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1.
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
2.
Immunity ; 54(11): 2595-2610.e7, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34506733

RESUMO

Fungal airway infection (airway mycosis) is an important cause of allergic airway diseases such as asthma, but the mechanisms by which fungi trigger asthmatic reactions are poorly understood. Here, we leverage wild-type and mutant Candida albicans to determine how this common fungus elicits characteristic Th2 and Th17 cell-dependent allergic airway disease in mice. We demonstrate that rather than proteinases that are essential virulence factors for molds, C. albicans instead promoted allergic airway disease through the peptide toxin candidalysin. Candidalysin activated platelets through the Von Willebrand factor (VWF) receptor GP1bα to release the Wnt antagonist Dickkopf-1 (Dkk-1) to drive Th2 and Th17 cell responses that correlated with reduced lung fungal burdens. Platelets simultaneously precluded lethal pulmonary hemorrhage resulting from fungal lung invasion. Thus, in addition to hemostasis, platelets promoted protection against C. albicans airway mycosis through an antifungal pathway involving candidalysin, GP1bα, and Dkk-1 that promotes Th2 and Th17 responses.


Assuntos
Plaquetas/imunologia , Candida albicans/fisiologia , Candidíase/complicações , Candidíase/imunologia , Suscetibilidade a Doenças , Interações Hospedeiro-Patógeno/imunologia , Hipersensibilidade/complicações , Hipersensibilidade/imunologia , Subpopulações de Linfócitos T/imunologia , Plaquetas/metabolismo , Hipersensibilidade/metabolismo , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Células Th2/imunologia , Células Th2/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
4.
PLoS Pathog ; 20(3): e1012031, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38427950

RESUMO

The opportunistic fungal pathogen Candida albicans thrives on human mucosal surfaces as a harmless commensal, but frequently causes infections under certain predisposing conditions. Translocation across the intestinal barrier into the bloodstream by intestine-colonizing C. albicans cells serves as the main source of disseminated candidiasis. However, the host and microbial mechanisms behind this process remain unclear. In this study we identified fungal and host factors specifically involved in infection of intestinal epithelial cells (IECs) using dual-RNA sequencing. Our data suggest that host-cell damage mediated by the peptide toxin candidalysin-encoding gene ECE1 facilitates fungal zinc acquisition. This in turn is crucial for the full virulence potential of C. albicans during infection. IECs in turn exhibit a filamentation- and damage-specific response to C. albicans infection, including NFκB, MAPK, and TNF signaling. NFκB activation by IECs limits candidalysin-mediated host-cell damage and mediates maintenance of the intestinal barrier and cell-cell junctions to further restrict fungal translocation. This is the first study to show that candidalysin-mediated damage is necessary for C. albicans nutrient acquisition during infection and to explain how IECs counteract damage and limit fungal translocation via NFκB-mediated maintenance of the intestinal barrier.


Assuntos
Candida albicans , Candidíase , Humanos , Zinco , Células Epiteliais , Intestinos
5.
EMBO Rep ; 24(11): e57571, 2023 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-37795769

RESUMO

The peptide toxin candidalysin, secreted by Candida albicans hyphae, promotes stimulation of neutrophil extracellular traps (NETs). However, candidalysin alone triggers a distinct mechanism for NET-like structures (NLS), which are more compact and less fibrous than canonical NETs. Candidalysin activates NADPH oxidase and calcium influx, with both processes contributing to morphological changes in neutrophils resulting in NLS formation. NLS are induced by leucotoxic hypercitrullination, which is governed by calcium-induced protein arginine deaminase 4 activation and initiation of intracellular signalling events in a dose- and time-dependent manner. However, activation of signalling by candidalysin does not suffice to trigger downstream events essential for NET formation, as demonstrated by lack of lamin A/C phosphorylation, an event required for activation of cyclin-dependent kinases that are crucial for NET release. Candidalysin-triggered NLS demonstrate anti-Candida activity, which is resistant to nuclease treatment and dependent on the deprivation of Zn2+ . This study reveals that C. albicans hyphae releasing candidalysin concurrently trigger canonical NETs and NLS, which together form a fibrous sticky network that entangles C. albicans hyphae and efficiently inhibits their growth.


Assuntos
Candida albicans , Armadilhas Extracelulares , Candida albicans/metabolismo , Armadilhas Extracelulares/metabolismo , Cálcio/metabolismo , Proteínas Fúngicas/metabolismo
6.
J Biol Chem ; 298(10): 102419, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36037968

RESUMO

Candida albicans (C. albicans) is a dimorphic commensal human fungal pathogen that can cause severe oropharyngeal candidiasis (oral thrush) in susceptible hosts. During invasive infection, C. albicans hyphae invade oral epithelial cells (OECs) and secrete candidalysin, a pore-forming cytolytic peptide that is required for C. albicans pathogenesis at mucosal surfaces. Candidalysin is produced in the hyphal invasion pocket and triggers cell damage responses in OECs. Candidalysin also activates multiple MAPK-based signaling events that collectively drive the production of downstream inflammatory mediators that coordinate downstream innate and adaptive immune responses. The activities of candidalysin are dependent on signaling through the epidermal growth factor receptor (EGFR). Here, we interrogated known EGFR-MAPK signaling intermediates for their roles mediating the OEC response to C. albicans infection. Using RNA silencing and pharmacological inhibition, we identified five key adaptors, including growth factor receptor-bound protein 2 (Grb2), Grb2-associated binding protein 1 (Gab1), Src homology and collagen (Shc), SH2-containing protein tyrosine phosphatase-2 (Shp2), and casitas B-lineage lymphoma (c-Cbl). We determined that all of these signaling effectors were inducibly phosphorylated in response to C. albicans. These phosphorylation events occurred in a candidalysin-dependent manner and additionally required EGFR phosphorylation, matrix metalloproteinases (MMPs), and cellular calcium flux to activate a complete OEC response to fungal infection. Of these, Gab1, Grb2, and Shp2 were the dominant drivers of ERK1/2 activation and the subsequent production of downstream innate-acting cytokines. Together, these results identify the key adaptor proteins that drive the EGFR signaling mechanisms that underlie oral epithelial responses to C. albicans.


Assuntos
Candida albicans , Candidíase Bucal , Receptores ErbB , Proteínas Fúngicas , Mucosa Bucal , Humanos , Candida albicans/metabolismo , Candida albicans/patogenicidade , Citocinas/metabolismo , Receptores ErbB/metabolismo , Proteínas Fúngicas/metabolismo , Proteínas Adaptadoras da Sinalização Shc/metabolismo , Candidíase Bucal/metabolismo , Candidíase Bucal/microbiologia , Mucosa Bucal/metabolismo , Mucosa Bucal/microbiologia , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia
7.
Infect Immun ; 91(2): e0033322, 2023 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-36625602

RESUMO

The human lung is constantly exposed to Aspergillus fumigatus spores, the most prevalent worldwide cause of fungal respiratory disease. Pulmonary tissue damage is a unifying feature of Aspergillus-related diseases; however, the mechanistic basis of damage is not understood. In the lungs of susceptible hosts, A. fumigatus undergoes an obligatory morphological switch involving spore germination and hyphal growth. We modeled A. fumigatus infection in cultured A549 human pneumocytes, capturing the phosphoactivation status of five host signaling pathways, nuclear translocation and DNA binding of eight host transcription factors, and expression of nine host response proteins over six time points encompassing exposures to live fungus and the secretome thereof. The resulting data set, comprised of more than 1,000 data points, reveals that pneumocytes mount differential responses to A. fumigatus spores, hyphae, and soluble secreted products via the NF-κB, JNK, and JNK + p38 pathways, respectively. Importantly, via selective degradation of host proinflammatory (IL-6 and IL-8) cytokines and growth factors (FGF-2), fungal secreted products reorchestrate the host response to fungal challenge as well as driving multiparameter epithelial damage, culminating in cytolysis. Dysregulation of NF-κB signaling, involving sequential stimulation of canonical and noncanonical signaling, was identified as a significant feature of host damage both in vitro and in a mouse model of invasive aspergillosis. Our data demonstrate that composite tissue damage results from iterative (repeated) exposures to different fungal morphotypes and secreted products and suggest that modulation of host responses to fungal challenge might represent a unified strategy for therapeutic control of pathologically distinct types of Aspergillus-related disease.


Assuntos
Aspergilose , Aspergillus fumigatus , Animais , Camundongos , Humanos , NF-kappa B/metabolismo , Pulmão/microbiologia , Homeostase , Esporos Fúngicos
8.
PLoS Pathog ; 17(9): e1009884, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34506615

RESUMO

Vulvovaginal candidiasis (VVC), caused primarily by the human fungal pathogen Candida albicans, results in significant quality-of-life issues for women worldwide. Candidalysin, a toxin derived from a polypeptide (Ece1p) encoded by the ECE1 gene, plays a crucial role in driving immunopathology at the vaginal mucosa. This study aimed to determine if expression and/or processing of Ece1p differs across C. albicans isolates and whether this partly underlies differential pathogenicity observed clinically. Using a targeted sequencing approach, we determined that isolate 529L harbors a similarly expressed, yet distinct Ece1p isoform variant that encodes for a predicted functional candidalysin; this isoform was conserved amongst a collection of clinical isolates. Expression of the ECE1 open reading frame (ORF) from 529L in an SC5314-derived ece1Δ/Δ strain resulted in significantly reduced vaginopathogenicity as compared to an isogenic control expressing a wild-type (WT) ECE1 allele. However, in vitro challenge of vaginal epithelial cells with synthetic candidalysin demonstrated similar toxigenic activity amongst SC5314 and 529L isoforms. Creation of an isogenic panel of chimeric strains harboring swapped Ece1p peptides or HiBiT tags revealed reduced secretion with the ORF from 529L that was associated with reduced virulence. A genetic survey of 78 clinical isolates demonstrated a conserved pattern between Ece1p P2 and P3 sequences, suggesting that substrate specificity around Kex2p-mediated KR cleavage sites involved in protein processing may contribute to differential pathogenicity amongst clinical isolates. Therefore, we present a new mechanism for attenuation of C. albicans virulence at the ECE1 locus.


Assuntos
Candida albicans/genética , Candidíase Vulvovaginal/microbiologia , Proteínas Fúngicas/genética , Alelos , Animais , Candida albicans/patogenicidade , Feminino , Variação Genética , Humanos , Camundongos , Virulência
10.
Cell Microbiol ; 23(10): e13371, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34085369

RESUMO

Candida albicans is a common opportunistic fungal pathogen that causes a wide range of infections from superficial mucosal to hematogenously disseminated candidiasis. The hyphal form plays an important role in the pathogenic process by invading epithelial cells and causing tissue damage. Notably, the secretion of the hyphal toxin candidalysin is essential for both epithelial cell damage and activation of mucosal immune responses. However, the mechanism of candidalysin-induced cell death remains unclear. Here, we examined the induction of cell death by candidalysin in oral epithelial cells. Fluorescent imaging using healthy/apoptotic/necrotic cell markers revealed that candidalysin causes a rapid and marked increase in the population of necrotic rather than apoptotic cells in a concentration dependent manner. Activation of a necrosis-like pathway was confirmed since C. albicans and candidalysin failed to activate caspase-8 and -3, or the cleavage of poly (ADP-ribose) polymerase. Furthermore, oral epithelial cells treated with candidalysin showed rapid production of reactive oxygen species, disruption of mitochondria activity and mitochondrial membrane potential, ATP depletion and cytochrome c release. Collectively, these data demonstrate that oral epithelial cells respond to the secreted fungal toxin candidalysin by triggering numerous cellular stress responses that induce necrotic death. TAKE AWAYS: Candidalysin secreted from Candida albicans causes epithelial cell stress. Candidalysin induces calcium influx and oxidative stress in host cells. Candidalysin induces mitochondrial dysfunction, ATP depletion and epithelial necrosis. The toxicity of candidalysin is mediated from the epithelial cell surface.


Assuntos
Candidíase , Proteínas Fúngicas , Candida albicans , Células Epiteliais , Humanos , Necrose
11.
Cell Microbiol ; 23(10): e13378, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34245079

RESUMO

The human pathogenic fungus Candida albicans is a frequent cause of mucosal infections. Although the ability to transition from the yeast to the hypha morphology is essential for virulence, hypha formation and host cell invasion per se are not sufficient for the induction of epithelial damage. Rather, the hypha-associated peptide toxin, candidalysin, a product of the Ece1 polyprotein, is the critical damaging factor. While synthetic, exogenously added candidalysin is sufficient to damage epithelial cells, the level of damage does not reach the same level as invading C. albicans hyphae. Therefore, we hypothesized that a combination of fungal attributes is required to deliver candidalysin to the invasion pocket to enable the full damaging potential of C. albicans during infection. Utilising a panel of C. albicans mutants with known virulence defects, we demonstrate that the full damage potential of C. albicans requires the coordinated delivery of candidalysin to the invasion pocket. This process requires appropriate epithelial adhesion, hyphal extension and invasion, high levels of ECE1 transcription, proper Ece1 processing and secretion of candidalysin. To confirm candidalysin delivery, we generated camelid VH Hs (nanobodies) specific for candidalysin and demonstrate localization and accumulation of the toxin only in C. albicans-induced invasion pockets. In summary, a defined combination of virulence attributes and cellular processes is critical for delivering candidalysin to the invasion pocket to enable the full damage potential of C. albicans during mucosal infection. TAKE AWAYS: Candidalysin is a peptide toxin secreted by C. albicans causing epithelial damage. Candidalysin delivery to host cell membranes requires specific fungal attributes. Candidalysin accumulates in invasion pockets created by invasive hyphae. Camelid nanobodies enabled visualisation of candidalysin in the invasion pocket.


Assuntos
Candida albicans , Proteínas Fúngicas , Proteínas Fúngicas/genética , Humanos , Hifas , Virulência
12.
Nature ; 532(7597): 64-8, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27027296

RESUMO

Cytolytic proteins and peptide toxins are classical virulence factors of several bacterial pathogens which disrupt epithelial barrier function, damage cells and activate or modulate host immune responses. Such toxins have not been identified previously in human pathogenic fungi. Here we identify the first, to our knowledge, fungal cytolytic peptide toxin in the opportunistic pathogen Candida albicans. This secreted toxin directly damages epithelial membranes, triggers a danger response signalling pathway and activates epithelial immunity. Membrane permeabilization is enhanced by a positive charge at the carboxy terminus of the peptide, which triggers an inward current concomitant with calcium influx. C. albicans strains lacking this toxin do not activate or damage epithelial cells and are avirulent in animal models of mucosal infection. We propose the name 'Candidalysin' for this cytolytic peptide toxin; a newly identified, critical molecular determinant of epithelial damage and host recognition of the clinically important fungus, C. albicans.


Assuntos
Candida albicans/metabolismo , Candida albicans/patogenicidade , Citotoxinas/metabolismo , Proteínas Fúngicas/toxicidade , Micotoxinas/toxicidade , Fatores de Virulência/metabolismo , Cálcio/metabolismo , Candida albicans/imunologia , Candidíase/metabolismo , Candidíase/microbiologia , Candidíase/patologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Citotoxinas/genética , Citotoxinas/toxicidade , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/patologia , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Mucosa/microbiologia , Mucosa/patologia , Micotoxinas/genética , Micotoxinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Virulência/efeitos dos fármacos , Fatores de Virulência/genética , Fatores de Virulência/toxicidade
13.
J Infect Dis ; 224(7): 1219-1224, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-33733279

RESUMO

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.


Assuntos
Aspergilose/diagnóstico , Aspergillus fumigatus/isolamento & purificação , Infecções Fúngicas Invasivas , Lectinas Tipo C/genética , Deleção de Sequência/genética , Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Evolução Fatal , Interações Hospedeiro-Patógeno , Humanos , Hospedeiro Imunocomprometido , Infecções Fúngicas Invasivas/diagnóstico , Infecções Fúngicas Invasivas/tratamento farmacológico
14.
Semin Cell Dev Biol ; 89: 58-70, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-29501618

RESUMO

The tremendous diversity in microbial species that colonise the mucosal surfaces of the human body is only now beginning to be fully appreciated. Distinguishing between the behaviour of commensal microbes and harmful pathogens that reside at mucosal sites in the body is a complex, and exquisitely fine-tuned process central to mucosal health. The fungal pathobiont Candida albicans is frequently isolated from mucosal surfaces with an asymptomatic carriage rate of approximately 60% in the human population. While normally a benign member of the microbiota, overgrowth of C. albicans often results in localised mucosal infection causing morbidity in otherwise healthy individuals, and invasive infection that often causes death in the absence of effective immune defence. C. albicans triggers numerous innate immune responses at mucosal surfaces, and detection of C. albicans hyphae in particular, stimulates the production of antimicrobial peptides, danger-associated molecular patterns and cytokines that function to reduce fungal burdens during infection. This review will summarise our current understanding of innate immune responses to C. albicans at mucosal surfaces.


Assuntos
Candida albicans/imunologia , Imunidade Inata , Micoses/imunologia , Candida albicans/patogenicidade , Citocinas/biossíntese , Citocinas/imunologia , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Humanos , Hifas/imunologia , Hifas/patogenicidade , Mucosa/imunologia , Mucosa/microbiologia , Micoses/microbiologia
15.
Immunology ; 162(1): 11-16, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32880925

RESUMO

As our understanding of mycology progresses, the impact of fungal microbes on human health has become increasingly evident. Candida albicans is a common commensal fungus that gives rise to local and systemic infections, particularly in immunocompromised patients where it can result in mortality. However, C. albicans has also been quietly linked with a variety of inflammatory disorders, to which it has traditionally been considered incidental; recent studies may now provide new aspects of these relationships for further consideration. This review provides a novel perspective on the impact of C. albicans and its peptide toxin, candidalysin, on human health, exploring their contributions to pathology within a variety of diseases.


Assuntos
Candida albicans/metabolismo , Proteínas Fúngicas/metabolismo , Inflamação/microbiologia , Neoplasias/microbiologia , Animais , Candidíase/microbiologia , Humanos
16.
Crit Rev Microbiol ; 47(1): 91-111, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33482069

RESUMO

Candida albicans is a common fungus of the human microbiota. While generally a harmless commensal in healthy individuals, several factors can lead to its overgrowth and cause a range of complications within the host, from localized superficial infections to systemic life-threatening disseminated candidiasis. A major virulence factor of C. albicans is its ability to form biofilms, a closely packed community of cells that can grow on both abiotic and biotic substrates, including implanted medical devices and mucosal surfaces. These biofilms are extremely hard to eradicate, are resistant to conventional antifungal treatment and are associated with high morbidity and mortality rates, making biofilm-associated infections a major clinical challenge. Here, we review the current knowledge of the processes involved in C. albicans biofilm formation and development, including the central processes of adhesion, extracellular matrix production and the transcriptional network that regulates biofilm development. We also consider the advantages of the biofilm lifestyle and explore polymicrobial interactions within multispecies biofilms that are formed by C. albicans and selected microbial species.


Assuntos
Biofilmes , Candida albicans/fisiologia , Candidíase/microbiologia , Animais , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Candida albicans/genética , Candidíase/tratamento farmacológico , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Humanos , Fatores de Virulência/genética , Fatores de Virulência/metabolismo
17.
J Immunol ; 201(2): 627-634, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29891557

RESUMO

Protection against microbial infection by the induction of inflammation is a key function of the IL-1 superfamily, including both classical IL-1 and the new IL-36 cytokine families. Candida albicans is a frequent human fungal pathogen causing mucosal infections. Although the initiators and effectors important in protective host responses to C. albicans are well described, the key players in driving these responses remain poorly defined. Recent work has identified a central role played by IL-1 in inducing innate Type-17 immune responses to clear C. albicans infections. Despite this, lack of IL-1 signaling does not result in complete loss of immunity, indicating that there are other factors involved in mediating protection to this fungus. In this study, we identify IL-36 cytokines as a new player in these responses. We show that C. albicans infection of the oral mucosa induces the production of IL-36. As with IL-1α/ß, induction of epithelial IL-36 depends on the hypha-associated peptide toxin Candidalysin. Epithelial IL-36 gene expression requires p38-MAPK/c-Fos, NF-κB, and PI3K signaling and is regulated by the MAPK phosphatase MKP1. Oral candidiasis in IL-36R-/- mice shows increased fungal burdens and reduced IL-23 gene expression, indicating a key role played by IL-36 and IL-23 in innate protective responses to this fungus. Strikingly, we observed no impact on gene expression of IL-17 or IL-17-dependent genes, indicating that this protection occurs via an alternative pathway to IL-1-driven immunity. Thus, IL-1 and IL-36 represent parallel epithelial cell-driven protective pathways in immunity to oral C. albicans infection.


Assuntos
Candida albicans/imunologia , Candidíase/imunologia , Proteínas Fúngicas/metabolismo , Interleucina-17/metabolismo , Interleucina-1/metabolismo , Mucosa Bucal/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linhagem Celular , Regulação da Expressão Gênica , Imunidade Inata , Interleucina-23/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucosa Bucal/microbiologia , Receptores de Interleucina-1/genética , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
Oral Dis ; 26 Suppl 1: 91-102, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32862535

RESUMO

Oral candidiasis (OC) is the most prevalent HIV-related oral lesion in patients on combined anti-retroviral therapy (cART) or without cART. Management is challenged in some patients by development of resistance to azole drugs, such as fluconazole. Recent scientific knowledge about OC pathogenesis, the role of OC in the immune reconstitution inflammatory syndrome (IRIS), the relationship of OC with the microbiome, and novelties in OC treatment was discussed in an international workshop format. Literature searches were conducted to address five questions: (a) Considering the pathogenesis of Candida spp. infection, are there any potential therapeutic targets that could be considered, mainly in HIV-infected individuals resistant to fluconazole? (b) Is oral candidiasis part of IRIS in HIV patients who receive cART? (c) Can management of the oral microbiome reduce occurrence of OC in patients with HIV infection? (d) What are the recent advances (since 2015) regarding plant-based and alternative medicines in management of OC? and (e) Is there a role for photodynamic therapy in management of OC in HIV-infected patients? A number of the key areas where further research is necessary were identified to allow a deeper insight into this oral condition that could help to understand its nature and recommend alternatives for care.


Assuntos
Antifúngicos , Candidíase Bucal , Infecções por HIV , Antifúngicos/uso terapêutico , Candidíase Bucal/tratamento farmacológico , Candidíase Bucal/prevenção & controle , Fluconazol/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos
19.
Oral Dis ; 26 Suppl 1: 69-79, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32862519

RESUMO

A crucial aspect of mucosal HIV transmission is the interaction between HIV, the local environmental milieu and immune cells. The oral mucosa comprises many host cell types including epithelial cells, CD4 + T cells, dendritic cells and monocytes/macrophages, as well as a diverse microbiome predominantly comprising bacterial species. While the oral epithelium is one of the first sites exposed to HIV through oral-genital contact and nursing infants, it is largely thought to be resistant to HIV transmission via mechanisms that are still unclear. HIV-1 infection is also associated with predisposition to secondary infections, such as tuberculosis, and other diseases including cancer. This review addresses the following questions that were discussed at the 8th World Workshop on Oral Health and Disease in AIDS held in Bali, Indonesia, 13 September -15 September 2019: (a) How does HIV infection affect epithelial cell signalling? (b) How does HIV infection affect the production of cytokines and other innate antimicrobial factors, (c) How is the mucosal distribution and function of immune cells altered in HIV infection? (d) How do T cells affect HIV (oral) pathogenesis and cancer? (e) How does HIV infection lead to susceptibility to TB infections?


Assuntos
Infecções por HIV , Imunidade Inata , Mucosa Bucal , Linfócitos T CD4-Positivos , Infecções por HIV/imunologia , Humanos , Imunidade nas Mucosas , Lactente , Mucosa Bucal/imunologia , Mucosa Bucal/virologia
20.
J Infect Dis ; 220(9): 1477-1488, 2019 09 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.


Assuntos
Candida albicans/imunologia , Candida albicans/metabolismo , Candidíase Invasiva/microbiologia , Candidíase Invasiva/patologia , Proteínas Fúngicas/metabolismo , Infiltração de Neutrófilos , Fatores de Virulência/metabolismo , Animais , Candida albicans/crescimento & desenvolvimento , Citocinas/metabolismo , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Feminino , Masculino , Camundongos Endogâmicos BALB C , Transdução de Sinais , Análise de Sobrevida , Virulência , Peixe-Zebra
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