Inmunidad Adaptativa/efectos de los fármacos , Antifúngicos/inmunología , Hongos/efectos de los fármacos , Hongos/patogenicidad , Humanos , Inmunidad Innata/efectos de los fármacos , Micosis/tratamiento farmacológico , Micosis/microbiologíaRESUMEN
Niemann-Pick disease, type C1 (NPC1) is a neurodegenerative disorder with limited treatment options. NPC1 is associated with neuroinflammation; however, attempts to therapeutically target neuroinflammation in NPC1 have had mixed success. We show here that NPC1 neuroinflammation is characterized by an atypical microglia activation phenotype. Specifically, Npc1-/- microglia demonstrated altered morphology, reduced levels of lineage markers and a shift toward glycolytic metabolism. Treatment with 2-hydroxypropyl-ß-cyclodextrin (HPßCD), a drug currently being studied in a phase 2b/3 clinical trial, reversed all microglia-associated defects in Npc1-/- animals. In addition, impairing microglia mediated neuroinflammation by genetic deletion of IRF8 led to decreased symptoms and increased lifespan. We identified CD22 as a marker of dysregulated microglia in Npc1 mutant mice and subsequently demonstrated that elevated cerebrospinal fluid levels of CD22 in NPC1 patients responds to HPßCD administration. Collectively, these data provide the first in-depth analysis of microglia function in NPC1 and suggest possible new therapeutic approaches.
Asunto(s)
Inflamación/tratamiento farmacológico , Proteína Niemann-Pick C1/genética , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , Lectina 2 Similar a Ig de Unión al Ácido Siálico/genética , 2-Hidroxipropil-beta-Ciclodextrina/administración & dosificación , Adolescente , Adulto , Animales , Cerebelo/efectos de los fármacos , Cerebelo/patología , Niño , Preescolar , Modelos Animales de Enfermedad , Femenino , Humanos , Lactante , Inflamación/genética , Inflamación/patología , Factores Reguladores del Interferón , Masculino , Ratones , Microglía/efectos de los fármacos , Microglía/patología , Enfermedad de Niemann-Pick Tipo C/líquido cefalorraquídeo , Enfermedad de Niemann-Pick Tipo C/genética , Enfermedad de Niemann-Pick Tipo C/patología , Lectina 2 Similar a Ig de Unión al Ácido Siálico/líquido cefalorraquídeoRESUMEN
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.
Asunto(s)
Candida albicans/inmunología , Candida albicans/metabolismo , Candidiasis Invasiva/microbiología , Candidiasis Invasiva/patología , Proteínas Fúngicas/metabolismo , Infiltración Neutrófila , Factores de Virulencia/metabolismo , Animales , Candida albicans/crecimiento & desarrollo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Células Endoteliales/inmunología , Células Endoteliales/metabolismo , Femenino , Masculino , Ratones Endogámicos BALB C , Transducción de Señal , Análisis de Supervivencia , Virulencia , Pez CebraRESUMEN
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.
Asunto(s)
Microglía/metabolismo , Mucolipidosis/genética , Mucolipidosis/patología , Transcriptoma , Animales , Enfermedad de Fabry/genética , Enfermedad de Fabry/metabolismo , Enfermedad de Fabry/patología , Humanos , Ratones , Ratones Transgénicos , Microglía/patología , Mucolipidosis/metabolismoRESUMEN
UNLABELLED: Pneumonia virus of mice (PVM) is a natural rodent pathogen that replicates in bronchial epithelial cells and reproduces many clinical and pathological features of the more severe forms of disease associated with human respiratory syncytial virus. In order to track virus-target cell interactions during acute infection in vivo, we developed rK2-PVM, bacterial artificial chromosome-based recombinant PVM strain J3666 that incorporates the fluorescent tag monomeric Katushka 2 (mKATE2). The rK2-PVM pathogen promotes lethal infection in BALB/c mice and elicits characteristic cytokine production and leukocyte recruitment to the lung parenchyma. Using recombinant virus, we demonstrate for the first time PVM infection of both dendritic cells (DCs; CD11c(+) major histocompatibility complex class II(+)) and alveolar macrophages (AMs; CD11c(+) sialic acid-binding immunoglobulin-like lectin F(+)) in vivo and likewise detect mKATE2(+) DCs in mediastinal lymph nodes from infected mice. AMs support both active virus replication and production of infectious virions. Furthermore, we report that priming of the respiratory tract with immunobiotic Lactobacillus plantarum, a regimen that results in protection against the lethal inflammatory sequelae of acute respiratory virus infection, resulted in differential recruitment of neutrophils, DCs, and lymphocytes to the lungs in response to rK2-PVM and a reduction from â¼ 40% to <10% mKATE2(+) AMs in association with a 2-log drop in the release of infectious virions. In contrast, AMs from L. plantarum-primed mice challenged with virus ex vivo exhibited no differential susceptibility to rK2-PVM. Although the mechanisms underlying Lactobacillus-mediated viral suppression remain to be fully elucidated, this study provides insight into the cellular basis of this response. IMPORTANCE: Pneumonia virus of mice (PVM) is a natural mouse pathogen that serves as a model for severe human respiratory syncytial virus disease. We have developed a fully functional recombinant PVM strain with a fluorescent reporter protein (rK2-PVM) that permits us to track infection of target cells in vivo. With rK2-PVM, we demonstrate infection of leukocytes in the lung, notably, dendritic cells and alveolar macrophages. Alveolar macrophages undergo productive infection and release infectious virions. We have shown previously that administration of immunobiotic Lactobacillus directly to the respiratory mucosa protects mice from the lethal sequelae of PVM infection in association with profound suppression of the virus-induced inflammatory response. We show here that Lactobacillus administration also limits infection of leukocytes in vivo and results in diminished release of infectious virions from alveolar macrophages. This is the first study to provide insight into the cellular basis of the antiviral impact of immunobiotic L. plantarum.
Asunto(s)
Factores Inmunológicos/administración & dosificación , Lactobacillus plantarum/inmunología , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/virología , Virus de la Neumonía Murina/inmunología , Probióticos/administración & dosificación , Sistema Respiratorio/inmunología , Animales , Células Dendríticas/inmunología , Células Dendríticas/virología , Femenino , Ganglios Linfáticos/inmunología , Ratones Endogámicos BALB CRESUMEN
Candida is the most common human fungal pathogen and causes systemic infections that require neutrophils for effective host defense. Humans deficient in the C-type lectin pathway adaptor protein CARD9 develop spontaneous fungal disease that targets the central nervous system (CNS). However, how CARD9 promotes protective antifungal immunity in the CNS remains unclear. Here, we show that a patient with CARD9 deficiency had impaired neutrophil accumulation and induction of neutrophil-recruiting CXC chemokines in the cerebrospinal fluid despite uncontrolled CNS Candida infection. We phenocopied the human susceptibility in Card9-/- mice, which develop uncontrolled brain candidiasis with diminished neutrophil accumulation. The induction of neutrophil-recruiting CXC chemokines is significantly impaired in infected Card9-/- brains, from both myeloid and resident glial cellular sources, whereas cell-intrinsic neutrophil chemotaxis is Card9-independent. Taken together, our data highlight the critical role of CARD9-dependent neutrophil trafficking into the CNS and provide novel insight into the CNS fungal susceptibility of CARD9-deficient humans.
Asunto(s)
Proteínas Adaptadoras de Señalización CARD/inmunología , Candidiasis/inmunología , Infecciones del Sistema Nervioso Central/inmunología , Síndromes de Inmunodeficiencia/inmunología , Infiltración Neutrófila/inmunología , Animales , Western Blotting , Proteínas Adaptadoras de Señalización CARD/deficiencia , Femenino , Citometría de Flujo , Humanos , Síndromes de Inmunodeficiencia/microbiología , Ratones , Ratones NoqueadosRESUMEN
BACKGROUND: Myeloid inhibitory C-type lectin-like receptor (MICL, Clec12A) is a C-type lectin receptor (CLR) expressed predominantly by myeloid cells. Previous studies have suggested that MICL is involved in controlling inflammation. OBJECTIVE: To determine the role of this CLR in inflammatory pathology using Clec12A(-/-) mice. METHODS: Clec12A(-/-) mice were generated commercially and primarily characterised using the collagen antibody-induced arthritis (CAIA) model. Mechanisms and progress of disease were characterised by clinical scoring, histology, flow cytometry, irradiation bone-marrow chimera generation, administration of blocking antibodies and in vivo imaging. Characterisation of MICL in patients with rheumatoid arthritis (RA) was determined by immunohistochemistry and single nucleotide polymorphism analysis. Anti-MICL antibodies were detected in patient serum by ELISA and dot-blot analysis. RESULTS: MICL-deficient animals did not present with pan-immune dysfunction, but exhibited markedly exacerbated inflammation during CAIA, owing to the inappropriate activation of myeloid cells. Polymorphisms of MICL were not associated with disease in patients with RA, but this CLR was the target of autoantibodies in a subset of patients with RA. In wild-type mice the administration of such antibodies recapitulated the Clec12A(-/-) phenotype. CONCLUSIONS: MICL plays an essential role in regulating inflammation during arthritis and is an autoantigen in a subset of patients with RA. These data suggest an entirely new mechanism underlying RA pathogenesis, whereby the threshold of myeloid cell activation can be modulated by autoantibodies that bind to cell membrane-expressed inhibitory receptors.
Asunto(s)
Artritis Experimental/genética , Artritis Reumatoide/genética , Lectinas Tipo C/fisiología , Receptores Mitogénicos/fisiología , Animales , Artritis Reumatoide/sangre , Artritis Reumatoide/etiología , Artritis Reumatoide/patología , Autoanticuerpos/metabolismo , Ensayo de Inmunoadsorción Enzimática , Humanos , Lectinas Tipo C/deficiencia , Lectinas Tipo C/inmunología , Ratones , Células Mieloides/metabolismo , Polimorfismo Genético , Receptores Mitogénicos/deficiencia , Receptores Mitogénicos/inmunología , Membrana Sinovial/patologíaRESUMEN
The ability of Candida albicans to cause disease is associated with its capacity to undergo morphological transition between yeast and filamentous forms, but the role of morphology in colonization and dissemination from the gastrointestinal (GI) tract remains poorly defined. To explore this, we made use of wild-type and morphological mutants of C. albicans in an established model of GI tract colonization, induced following antibiotic treatment of mice. Our data reveal that GI tract colonization favours the yeast form of C. albicans, that there is constitutive low level systemic dissemination in colonized mice that occurs irrespective of fungal morphology, and that colonization is not controlled by Th17 immunity in otherwise immunocompetent animals. These data provide new insights into the mechanisms of pathogenesis and commensalism of C. albicans, and have implications for our understanding of human disease.
Asunto(s)
Candida albicans/citología , Candida albicans/fisiología , Candidiasis/inmunología , Candidiasis/microbiología , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/microbiología , Células Th17/inmunología , Animales , Candida albicans/crecimiento & desarrollo , Candida albicans/inmunología , Modelos Animales de Enfermedad , RatonesRESUMEN
Candida albicans is the leading cause of systemic candidiasis, a fungal disease associated with high mortality and poor treatment options. The kidney is the target organ during infection and whose control is largely dependent on innate immunity, because lymphocytes appear redundant for protection. In this article, we show that this apparent redundancy stems from a failure of Ag-specific CD4(+) T cells to migrate into infected kidneys. In contrast, Ag-specific CD8(+) T cells are recruited normally. Using Ag-loaded immunoliposomes to artificially reverse this defective migration, we show that recruited Ag-specific CD4(+) T cells polarize toward a Th17 phenotype in the kidney and are protective during fungal infection. Therefore, our data explain the redundancy of CD4(+) T cells for defense against systemic infection with C. albicans and have important implications for our understanding of antifungal immunity and the control of renal infections.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Candida albicans/inmunología , Candidiasis/inmunología , Riñón/inmunología , Células Th17/inmunología , Animales , Antígenos/inmunología , Antígenos/metabolismo , Linfocitos T CD4-Positivos/microbiología , Linfocitos T CD4-Positivos/trasplante , Linfocitos T CD8-positivos/microbiología , Movimiento Celular , Células Cultivadas , Citoprotección , Femenino , Inmunidad Innata , Riñón/microbiología , Liposomas/inmunología , Liposomas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T/genética , Células Th17/microbiologíaRESUMEN
RATIONALE: The clinical features of patients infected with pulmonary nontuberculous mycobacteria (PNTM) are well described, but the genetic components of infection susceptibility are not. OBJECTIVES: To examine genetic variants in patients with PNTM, their unaffected family members, and a control group. METHODS: Whole-exome sequencing was done on 69 white patients with PNTM and 18 of their white unaffected family members. We performed a candidate gene analysis using immune, cystic fibrosis transmembrance conductance regulator (CFTR), cilia, and connective tissue gene sets. The numbers of patients, family members, and control subjects with variants in each category were compared, as was the average number of variants per person. MEASUREMENTS AND MAIN RESULTS: A significantly higher number of patients with PNTM than the other subjects had low-frequency, protein-affecting variants in immune, CFTR, cilia, and connective tissue categories (35, 26, 90, and 90%, respectively). Patients with PNTM also had significantly more cilia and connective tissue variants per person than did control subjects (2.47 and 2.55 compared with 1.38 and 1.40, respectively; P = 1.4 × 10(-6) and P = 2.7 × 10(-8), respectively). Patients with PNTM had an average of 5.26 variants across all categories (1.98 in control subjects; P = 2.8 × 10(-17)), and they were more likely than control subjects to have variants in multiple categories. We observed similar results for family members without PNTM infection, with the exception of the immune category. CONCLUSIONS: Patients with PNTM have more low-frequency, protein-affecting variants in immune, CFTR, cilia, and connective tissue genes than their unaffected family members and control subjects. We propose that PNTM infection is a multigenic disease in which combinations of variants across gene categories, plus environmental exposures, increase susceptibility to the infection.
Asunto(s)
Cilios/genética , Tejido Conectivo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Inmunidad/genética , Infecciones por Mycobacterium no Tuberculosas/genética , Tuberculosis Pulmonar/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Causalidad , Estudios de Cohortes , Exoma , Familia , Femenino , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , Masculino , Persona de Mediana Edad , Análisis de Componente Principal , Análisis de Secuencia de ADNRESUMEN
It is now recognized that innate immunity to intestinal microflora plays a significant role in mediating immune health, and modulation of microbial sensing may underpin the impact of plant natural products in the diet or when used as nutraceuticals. In this context, we have examined five classes of plant-derived flavonoids (flavonols, flavones, flavanones, catechins, and cyanidin) for their ability to regulate cytokine release induced by the Toll-like receptor 2 (TLR2) agonist Pam3CSK4. We found that the flavonols selectively co-stimulated IL-1ß secretion but had no impact on the secretion of IL-6. Importantly, this costimulation of TLR2-induced cytokine secretion was dependent on regiospecific methylation of the flavonol scaffold with a rank order of quercetin-3,4'-dimethylether > quercetin-3-methylether > casticin. The mechanism underpinning this costimulation did not involve enhanced inflammasome activation. In contrast, the methylated flavonols enhanced IL-1ß gene expression through transcriptional regulation, involving mechanisms that operate downstream of the initial NF-κB and STAT1 activation events. These studies demonstrate an exquisite level of control of scaffold bioactivity by regiospecific methylation, with important implications for understanding how natural products affect innate immunity and for their development as novel immunomodulators for clinical use.
Asunto(s)
Flavonoides/química , Interleucina-1beta/biosíntesis , Monocitos/metabolismo , Receptor Toll-Like 2/metabolismo , Caspasa 1/metabolismo , Línea Celular , Cicloheximida/farmacología , Sinergismo Farmacológico , Flavonoides/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Lipopéptidos/farmacología , Metilación/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Modelos Biológicos , Monocitos/efectos de los fármacos , Monocitos/enzimología , Fosforilación/efectos de los fármacos , Quercetina/análogos & derivados , ARN Mensajero/genética , ARN Mensajero/metabolismo , Estereoisomerismo , Receptor Toll-Like 2/agonistas , Transcripción Genética/efectos de los fármacosAsunto(s)
Proteínas Adaptadoras de Señalización CARD/deficiencia , Candidiasis/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Meningoencefalitis/tratamiento farmacológico , Neutropenia/tratamiento farmacológico , Animales , Proteínas Adaptadoras de Señalización CARD/genética , Candida albicans , Candidiasis/microbiología , Femenino , Humanos , Síndromes de Inmunodeficiencia/microbiología , Meningoencefalitis/microbiología , Ratones Endogámicos C57BL , Ratones Noqueados , Neutropenia/microbiologíaRESUMEN
Gut-resident fungi have a broad influence over health and disease. In this issue of JEM, Sekeresova Kralova et al. (https://doi.org/10.1084/jem.20231686) identify a commensal yeast that displaced fungal pathogen Candida albicans and protected against subsequent invasive infections that originate from the gut.
Asunto(s)
HongosRESUMEN
PLX5622 is a small molecular inhibitor of the CSF1 receptor (CSF1R) and is widely used to deplete macrophages within the central nervous system (CNS). We investigated the impact of PLX5622 treatment in wild-type C57BL/6 mice and discovered that one-week treatment with PLX5622 was sufficient to deplete interstitial macrophages in the lung and brain-infiltrating Ly6Clow patrolling monocytes, in addition to CNS-resident macrophages. These cell types were previously indicated to act as infection reservoirs for the pathogenic fungus Cryptococcus neoformans. We found that PLX5622-treated mice had significantly reduced fungal lung infection and reduced extrapulmonary dissemination to the CNS but not to the spleen or liver. Fungal lung infection mapped to MHCIIhi interstitial lung macrophages, which underwent significant expansion during infection following monocyte replenishment and not local division. Although PLX5622 depleted CNS infiltrating patrolling monocytes, these cells did not accumulate in the fungal-infected CNS following pulmonary infection. In addition, Nr4a1-deficient mice, which lack patrolling monocytes, had similar control and dissemination of C. neoformans infection to wild-type controls. PLX5622 did not directly affect CD4 T-cell responses, or significantly affect production of antibody in the lung during infection. However, we found that mice lacking lymphocytes had reduced numbers of MHCIIhi interstitial macrophages in the lung, which correlated with reduced infection load. Accordingly, PLX5622 treatment did not alter fungal burdens in the lungs of lymphocyte-deficient mice. Our data demonstrate that PLX5622 may help reduce lung burden of pathogenic fungi that utilise CSF1R-dependent myeloid cells as infection reservoirs, an effect which is dependent on the presence of lymphocytes.