The body is host to a wide variety of microbial communities from which the immune system protects us and that are important for the normal development of the immune system and for the maintenance of ...healthy tissues and physiological processes. Investigators have mostly focused on the bacterial members of these communities, but fungi are increasingly being recognized to have a role in defining these communities and to interact with immune cells. In this Review, we discuss what is currently known about the makeup of fungal communities in the body and the features of the immune system that are particularly important for interacting with fungi at these sites.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The mammalian intestine is colonized by a wealth of microorganisms—including bacteria, viruses, protozoa, and fungi—that are all integrated into a functional trans-kingdom community. Characterization ...of the composition of the fungal community—the mycobiota—has advanced further than the much-needed mechanistic studies. Recent findings have revealed roles for the gut mycobiota in the regulation of host immunity and in the development and progression of human diseases of inflammatory origin. We review these findings here while placing them in the context of the current understanding of the pathways and cellular networks that induce local and systemic immune responses to fungi in the gastrointestinal tract. We discuss gaps in knowledge and argue for the importance of considering bacteria-fungal interactions as we aim to define the roles of mycobiota in immune homeostasis and immune-associated pathologies.
Iliev and colleagues review the impact of the gut mycobiota on the regulation of host immunity in homeostasis and in human disease and discuss the current understanding of the mechanisms that underlie these effects.
Fungal microorganisms (mycobiota) comprise a small but immunoreactive component of the human microbiome, yet little is known about their role in human cancers. Pan-cancer analysis of multiple body ...sites revealed tumor-associated mycobiomes at up to 1 fungal cell per 10
tumor cells. In lung cancer, Blastomyces was associated with tumor tissues. In stomach cancers, high rates of Candida were linked to the expression of pro-inflammatory immune pathways, while in colon cancers Candida was predictive of metastatic disease and attenuated cellular adhesions. Across multiple GI sites, several Candida species were enriched in tumor samples and tumor-associated Candida DNA was predictive of decreased survival. The presence of Candida in human GI tumors was confirmed by external ITS sequencing of tumor samples and by culture-dependent analysis in an independent cohort. These data implicate the mycobiota in the pathogenesis of GI cancers and suggest that tumor-associated fungal DNA may serve as diagnostic or prognostic biomarkers.
Studying the microbial composition of internal organs and their associations with disease remains challenging due to the difficulty of acquiring clinical biopsies. We designed a statistical model to ...analyze the prevalence of species across sample types from The Cancer Genome Atlas (TCGA), revealing that species equiprevalent across sample types are predominantly contaminants, bearing unique signatures from each TCGA-designated sequencing center. Removing such species mitigated batch effects and isolated the tissue-resident microbiome, which was validated by original matched TCGA samples. Gene copies and nucleotide variants can further distinguish mixed-evidence species. We, thus, present The Cancer Microbiome Atlas (TCMA), a collection of curated, decontaminated microbial compositions of oropharyngeal, esophageal, gastrointestinal, and colorectal tissues. This led to the discovery of prognostic species and blood signatures of mucosal barrier injuries and enabled systematic matched microbe-host multi-omic analyses, which will help guide future studies of the microbiome’s role in human health and disease.
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•Decontaminated microbial compositions for 3,689 gastrointestinal cancer samples•Resolved “mixed-evidence” species with gene and nucleotide resolution•Identified prognostic species and blood signatures of mucosal barrier injury•Enabled matched multi-omic, pan-cancer analyses of host-microbe interactions
Dohlman et al. present The Cancer Microbiome Atlas, a public database of decontaminated, tissue-resident microbial profiles of TCGA gastrointestinal cancer tissues. As these profiles are matched to specific TCGA tissue samples, this work allows identification of prognostic species and provides a resource for performing multi-omic, pan-cancer analyses of host-microbe interactions.
Intestinal fungi are an important component of the microbiota, and recent studies have unveiled their potential in modulating host immune homeostasis and inflammatory disease. Nonetheless, the ...mechanisms governing immunity to gut fungal communities (mycobiota) remain unknown. We identified CX3CR1
mononuclear phagocytes (MNPs) as being essential for the initiation of innate and adaptive immune responses to intestinal fungi. CX3CR1
MNPs express antifungal receptors and activate antifungal responses in a Syk-dependent manner. Genetic ablation of CX3CR1
MNPs in mice led to changes in gut fungal communities and to severe colitis that was rescued by antifungal treatment. In Crohn's disease patients, a missense mutation in the gene encoding CX3CR1 was identified and found to be associated with impaired antifungal responses. These results unravel a role of CX3CR1
MNPs in mediating interactions between intestinal mycobiota and host immunity at steady state and during inflammatory disease.
While the use of probiotics to treat or prevent inflammatory bowel disease (IBD) has been proposed, to this point the clinical benefits have been limited. In this report we analyzed the immunological ...activity of three strains of Lactobacillus to predict their in vivo efficacy in protecting against experimental colitis.
We compared the immunological properties of Lactobacillus plantarum NCIMB8826, L. rhamnosus GG (LGG), L. paracasei B21060 and pathogenic Salmonella typhimurium (SL1344). We studied the stimulatory effects of these different strains upon dendritic cells (DCs) either directly by co-culture or indirectly via conditioning of an epithelial intermediary. Furthermore, we characterized the effects of these strains in vivo using a Dextran sulphate sodium (DSS) model of colitis. We found that the three strains exhibited different abilities to induce inflammatory cytokine production by DCs with L. plantarum being the most effective followed by LGG and L. paracasei. L. paracasei minimally induced the release of cytokines, while it also inhibited the potential of DCs to both produce inflammatory cytokines (IL-12 and TNF-alpha) and to drive Th1 T cells in response to Salmonella. This effect on DCs was found under both direct and indirect stimulatory conditions - i.e. mediated by epithelial cells - and was dependent upon an as yet unidentified soluble mediator. When tested in vivo, L. plantarum and LGG exacerbated the development of DSS-induced colitis and caused the death of treated mice, while, conversely L. paracasei was protective.
We describe a new property of probiotics to either directly or indirectly inhibit DC activation by inflammatory bacteria. Moreover, some immunostimulatory probiotics not only failed to protect against colitis, they actually amplified the disease progression. In conclusion, caution must be exercised when choosing a probiotic strain to treat IBD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In mice, a subpopulation of gut dendritic cells (DCs) expressing CD103 drives the development of regulatory T (T(reg)) cells. Further, it was recently described that the cross-talk between human ...intestinal epithelial cells (IECs) and DCs helps in maintaining gut immune homeostasis via the induction of non-inflammatory DCs. In this study, an analysis was carried out to determine whether IECs could promote the differentiation of CD103+ tolerogenic DCs, and the function of primary CD103+ DCs isolated from human mesenteric lymph nodes (MLNs) was evaluated.
Monocyte-derived DCs (MoDCs) and circulating CD1c+ DCs were conditioned or not with supernatants from Caco-2 cells or IECs isolated from healthy donors or donors with Crohn's disease and analysed for their ability to induce T(reg) cell differentiation. In some cases, transforming growth factor beta (TGFbeta), retinoic acid (RA) or thymic stromal lymphopoietin (TSLP) were neutralised before conditioning. CD103+ and CD103- DCs were sorted by fluorescence-activated cell sorting (FACS) from MLNs and used in T(reg) cell differentiation experiments.
It was found that human IECs promoted the differentiation of tolerogenic DCs able to drive the development of adaptive Foxp3+ T(reg) cells. This control was lost in patients with Crohn's disease and paralleled a reduced expression of tolerogenic factors by primary IECs. MoDCs differentiated with RA or IEC supernatant upregulated the expression of CD103. Consistently, human primary CD103+ DCs isolated from MLNs were endowed with the ability to drive T(reg) cell differentiation. This subset of DCs expressed CCR7 and probably represents a lamina propria-derived migratory population.
A population of tolerogenic CD103+ DCs was identified in the human gut that probably differentiate in response to IEC-derived factors and drive T(reg) cell development.
The intestinal microflora, typically equated with bacteria, influences diseases such as obesity and inflammatory bowel disease. Here, we show that the mammalian gut contains a rich fungal community ...that interacts with the immune system through the innate immune receptor Dectin-1. Mice lacking Dectin-1 exhibited increased susceptibility to chemically induced colitis, which was the result of altered responses to indigenous fungi. In humans, we identified a polymorphism in the gene for Dectin-1 (CLEC7A) that is strongly linked to a severe form of ulcerative colitis. Together, our findings reveal a eukaryotic fungal community in the gut (the "mycobiome") that coexists with bacteria and substantially expands the repertoire of organisms interacting with the intestinal immune system to influence health and disease.
CD103(+) gut dendritic cells (DCs) have been shown to be required for de novo conversion of adaptive T regulatory (Treg) cells. Indoleamine 2,3-dioxygenase (IDO) is an enzyme involved in tryptophan ...catabolism that is expressed by DCs isolated from tumour-draining lymph nodes. IDO-expressing DCs sustain and differentiate Tregs. The aim of this study was to investigate the expression and the possible physiological role of IDO in the tolerogenic properties of intestinal DCs.
The expression level of IDO in CD103(+) and CD103(-) DCs was analysed by qRT-PCR, western blot and immunofluorescence. CD103(+) and CD103(-) DCs were sorted from mesenteric lymph nodes (MLNs) and the small intestinal lamina propria, and the role of IDO in the conversion of Tregs and Th effector cell development was evaluated via specific inhibition or gene deletion. Oral tolerance, experimental colitis and T cell differentiation in vivo were assessed upon IDO inactivation.
We show that, primarily, CD103(+) but not CD103(-) gut DCs express IDO whose inhibition results in reduced CD4(+)Foxp3(+) T regulatory cell conversion and enhanced T cell proliferation. When IDO was inhibited or genetically deleted there was an increase in Th1 and Th17 differentiation both in vitro and in vivo. Finally, in vivo IDO blockade affected the development of Tregs specific for orally administered antigens, impaired oral tolerance induction and exacerbated colitis.
We identified a new IDO-dependent pathway leading to acquisition of tolerogenic functions in mucosal CD103-expressing DCs, indicating IDO as a possible therapeutic target for gut disorders.
Defects in BRCA1, BRCA2, and other members of the homologous recombination pathway have potential therapeutic relevance when used to support agents that introduce or exploit double-stranded DNA ...breaks. This study examines the association between homologous recombination defects and genomic patterns of loss of heterozygosity (LOH).
Ovarian tumours from two independent data sets were characterised for defects in BRCA1, BRCA2, and RAD51C, and LOH profiles were generated. Publically available data were downloaded for a third independent data set. The same analyses were performed on 57 cancer cell lines.
Loss of heterozygosity regions of intermediate size were observed more frequently in tumours with defective BRCA1 or BRCA2 (P=10(-11)). The homologous recombination deficiency (HRD) score was defined as the number of these regions observed in a tumour sample. The association between HRD score and BRCA deficiency was validated in two independent ovarian cancer data sets (P=10(-5) and 10(-29)), and identified breast and pancreatic cell lines with BRCA defects.
The HRD score appears capable of detecting homologous recombination defects regardless of aetiology or mechanism. This score could facilitate the use of PARP inhibitors and platinum in breast, ovarian, and other cancers.
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