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1.
PLoS Genet ; 20(5): e1011281, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38743788

RESUMEN

CgHog1, terminal kinase of the high-osmolarity glycerol signalling pathway, orchestrates cellular response to multiple external stimuli including surplus-environmental iron in the human fungal pathogen Candida glabrata (Cg). However, CgHog1 substrates remain unidentified. Here, we show that CgHog1 adversely affects Cg adherence to host stomach and kidney epithelial cells in vitro, but promotes Cg survival in the iron-rich gastrointestinal tract niche. Further, CgHog1 interactome and in vitro phosphorylation analysis revealed CgSub2 (putative RNA helicase) to be a CgHog1 substrate, with CgSub2 also governing iron homeostasis and host adhesion. CgSub2 positively regulated EPA1 (encodes a major adhesin) expression and host adherence via its interactor CgHtz1 (histone H2A variant). Notably, both CgHog1 and surplus environmental iron had a negative impact on CgSub2-CgHtz1 interaction, with CgHTZ1 or CgSUB2 deletion reversing the elevated adherence of Cghog1Δ to epithelial cells. Finally, the surplus-extracellular iron led to CgHog1 activation, increased CgSub2 phosphorylation, elevated CgSub2-CgHta (canonical histone H2A) interaction, and EPA1 transcriptional activation, thereby underscoring the iron-responsive, CgHog1-induced exchange of histone partners of CgSub2. Altogether, our work mechanistically defines how CgHog1 couples Epa1 adhesin expression with iron abundance, and point towards specific chromatin composition modification programs that probably aid fungal pathogens align their adherence to iron-rich (gut) and iron-poor (blood) host niches.


Asunto(s)
Candida glabrata , Adhesión Celular , Células Epiteliales , Proteínas Fúngicas , Histonas , Candida glabrata/genética , Candida glabrata/metabolismo , Humanos , Histonas/metabolismo , Histonas/genética , Células Epiteliales/microbiología , Células Epiteliales/metabolismo , Adhesión Celular/genética , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , Fosforilación , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Quinasas Activadas por Mitógenos/genética , Hierro/metabolismo , Regulación Fúngica de la Expresión Génica , Candidiasis/microbiología , Candidiasis/genética , Transducción de Señal
2.
J Clin Immunol ; 44(1): 18, 2023 12 22.
Artículo en Inglés | MEDLINE | ID: mdl-38129603

RESUMEN

PURPOSE: Inborn errors of the IL-17A/F-responsive pathway lead to chronic mucocutaneous candidiasis (CMC) as a predominant clinical phenotype, without other significant clinical manifestations apart from mucocutaneous staphylococcal diseases. Among inborn errors affecting IL-17-dependent immunity, autosomal recessive (AR) IL-17RC deficiency is a rare disease with only three kindreds described to date. The lack of an in vitro functional evaluation system of IL17RC variants renders its diagnosis difficult. We sought to characterize a 7-year-old Japanese girl with CMC carrying a novel homozygous duplication variant of IL17RC and establish a simple in vitro system to evaluate the impact of this variant. METHODS: Flow cytometry, qPCR, RNA-sequencing, and immunoblotting were conducted, and an IL17RC-knockout cell line was established for functional evaluation. RESULTS: The patient presented with oral and mucocutaneous candidiasis without staphylococcal diseases since the age of 3 months. Genetic analysis showed that the novel duplication variant (Chr3: 9,971,476-9,971,606 dup (+131bp)) involving exon 13 of IL17RC results in a premature stop codon (p.D457Afs*16 or p.D457Afs*17). Our functional evaluation system revealed this duplication to be loss-of-function and enabled discrimination between loss-of-function and neutral IL17RC variants. The lack of response to IL-17A by the patient's SV40-immortalized fibroblasts was restored by introducing WT-IL17RC, suggesting that the genotype identified is responsible for her clinical phenotype. CONCLUSIONS: The clinical and cellular phenotype of the current case of AR IL-17RC deficiency supports a previous report on this rare disorder. Our newly established evaluation system will be useful for the diagnosis of AR IL-17RC deficiency, providing accurate validation of unknown IL17RC variants.


Asunto(s)
Candidiasis Mucocutánea Crónica , Candidiasis , Femenino , Humanos , Lactante , Niño , Candidiasis Mucocutánea Crónica/diagnóstico , Candidiasis Mucocutánea Crónica/genética , Interleucina-17/genética , Candidiasis/genética , Fibroblastos/metabolismo , Secuencia de Bases
3.
Emerg Infect Dis ; 29(3): 576-584, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36823029

RESUMEN

Candida haemulonii, a relative of C. auris, frequently shows antifungal resistance and is transmissible. However, molecular tools for genotyping and investigating outbreaks are not yet established. We performed genome-based population analysis on 94 C. haemulonii strains, including 58 isolates from China and 36 other published strains. Phylogenetic analysis revealed that C. haemulonii can be divided into 4 clades. Clade 1 comprised strains from China and other global strains; clades 2-4 contained only isolates from China, were more recently evolved, and showed higher antifungal resistance. Four regional epidemic clusters (A, B, C, and D) were identified in China, each comprising ≥5 cases (largest intracluster pairwise single-nucleotide polymorphism differences <50 bp). Cluster A was identified in 2 hospitals located in the same city, suggesting potential intracity transmissions. Cluster D was resistant to 3 classes of antifungals. The emergence of more resistant phylogenetic clades and regional dissemination of antifungal-resistant C. haemulonii warrants further monitoring.


Asunto(s)
Antifúngicos , Candida , Candidiasis , Farmacorresistencia Fúngica , Antifúngicos/uso terapéutico , Candida/efectos de los fármacos , Candida/genética , Candidiasis/tratamiento farmacológico , Candidiasis/genética , Candidiasis/microbiología , China , Pruebas de Sensibilidad Microbiana , Filogenia , Células Clonales , Farmacorresistencia Fúngica/genética
4.
Nat Immunol ; 23(7): 1098-1108, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35761088

RESUMEN

Patients with loss of function in the gene encoding the master regulator of central tolerance AIRE suffer from a devastating disorder called autoimmune polyendocrine syndrome type 1 (APS-1), characterized by a spectrum of autoimmune diseases and severe mucocutaneous candidiasis. Although the key mechanisms underlying the development of autoimmunity in patients with APS-1 are well established, the underlying cause of the increased susceptibility to Candida albicans infection remains less understood. Here, we show that Aire+MHCII+ type 3 innate lymphoid cells (ILC3s) could sense, internalize and present C. albicans and had a critical role in the induction of Candida-specific T helper 17 (TH17) cell clones. Extrathymic Rorc-Cre-mediated deletion of Aire resulted in impaired generation of Candida-specific TH17 cells and subsequent overgrowth of C. albicans in the mucosal tissues. Collectively, our observations identify a previously unrecognized regulatory mechanism for effective defense responses against fungal infections.


Asunto(s)
Enfermedades Autoinmunes , Candidiasis , Poliendocrinopatías Autoinmunes , Candida albicans , Candidiasis/genética , Humanos , Inmunidad Innata , Poliendocrinopatías Autoinmunes/genética , Células Th17
5.
Methods Cell Biol ; 168: 315-327, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35366989

RESUMEN

The human fungal pathogen Candida albicans (C. albicans) causes invasive candidiasis, characterized by fatal organ failure due to disseminated fungal growth and inflammatory damage. To better understand fungal pathogenicity mechanisms and host protective responses, a murine model of invasive candidiasis has been developed in which C. albicans is administered systemically via intravenous injection. In this infection model, all major tissues are seeded within 0-4h. Of all the peripheral organs, the kidneys provide the most favorable niches for fungal proliferation and the morphogenetic switch to a hyphal state. As a consequence, the kidneys are a focal point for analyzing many of the genetic and immunological factors that underlie disease progression. Herein, we describe a number of well-established techniques that allow investigation into specific mechanisms that impact host-pathogen interactions.


Asunto(s)
Candida albicans , Candidiasis , Animales , Candida albicans/genética , Candidiasis/genética , Candidiasis/microbiología , Interacciones Huésped-Patógeno , Riñón , Ratones
6.
Eur J Med Res ; 27(1): 43, 2022 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-35314002

RESUMEN

BACKGROUND: Opportunistic Candida species causes severe infections when the human immune system is weakened, leading to high mortality. METHODS: In our study, bioinformatics analysis was used to study the high-throughput sequencing data of samples infected with four kinds of Candida species. And the hub genes were obtained by statistical analysis. RESULTS: A total of 547, 422, 415 and 405 differentially expressed genes (DEGs) of Candida albicans, Candida glabrata, Candida parapsilosis and Candida tropicalis groups were obtained, respectively. A total of 216 DEGs were obtained after taking intersections of DEGs from the four groups. A protein-protein interaction (PPI) network was established using these 216 genes. The top 10 hub genes (FOSB, EGR1, JUNB, ATF3, EGR2, NR4A1, NR4A2, DUSP1, BTG2, and EGR3) were acquired through calculation by the cytoHubba plug-in in Cytoscape software. Validated by the sequencing data of peripheral blood, JUNB, ATF3 and EGR2 genes were  significant statistical significance. CONCLUSIONS: In conclusion, our study demonstrated the potential pathogenic genes in Candida species and their underlying mechanisms by bioinformatic analysis methods. Further, after statistical validation, JUNB, ATF3 and EGR2 genes were attained, which may be used as potential biomarkers with Candida species infection.


Asunto(s)
Biomarcadores , Candidiasis/diagnóstico , Candidiasis/genética , Candidiasis/fisiopatología , Biología Computacional/métodos , Transducción de Señal/genética , Candida albicans/genética , Candida glabrata/genética , Candida tropicalis/genética , Regulación de la Expresión Génica , Variación Genética , Genotipo , Humanos
7.
Dis Model Mech ; 15(5)2022 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-35142345

RESUMEN

Candida infections constitute a blind spot in global public health as very few new anti-fungal drugs are being developed. Genetic surveys of host susceptibilities to such infections using mammalian models have certain disadvantages in that obtaining results is time-consuming, owing to relatively long lifespans, and these results have low statistical resolution because sample sizes are usually small. Here, we report a targeted genetic screening of 5698 RNAi lines encompassing 4135 Drosophila genes with human homologues, several of which we identify as important for host survival after Candida albicans infection. These include genes in a variety of functional classes encompassing gene expression, intracellular signalling, metabolism and enzymatic regulation. Analysis of one of the screen hits, the infection-induced α-(1,3)-fucosylase FucTA, showed that N-glycan fucosylation has several targets among proteins involved in host defence, which provides multiple avenues of investigation for the mechanistic analysis of host survival to systemic C. albicans infection.


Asunto(s)
Candidiasis , Drosophila , Animales , Candida albicans , Candidiasis/genética , Candidiasis/microbiología , Pruebas Genéticas , Mamíferos , Interferencia de ARN
8.
J Microbiol ; 60(4): 402-410, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35157222

RESUMEN

Acute lung injury caused by Candida albicans could result in high mortality and morbidity. MicroRNA-155 (miR-155) and suppressor of cytokine signaling 1 (SOCS1) have been believed to play a key in the regulation of inflammatory response. Whether miR-155/SOCS1 axis could regulate the acute lung injury caused by C. albicans has not been reported. The acute lung injury animal model was established with acute infection of C. albicans. miR-155 inhibitor, miR-155 mimic, and sh-SOCS1 were constructed. The binding site between miR-155 and SOCS1 was identified with dual luciferase reporter assay. Knockdown of miR-155 markedly inhibited the germ tube formation of C. albicans. Knockdown of miR-155 significantly up-regulated the expression of SOCS1, and the binding site between miR-155 and SOCS1 was identified. Knockdown of miR-155 improved the acute lung injury, suppressed inflammatory factors and fungus loading through SOCS1. Knockdown of SOCS1 greatly reversed the influence of miR-155 inhibitor on the cell apoptosis in vitro. The improvement of acute lung injury caused by C. albicans, suppression of inflammatory response and C. albicans infection, and inhibitor of cell apoptosis were achieved by knocking down miR-155 through SOCS1. This research might provide a new thought for the prevention and treatment of acute lung injury caused by C. albicans through targeting miR-155/SOCS1 axis.


Asunto(s)
Lesión Pulmonar Aguda , Candida albicans , Candidiasis , MicroARNs , Proteína 1 Supresora de la Señalización de Citocinas , Lesión Pulmonar Aguda/genética , Lesión Pulmonar Aguda/inmunología , Lesión Pulmonar Aguda/metabolismo , Animales , Candida albicans/genética , Candida albicans/metabolismo , Candidiasis/genética , Candidiasis/metabolismo , Candidiasis/microbiología , Regulación hacia Abajo , Inflamación/metabolismo , Inflamación/microbiología , MicroARNs/genética , MicroARNs/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/genética , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo
9.
Gut Microbes ; 14(1): 2004798, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35086419

RESUMEN

Candida albicans (C. albicans) is an opportunistic pathogen causing infections ranging from superficial to life-threatening disseminated infections. In a susceptible host, C. albicans is able to translocate through the gut barrier, promoting its dissemination into deeper organs. C. albicans hyphae can invade human epithelial cells by two well-documented mechanisms: epithelial-driven endocytosis and C. albicans-driven active penetration. One mechanism by which host cells protect themselves against intracellular C. albicans is termed autophagy. The protective role of autophagy during C. albicans infection has been investigated in myeloid cells; however, far less is known regarding the role of this process during the infection of epithelial cells. In the present study, we investigated the role of autophagy-related proteins during the infection of epithelial cells, including intestinal epithelial cells and gut explants, by C. albicans. Using cell imaging, we show that key molecular players of the autophagy machinery (LC3-II, PI3P, ATG16L1, and WIPI2) were recruited at Candida invasion sites. We deepened these observations by electron microscopy analyses that reveal the presence of autophagosomes in the vicinity of invading hyphae. Importantly, these events occur during active penetration of C. albicans into host cells and are associated with plasma membrane damage. In this context, we show that the autophagy-related key proteins ATG5 and ATG16L1 contribute to plasma membrane repair mediated by lysosomal exocytosis and participate in protecting epithelial cells against C. albicans-induced cell death. Our findings provide a novel mechanism by which epithelial cells, forming the first line of defense against C. albicans in the gut, can react to limit C. albicans invasion.


Asunto(s)
Autofagia , Candida albicans/fisiología , Candidiasis/microbiología , Membrana Celular/microbiología , Células Epiteliales/microbiología , Proteína 5 Relacionada con la Autofagia/genética , Proteína 5 Relacionada con la Autofagia/metabolismo , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Candida albicans/genética , Candidiasis/genética , Candidiasis/metabolismo , Candidiasis/fisiopatología , Células Epiteliales/citología , Células Epiteliales/metabolismo , Microbioma Gastrointestinal , Interacciones Huésped-Patógeno , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas de Unión a Fosfato/genética , Proteínas de Unión a Fosfato/metabolismo
10.
G3 (Bethesda) ; 12(1)2022 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-34791169

RESUMEN

Candida metapsilosis is a member of the Candida parapsilosis species complex, a group of opportunistic human pathogens. Of all the members of this complex, C. metapsilosis is the least virulent, and accounts for a small proportion of invasive Candida infections. Previous studies established that all C. metapsilosis isolates are hybrids, originating from a single hybridization event between two lineages, parent A and parent B. Here, we use MinION and Illumina sequencing to characterize a C. metapsilosis isolate that originated from a separate hybridization. One of the parents of the new isolate is very closely related to parent A. However, the other parent (parent C) is not the same as parent B. Unlike C. metapsilosis AB isolates, the C. metapsilosis AC isolate has not undergone introgression at the mating type-like locus. In addition, the A and C haplotypes are not fully collinear. The C. metapsilosis AC isolate has undergone loss of heterozygosity with a preference for haplotype A, indicating that this isolate is in the early stages of genome stabilization.


Asunto(s)
Candida parapsilosis , Candidiasis , Antifúngicos , Candida/genética , Candida parapsilosis/genética , Candidiasis/genética , Genoma , Humanos , Hibridación Genética
11.
mBio ; 12(6): e0331721, 2021 12 21.
Artículo en Inglés | MEDLINE | ID: mdl-34903044

RESUMEN

Candida species are a leading cause of opportunistic, hospital-associated bloodstream infections with high mortality rates, typically in immunocompromised patients. Several species, including Candida albicans, the most prevalent cause of infection, belong to the monophyletic CUG clade of yeasts. Innate immune cells such as macrophages are crucial for controlling infection, and C. albicans responds to phagocytosis by a coordinated induction of pathways involved in catabolism of nonglucose carbon sources, termed alternative carbon metabolism, which together are essential for virulence. However, the interactions of other CUG clade species with macrophages have not been characterized. Here, we analyzed transcriptional responses to macrophage phagocytosis by six Candida species across a range of virulence and clinical importance. We define a core induced response common to pathogenic and nonpathogenic species alike, heavily weighted to alternative carbon metabolism. One prominent pathogen, Candida parapsilosis, showed species-specific expansion of phagocytosis-responsive genes, particularly metabolite transporters. C. albicans and Candida tropicalis, the other prominent pathogens, also had species-specific responses, but these were largely comprised of functionally uncharacterized genes. Transcriptional analysis of macrophages also demonstrated highly correlated proinflammatory transcriptional responses to different Candida species that were largely independent of fungal viability, suggesting that this response is driven by recognition of conserved cell wall components. This study significantly broadens our understanding of host interactions in CUG clade species, demonstrating that although metabolic plasticity is crucial for virulence in Candida, it alone is not sufficient to confer pathogenicity. Instead, we identify sets of mostly uncharacterized genes that may explain the evolution of pathogenicity. IMPORTANCE Candidiasis is a major fungal infection by Candida species, causing life-threatening invasive disease in immunocompromised patients. C. albicans, which is adapted to commensalism of human mucosae, is the most common cause. While several other species cause infection, most are less prevalent or less virulent. As innate immune cells are the primary defense against Candida infection, we compared the transcriptional responses of C. albicans and related species to phagocytosis by macrophages, to understand the basis of variation in pathogenesis. This response, including the metabolic remodeling required for virulence in C. albicans, was strikingly conserved across the virulence spectrum. Macrophage responses to different species were also highly similar. This study indicates that important elements of host-pathogen interactions in C. albicans are not driven by adaptation to the mammalian host and improves our understanding of pathogenicity in opportunistic fungal species that are understudied but collectively impose a significant threat of their own.


Asunto(s)
Candida/genética , Candidiasis/genética , Candidiasis/microbiología , Interacciones Huésped-Patógeno , Macrófagos/microbiología , Candida/clasificación , Candida/patogenicidad , Candida/fisiología , Candidiasis/inmunología , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Humanos , Macrófagos/inmunología , Viabilidad Microbiana , Fagocitosis , Filogenia , Transcriptoma , Virulencia
12.
Nat Commun ; 12(1): 6699, 2021 11 18.
Artículo en Inglés | MEDLINE | ID: mdl-34795266

RESUMEN

Candida albicans is the most common cause of fungal sepsis. Inhibition of inflammasome activity confers resistance to polymicrobial and LPS-induced sepsis; however, inflammasome signaling appears to protect against C. albicans infection, so inflammasome inhibitors are not clinically useful for candidiasis. Here we show disruption of GSDMD, a known inflammasome target and key pyroptotic cell death mediator, paradoxically alleviates candidiasis, improving outcomes and survival of Candida-infected mice. Mechanistically, C. albicans hijacked the canonical inflammasome-GSDMD axis-mediated pyroptosis to promote their escape from macrophages, deploying hyphae and candidalysin, a pore-forming toxin expressed by hyphae. GSDMD inhibition alleviated candidiasis by preventing C. albicans escape from macrophages while maintaining inflammasome-dependent but GSDMD-independent IL-1ß production for anti-fungal host defenses. This study demonstrates key functions for GSDMD in Candida's escape from host immunity in vitro and in vivo and suggests that GSDMD may be a potential therapeutic target in C. albicans-induced sepsis.


Asunto(s)
Candida albicans/inmunología , Candidiasis/inmunología , Inflamasomas/inmunología , Péptidos y Proteínas de Señalización Intracelular/inmunología , Macrófagos/inmunología , Proteínas de Unión a Fosfato/inmunología , Animales , Candida albicans/fisiología , Candidiasis/genética , Candidiasis/microbiología , Caspasa 1/genética , Caspasa 1/inmunología , Caspasa 1/metabolismo , Células Cultivadas , Femenino , Interacciones Huésped-Patógeno/inmunología , Humanos , Inflamasomas/genética , Inflamasomas/metabolismo , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Estimación de Kaplan-Meier , Riñón/inmunología , Riñón/metabolismo , Riñón/microbiología , Macrófagos/metabolismo , Macrófagos/microbiología , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Unión a Fosfato/genética , Proteínas de Unión a Fosfato/metabolismo
13.
Nat Immunol ; 22(11): 1382-1390, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34663978

RESUMEN

Intergenerational inheritance of immune traits linked to epigenetic modifications has been demonstrated in plants and invertebrates. Here we provide evidence for transmission of trained immunity across generations to murine progeny that survived a sublethal systemic infection with Candida albicans or a zymosan challenge. The progeny of trained mice exhibited cellular, developmental, transcriptional and epigenetic changes associated with the bone marrow-resident myeloid effector and progenitor cell compartment. Moreover, the progeny of trained mice showed enhanced responsiveness to endotoxin challenge, alongside improved protection against systemic heterologous Escherichia coli and Listeria monocytogenes infections. Sperm DNA of parental male mice intravenously infected with the fungus C. albicans showed DNA methylation differences linked to immune gene loci. These results provide evidence for inheritance of trained immunity in mammals, enhancing protection against infections.


Asunto(s)
Candida albicans/inmunología , Candidiasis/inmunología , Infecciones por Escherichia coli/inmunología , Escherichia coli/inmunología , Herencia , Inmunidad Innata/genética , Listeria monocytogenes/inmunología , Listeriosis/inmunología , Células Mieloides/inmunología , Animales , Candida albicans/patogenicidad , Candidiasis/genética , Candidiasis/metabolismo , Candidiasis/microbiología , Células Cultivadas , Metilación de ADN , Modelos Animales de Enfermedad , Epigénesis Genética , Escherichia coli/patogenicidad , Infecciones por Escherichia coli/genética , Infecciones por Escherichia coli/metabolismo , Infecciones por Escherichia coli/microbiología , Interacciones Huésped-Patógeno , Listeria monocytogenes/patogenicidad , Listeriosis/genética , Listeriosis/metabolismo , Listeriosis/microbiología , Masculino , Ratones Transgénicos , Células Mieloides/metabolismo , Células Mieloides/microbiología , Espermatozoides/inmunología , Espermatozoides/metabolismo , Transcripción Genética
14.
PLoS One ; 16(10): e0258108, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34614005

RESUMEN

Candida is an opportunistic pathogen and a common cause of fungal infections worldwide. Anti-fungal use against Candida infections has resulted in the appearance of resistant strains. The limited choice of anti-fungal therapy means alternative strategies are needed to control fungal infectious diseases. The aim of this study was to evaluate the inhibition of Candida biofilm formation by Hedera rhombea (Korean name: songak) extract. Biofilm formation was assessed using the crystal violet assay which showed a dose dependent reduction in the presence of extract with the biofilm formation inhibitory concentration of C. albicans (IC50 = 12.5µg/ml), C. tropicalis var. tropicalis (IC50 = 25µg/ml), C. parapsilosis var. parapsilosis (IC50 = 6.25µg/ml), C. glabrata (IC50 = 6.25µg/ml), C. tropicalis (IC50 = 12.5µg/ml), and C. parapsilosis (IC50 = 12.5µg/ml) without directly reducing Candida growth. Treatment with 6.25µg/mL of extract increased the antifungal susceptibility to miconazole from 32% decreasing of fungal growth to 98.8% of that based on the fungal growth assay. Treatment of extract dose-dependently reduced the dimorphic transition of Candida based on the dimorphic transition assay and treatment of 3.125µg/mL of extract completely blocked the adherence of Candida to the HaCaT cells. To know the molecular mechanisms of biofilm formation inhibition by extract, qRT-PCR analysis was done, and the extract was found to dose dependently reduce the expression of hyphal-associated genes (ALS3, ECE1, HWP1, PGA50, and PBR1), extracellular matrix genes (GSC1, ZAP1, ADH5, and CSH1), Ras1-cAMP-PKA pathway genes (CYR1, EFG1, and RAS1), Cph2-Tec1 pathway gene (TEC1) and MAP kinases pathway gene (HST7). In this study, Hedera rhombea extract showed inhibition of fungal biofilm formation, activation of antifungal susceptibility, and reduction of infection. These results suggest that fungal biofilm formation is good screen for developing the antifungal adjuvant and Hedera rhombea extract should be a good candidate against biofilm-related fungal infection.


Asunto(s)
Antifúngicos/farmacología , Candida/efectos de los fármacos , Candidiasis/tratamiento farmacológico , Hedera/química , Antifúngicos/química , Biopelículas/efectos de los fármacos , Candida/genética , Candida/patogenicidad , Candidiasis/genética , Candidiasis/microbiología , Farmacorresistencia Fúngica/efectos de los fármacos , Proteínas Fúngicas/genética , Regulación Fúngica de la Expresión Génica/efectos de los fármacos , Humanos , Hifa/química , Pruebas de Sensibilidad Microbiana
15.
Signal Transduct Target Ther ; 6(1): 298, 2021 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-34362877

RESUMEN

Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase, which plays an essential role in both innate and adaptive immunity. However, the key molecular mechanisms that regulate SYK activity are poorly understood. Here we identified the E3 ligase TRIM31 as a crucial regulator of SYK activation. We found that TRIM31 interacted with SYK and catalyzed K27-linked polyubiquitination at Lys375 and Lys517 of SYK. This K27-linked polyubiquitination of SYK promoted its plasma membrane translocation and binding with the C-type lectin receptors (CLRs), and also prevented the interaction with the phosphatase SHP-1. Therefore, deficiency of Trim31 in bone marrow-derived dendritic cells (BMDCs) and macrophages (BMDMs) dampened SYK-mediated signaling and inhibited the secretion of proinflammatory cytokines and chemokines against the fungal pathogen Candida albicans infection. Trim31-/- mice were also more sensitive to C. albicans systemic infection than Trim31+/+ mice and exhibited reduced Th1 and Th17 responses. Overall, our study uncovered the pivotal role of TRIM31-mediated K27-linked polyubiquitination on SYK activation and highlighted the significance of TRIM31 in anti-C. albicans immunity.


Asunto(s)
Candidiasis/genética , Inmunidad Innata/genética , Lectinas Tipo C/genética , Quinasa Syk/genética , Animales , Candida albicans/genética , Candida albicans/patogenicidad , Candidiasis/tratamiento farmacológico , Candidiasis/microbiología , Células Dendríticas/metabolismo , Células Dendríticas/microbiología , Modelos Animales de Enfermedad , Humanos , Macrófagos/metabolismo , Macrófagos/microbiología , Ratones , Ratones Noqueados , Fagocitosis/genética , Unión Proteica/genética , Proteínas de Motivos Tripartitos/genética , Ubiquitina-Proteína Ligasas/genética
16.
Immunobiology ; 226(4): 152110, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34242877

RESUMEN

BACKGROUND: Chronic granulomatous disease (CGD) presents with a myriad of clinical manifestations pertaining to both immunodeficiency and hyperinflammation. Although Candida infection is a signature organism for patients with CGD, C. lusitaniae pneumonia in CGD has rarely been reported. C. lusitaniae is a ubiquitous ascomycete predominantly infecting immunocompromised hosts and has the potential to rapidly develop multi-drug resistance during therapy. Additionally, C. lusitaniae is recognized for its variable resistance against amphotericin B. To date, C. lusitaniae infections in patients with CGD have not been reviewed in detail. False-positive HIV serology, resulting from polyclonal hypergammaglobulinemia, has been reported in association with several infections, auto-immune diseases, and malignancies. Although CGD is often associated with hypergammaglobulinemia, a false-positive HIV serology in CGD has not been reported previously. PROCEDURE: We report a combination of unique findings in a child with CGD - a false-positive HIV serology, Candida lusitaniae pneumonia, and a novel CYBB mutation. We also provide a detailed review of C. lusitaniae infections in patients with CGD. RESULTS: In patients with CGD, C. lusitaniae has been reported to cause lymphadenitis (cervical, abdominal), fungemia, meningoencephalitis, or abscesses in the liver and spleen. Many CGD patients with C. lusitaniae infection have associated inflammatory complications of the gut (inflammatory bowel disease, colitis). Additionally, almost all C. lusitaniae infections in CGD have been reported in young infants or in patients receiving long-term immunosuppressive therapy. This reflects that further immunocompromise (in addition to the underlying immune deficiency in CGD) may specifically predispose to C. lusitaniae infection (unlike other candidal infections). Most of the CGD patients with documented C. lusitaniae infection have X-linked form of the disease which generally has been postulated to have a more severe clinical phenotype than the autosomal recessive forms of the disease. CONCLUSIONS: HIV serology may be positive in patients with CGD and other inborn errors of immunity as a result of hypergammaglobulinemia. C. lusitaniae, which may have peculiar and evolving antimicrobial sensitivity patterns, needs to be considered in patients with CGD and pneumonia. Lastly, to reiterate, CGD should to be considered in patients with proven C. lusitaniae infection.


Asunto(s)
Candidiasis , Enfermedad Granulomatosa Crónica , NADPH Oxidasa 2/genética , Neumonía , Saccharomycetales , Candidiasis/sangre , Candidiasis/genética , ADN Viral/genética , Reacciones Falso Positivas , Enfermedad Granulomatosa Crónica/sangre , Enfermedad Granulomatosa Crónica/genética , VIH/genética , VIH/inmunología , Infecciones por VIH/sangre , Infecciones por VIH/diagnóstico , Humanos , Lactante , Masculino , Mutación , Neumonía/sangre , Neumonía/genética , Proteínas Virales/inmunología
17.
JCI Insight ; 6(9)2021 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-33986196

RESUMEN

Trained immunity, induced by ß-glucan in monocytes, is mediated by activating metabolic pathways that result in epigenetic rewiring of cellular functional programs; however, molecular mechanisms underlying these changes remain unclear. Here, we report a key immunometabolic and epigenetic pathway mediated by the miR-9-5p-isocitrate dehydrogenase 3α (IDH3α) axis in trained immunity. We found that ß-glucan-trained miR-9-5p-/- monocytes showed decreased IL-1ß, IL-6, and TNF-α production after LPS stimulation. Trained miR-9-5p-/- mice produced decreased levels of proinflammatory cytokines upon rechallenge in vivo and had worse protection against Candida albicans infection. miR-9-5p targeted IDH3α and reduced α-ketoglutarate (α-KG) levels to stabilize HIF-1α, which promoted glycolysis. Accumulating succinate and fumarate via miR-9-5p action integrated immunometabolic circuits to induce histone modifications by inhibiting KDM5 demethylases. ß-Glucan-trained monocytes exhibited low IDH3α levels, and IDH3α overexpression blocked the induction of trained immunity by monocytes. Monocytes with IDH3α variants from autosomal recessive retinitis pigmentosa patients showed a trained immunity phenotype at immunometabolic and epigenetic levels. These findings suggest that miR-9-5p and IDH3α act as critical metabolic and epigenetic switches in trained immunity.


Asunto(s)
Epigénesis Genética/genética , Inmunidad Innata/genética , Memoria Inmunológica/genética , Isocitrato Deshidrogenasa/metabolismo , Redes y Vías Metabólicas/genética , MicroARNs/genética , Monocitos/metabolismo , Animales , Candida albicans , Candidiasis/genética , Candidiasis/inmunología , Epigénesis Genética/inmunología , Fumaratos/metabolismo , Glucólisis/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inmunidad Innata/inmunología , Memoria Inmunológica/inmunología , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Ácidos Cetoglutáricos/metabolismo , Lipopolisacáridos/farmacología , Redes y Vías Metabólicas/inmunología , Ratones , Ratones Noqueados , MicroARNs/metabolismo , Monocitos/efectos de los fármacos , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/metabolismo , Ácido Succínico/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , beta-Glucanos/inmunología
18.
Sci Rep ; 11(1): 9394, 2021 04 30.
Artículo en Inglés | MEDLINE | ID: mdl-33931672

RESUMEN

Our major concern was to address "yeast endobacteria" which was based on a few reports in the recent past where bacteria may find yeast as a niche for survival. In this study, we report the microbiota of twenty-nine axenic yeast cultures recovered from different habitats based on their 16S rRNA gene-amplicon metagenomes. Yeasts were identified based on D1/D2 or ITS gene sequences. Bacterial diversity was widespread, varied and rich among all yeasts except for four strains. Taxa belonging to the phylum Firmicutes, Proteobacteria, Actinobacteria and Bacteroidetes and the genera; Streptococcus, Propionibacterium were common to all the yeasts. Candida tropicalis was used as a model organism to confirm bacteria through fluorescence in situ hybridization (FISH), isolating and re-introducing the isolated bacteria into the yeast. FISH analysis confirmed the endobacteria of C. tropicalis and we have successfully isolated four bacteria only after lysis and disruption of yeast cells. These bacteria were identified as species of Pseudomonas, Chryseobacterium, Lysinibacillus and Propionibacterium. Guestimates indicate 95% of bacterial species of C. tropicalis are yet-to-be-cultivated. We have successfully reintroduced mCherry tagged Pseudomonas into C. tropicalis. Also, auto-fluorescent Prochlorococcus and Rhodopseudomonas could be introduced into C. tropicalis while mCherry tagged E. coli or Salmonella could not be introduced. FISH analysis confirmed the presence of both native and infected bacterial cells present in C. tropicalis. Our findings unveil the insights into the ghost microbiota associated with yeast, which otherwise are considered to be axenic cultures. Their inherent occurrence, together with co-cultivation experiments under laboratory conditions suggests that yeasts are a thriving hub for bacterial communities.


Asunto(s)
Bacterias/genética , Candidiasis/microbiología , Microbiota , Levaduras/fisiología , Bacterias/aislamiento & purificación , Candidiasis/genética , ARN Ribosómico 16S/genética , Levaduras/clasificación
19.
Cell Rep ; 35(1): 108955, 2021 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-33826894

RESUMEN

Trained immunity (TI) is a de facto innate immune memory program induced in monocytes/macrophages by exposure to pathogens or vaccines, which evolved as protection against infections. TI is characterized by immunometabolic changes and histone post-translational modifications, which enhance production of pro-inflammatory cytokines. As aberrant activation of TI is implicated in inflammatory diseases, tight regulation is critical; however, the mechanisms responsible for this modulation remain elusive. Interleukin-37 (IL-37) is an anti-inflammatory cytokine that curbs inflammation and modulates metabolic pathways. In this study, we show that administration of recombinant IL-37 abrogates the protective effects of TI in vivo, as revealed by reduced host pro-inflammatory responses and survival to disseminated candidiasis. Mechanistically, IL-37 reverses the immunometabolic changes and histone post-translational modifications characteristic of TI in monocytes, thus suppressing cytokine production in response to infection. IL-37 thereby emerges as an inhibitor of TI and as a potential therapeutic target in immune-mediated pathologies.


Asunto(s)
Antiinflamatorios/farmacología , Inmunidad Innata , Interleucina-1/farmacología , Animales , Candidiasis/genética , Candidiasis/inmunología , Candidiasis/microbiología , Epigénesis Genética/efectos de los fármacos , Glucólisis/efectos de los fármacos , Glucólisis/genética , Interacciones Huésped-Patógeno/efectos de los fármacos , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad Innata/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo
20.
PLoS Pathog ; 17(3): e1009138, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33788904

RESUMEN

Candida tropicalis is a human pathogen that primarily infects the immunocompromised. Whereas the genome of one isolate, C. tropicalis MYA-3404, was originally sequenced in 2009, there have been no large-scale, multi-isolate studies of the genetic and phenotypic diversity of this species. Here, we used whole genome sequencing and phenotyping to characterize 77 isolates of C. tropicalis from clinical and environmental sources from a variety of locations. We show that most C. tropicalis isolates are diploids with approximately 2-6 heterozygous variants per kilobase. The genomes are relatively stable, with few aneuploidies. However, we identified one highly homozygous isolate and six isolates of C. tropicalis with much higher heterozygosity levels ranging from 36-49 heterozygous variants per kilobase. Our analyses show that the heterozygous isolates represent two different hybrid lineages, where the hybrids share one parent (A) with most other C. tropicalis isolates, but the second parent (B or C) differs by at least 4% at the genome level. Four of the sequenced isolates descend from an AB hybridization, and two from an AC hybridization. The hybrids are MTLa/α heterozygotes. Hybridization, or mating, between different parents is therefore common in the evolutionary history of C. tropicalis. The new hybrids were predominantly found in environmental niches, including from soil. Hybridization is therefore unlikely to be associated with virulence. In addition, we used genotype-phenotype correlation and CRISPR-Cas9 editing to identify a genome variant that results in the inability of one isolate to utilize certain branched-chain amino acids as a sole nitrogen source.


Asunto(s)
Candida tropicalis/genética , Candida/genética , Candidiasis/genética , Genoma/genética , Virulencia/genética , Antifúngicos/farmacología , Candida tropicalis/clasificación , Candida tropicalis/patogenicidad , Farmacorresistencia Fúngica , Ambiente , Metagenómica/métodos , Pruebas de Sensibilidad Microbiana
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