The impact of the Fungus-Host-Microbiota interplay upon Candida albicans infections : current knowledge and new perspectives

ACKNOWLEDGEMENTS: We thank our friends and colleagues in the medical mycology, fungal immunology and microbiota fields for many thought-provoking discussions. FUNDING: We received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie action, Innovative Training Network: FunHoMic; grant N° 812969. CdE received funding from the French Government ‘Investissement d’Avenir’ program (Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases, ANR-10-LABX-62-IBEID), the Agence Nationale de la Recherche (ERA-Net Infect-ERA, FUNCOMPATH, ANR-14-IFEC-0004), the EU Horizon2020 consortium “Host-Directed Medicine in invasive FUNgal infections” - HDM-FUN (Grant Agreement 847507). SLL and CdE received funding from the Swiss National Science Foundation (Sinergia program, #CRSII5_173863). BIOASTER received funding from the French Government ‘Investissement d’Avenir’ program (Grant No. ANR-10-AIRT-03). MSG was supported by a Humboldt Research Fellowship for Postdoctoral Researchers by the Alexander von Humboldt-Foundation and the Deutsche Forschungsgemeinschaft (DFG) Emmy Noether Program (project no. 434385622 / GR 5617/1-1). BH was supported by the Deutsche Forschungsgemeinschaft (DFG) project Hu 532/20-1, project C1 within the Collaborative Research Centre (CRC)/Transregio 124 FungiNet and the Balance of the Microverse Cluster under Germany´s Excellence Strategy – EXC 2051 – Project-ID 390713860, the EU Horizon2020 consortium “Host-Directed Medicine in invasive FUNgal infections” - HDM-FUN (Grant Agreement 847507), the Leibniz Association Campus InfectoOptics SAS-2015-HKI-LWC and the Wellcome Trust (215599/Z/19/Z). IDJ was supported by the Deutsche orschungsgemeinschaft (DFG) project C5 within the Collaborative Research Centre (CRC)/Transregio 124 FungiNet and the Balance of the Microverse Cluster under Germany´s Excellence Strategy – EXC 2051 – Project-ID 390713860, the Leibniz Association Campus InfectoOptics SAS-2015-HKI-LWC and the Wellcome Trust (Grant 215599/Z/19/Z). CM received funding from the the Instituto de Salud Carlos III/FEDER. MGN was supported by an ERC Advanced Grant (#833247) and a Spinoza grant of the Netherlands Organization for Scientific Research. CAM was supported by EU Horizon2020 consortium “Host-Directed Medicine in invasive FUNgal infections” -HDM-FUN (Grant Agreement 847507) and the Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology (097377/Z/11/Z). AWW receives core funding support from the Scottish Government’s Rural and Environment Science and Analytical Services (RESAS). AJPB was supported by a programme grant from the UK Medical Research Council (MR/M026663/1) and by the Medical Research Council Centre for Medical Mycology at the University of Exeter (MR/N006364/1).Peer reviewedPublisher PD

Régulation de l'activation et de la survie des mastocytes par l'inositol-phosphatase SHIP1

L engagement des récepteurs de forte affinité pour les IgE (RFc I) et des récepteurs de faible affinité pour les IgG (RFc ) exprimés par les mastocytes participe, respectivement, au déclenchement de l allergie et de certaines maladies autoimmunes. Après engagement des RFc I à la surface des mastocytes, l adaptateur transmembranaire LAT devient tyrosyl-phosphorylé et organise le recrutement de molécules de signalisation. LAT intègre principalement des signaux positifs mais également des signaux négatifs. Cette première partie de mon travail de thèse est une étude des mécanismes moléculaires qui régulent négativement l activation des mastocytes après engagement des RFc I et qui dépendent de LAT. J ai observé que LAT recrute l inositol-phosphatase SHIP1 et que ce recrutement affecte la survie des mastocytes. Par ailleurs, l activation des mastocytes par des complexes immuns à IgG est capable de déclencher l apparition de certaines maladies autoimmunes. L absence de modèle cellulaire de mastocytes matures capable de répondre à une agrégation des RFc par des complexes immuns à IgG rend difficile l étude des mécanismes régulateurs mis en jeu dans ces pathologies. Cette deuxième partie de mon travail de thèse est la description d un nouveau modèle murin de mastocytes dérivé in vitro à partir de cellules du péritoine. Ce modèle représente des mastocytes séreux matures. Pour une raison indéterminée, SHIP1 est moins bien utilisé dans ces mastocytes, ce qui confère à ces cellules la capacité de répondre à une stimulation par des complexes immuns à IgG. Ce travail de thèse identifie SHIP1 comme une molécule régulatrice clé de l activation et de la survie des mastocytes.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Non-T Cell Activation Linker Promotes Mast Cell Survival by Dampening the Recruitment of SHIP1 by Linker for Activation of T Cells.

International audienceThe linker for activation of T cells (LAT) and the non-T cell activation linker (NTAL) are two transmembrane adapters which organize IgE receptor (FcepsilonRI) signaling complexes in mast cells. LAT positively regulates, whereas NTAL negatively regulates mast cell activation. We previously found that the four distal tyrosines of LAT can generate negative signals. We show here that two of these tyrosines provide two binding sites for SHIP1, that LAT recruits SHIP1 in vivo, and that SHIP1 recruitment is enhanced in NTAL-deficient cells. We show that NTAL negatively regulates mast cell activation by decreasing the recruitment, by LAT, of molecules involved in FcepsilonRI-dependent positive signaling. We show that NTAL also decreases the recruitment of SHIP1 by LAT, leading to an increased phosphorylation of the antiapoptotic molecule Akt, and positively regulates mast cell survival. We finally show that the positive effect of NTAL on Akt phosphorylation and mast cell survival requires LAT. Our data thus document the mechanisms by which LAT and NTAL can generate both positive and negative signals which differentially regulate mast cell activation and survival. They also provide molecular bases for the recruitment of SHIP1 in FcepsilonRI signaling complexes. SHIP1 is a major negative regulator of mast cell activation and, hence, of allergic reactions

Peritoneal cell-derived mast cells: an in vitro model of mature serosal-type mouse mast cells.

Bone marrow-derived mast cells (BMMC) have been used extensively as a mast cell model. BMMC, however, are immature cells that have no known physiological equivalent in tissues. They do not respond to IgG immune complexes. They may therefore not be appropriate for studying the physiopathology of IgE-induced allergies or IgG-induced tissue-specific inflammatory diseases which both depend on mature mast cells. Resident peritoneal mast cells are a minor population of differentiated cells that are not readily purified. They, however, can be expanded in culture to generate large numbers of homogeneous cells. We show here that these peritoneal cell-derived mast cells (PCMC) are mature serosal-type mouse mast cells which retain most morphological, phenotypic, and functional features of peritoneal mast cells. Like peritoneal mast cells, PCMC respond to IgG Abs. IgG immune complex-induced responses depended on FcgammaRIIIA and were negatively regulated by FcgammaRIIB. We found that a moderate FcgammaRIIB-dependent negative regulation, due not to a higher FcgammaRIIIA/FcgammaRIIB ratio, but to a relatively inefficient use of the lipid phosphatase SHIP1, determines this property of PCMC. PCMC also respond to IgE Abs. IgE-induced PCMC responses, however, differed quantitatively and qualitatively from BMMC responses. PCMC secreted no or much lower amounts of lipid mediators, chemokines, and cytokines, but they contained and released much higher amounts of preformed granular mediators. PCMC, but not BMMC, also contained and, upon degranulation, released molecules with a potent proteolytic activity. These properties make PCMC a useful new model for understanding the physiopathology of mast cells in IgE- and IgG-dependent tissue inflammation

Elemental sulfur enhances the anti-fungal effect of Lacticaseibacillus rhamnosus Lcr35

International audienceLacticaseibacillus rhamnosus Lcr35 is a well-known bacterial strain whose efficiency in preventing recurrent vulvovaginal candidiasis has been largely demonstrated in clinical trials. The presence of sodium thiosulfate (STS) has been shown to enhance its ability to inhibit the growth of Candida albicans strains. In this study, we confirmed that Lcr35 has a fungicidal effect not only on the planktonic form of C. albicans but also on other life forms such as hypha and biofilm. Transcriptomic analysis showed that the presence of C. albicans induced a metabolic adaptation of Lcr35 potentially associated with a competitive advantage over yeast cells. However, STS alone had no impact on the global gene expression of Lcr35, which is not in favor of the involvement of an enzymatic transformation of STS. Comparative HPLC and gas chromatography-mass spectrometry analysis of the organic phase from cell-free supernatant (CFS) fractions obtained from Lcr35 cultures performed in the presence and absence of STS identified elemental sulfur (S0) in the samples initially containing STS. In addition, the anti-Candida activity of CFS from STS-containing cultures was shown to be pH-dependent and occurred at acidic pH lower than 5. We next investigated the antifungal activity of lactic acid and acetic acid, the two main organic acids produced by lactobacilli. The two molecules affected the viability of C. albicans but only at pH 3.5 and in a dose-dependent manner, an antifungal effect that was enhanced in samples containing STS in which the thiosulfate was decomposed into S0. In conclusion, the use of STS as an excipient in the manufacturing process of Lcr35 exerted a dual action since the production of organic acids by Lcr35 facilitates the decomposition of thiosulfate into S0, thereby enhancing the bacteria's own anti-fungal effect

The impact of the Fungus-Host-Microbiota interplay upon Candida albicans infections: current knowledge and new perspectives

Candida albicans is a major fungal pathogen of humans. It exists as a commensal in the oral cavity, gut or genital tract of most individuals, constrained by the local microbiota, epithelial barriers and immune defences. Their perturbation can lead to fungal outgrowth and the development of mucosal infections such as oropharyngeal or vulvovaginal candidiasis, and patients with compromised immunity are susceptible to life-threatening systemic infections. The importance of the interplay between fungus, host and microbiota in driving the transition from C. albicans commensalism to pathogenicity is widely appreciated. However, the complexity of these interactions, and the significant impact of fungal, host and microbiota variability upon disease severity and outcome, are less well understood. Therefore, we summarise the features of the fungus that promote infection, and how genetic variation between clinical isolates influences pathogenicity. We discuss antifungal immunity, how this differs between mucosae, and how individual variation influences a person's susceptibility to infection. Also, we describe factors that influence the composition of gut, oral and vaginal microbiotas, and how these affect fungal colonisation and antifungal immunity. We argue that a detailed understanding of these variables, which underlie fungal-host-microbiota interactions, will present opportunities for directed antifungal therapies that benefit vulnerable patients

The impact of the Fungus-Host-Microbiota interplay upon Candida albicans infections: current knowledge and new perspectives

International audienceCandida albicans is a major fungal pathogen of humans. It exists as a commensal in the oral cavity, gut or genital tract of most individuals, constrained by the local microbiota, epithelial barriers and immune defences. Their perturbation can lead to fungal outgrowth and the development of mucosal infections such as oropharyngeal or vulvovaginal candidiasis, and patients with compromised immunity are susceptible to life-threatening systemic infections. The importance of the interplay between fungus, host and microbiota in driving the transition from C. albicans commensalism to pathogenicity is widely appreciated. However, the complexity of these interactions, and the significant impact of fungal, host and microbiota variability upon disease severity and outcome, are less well understood. Therefore, we summarise the features of the fungus that promote infection, and how genetic variation between clinical isolates influences pathogenicity. We discuss antifungal immunity, how this differs between mucosae, and how individual variation influences a person's susceptibility to infection. Also, we describe factors that influence the composition of gut, oral and vaginal microbiotas, and how these affect fungal colonisation and antifungal immunity. We argue that a detailed understanding of these variables, which underlie fungal-host-microbiota interactions, will present opportunities for directed antifungal therapies that benefit vulnerable patients

High Risk of Anal and Rectal Cancer in Patients With Anal and/or Perianal Crohn’s Disease

International audienceBackground & AimsLittle is known about the magnitude of the risk of anal and rectal cancer in patients with anal and/or perineal Crohn’s disease. We aimed to assess the risk of anal and rectal cancer in patients with Crohn’s perianal disease followed up in the Cancers Et Surrisque Associé aux Maladies Inflammatoires Intestinales En France (CESAME) cohort.MethodsWe collected data from 19,486 patients with inflammatory bowel disease (IBD) enrolled in the observational CESAME study in France, from May 2004 through June 2005; 14.9% of participants had past or current anal and/or perianal Crohn’s disease. Subjects were followed up for a median time of 35 months (interquartile range, 29–40 mo). To identify risk factors for anal cancer in the total CESAME population, we performed a case-control study in which participants were matched for age and sex.ResultsAmong the total IBD population, 8 patients developed anal cancer and 14 patients developed rectal cancer. In the subgroup of 2911 patients with past or current anal and/or perianal Crohn’s lesions at cohort entry, 2 developed anal squamous-cell carcinoma, 3 developed perianal fistula–related adenocarcinoma, and 6 developed rectal cancer. The corresponding incidence rates were 0.26 per 1000 patient-years for anal squamous-cell carcinoma, 0.38 per 1000 patient-years for perianal fistula–related adenocarcinoma, and 0.77 per 1000 patient-years for rectal cancer. Among the 16,575 patients with ulcerative colitis or Crohn’s disease without anal or perianal lesions, the incidence rate of anal cancer was 0.08 per 1000 patient-years and of rectal cancer was 0.21 per 1000 patient-years. Among factors tested by univariate conditional regression (IBD subtype, disease duration, exposure to immune-suppressive therapy, presence of past or current anal and/or perianal lesions), the presence of past or current anal and/or perianal lesions at cohort entry was the only factor significantly associated with development of anal cancer (odds ratio, 11.2; 95% CI, 1.18-551.51; P = .03).ConclusionsIn an analysis of data from the CESAME cohort in France, patients with anal and/or perianal Crohn’s disease have a high risk of anal cancer, including perianal fistula–related cancer, and a high risk of rectal cancer