Antifungal susceptibility and phenotypic characterization of oral isolates of a black fungus from a nasopharyngeal carcinoma patient under radiotherapy

10.1186/s12903-015-0023-9BMC Oral Health15

β-Glucan Grafted Microcapsule, a Tool for Studying the Immunomodulatory Effect of Microbial Cell Wall Polysaccharides

Acknowledgements This study was supported by the Centre Franco-Indien pour la Promotion de la Recherche avancée and Agence nationale de la recherche-Deutsche Forschungsgemeinschaft grants, the Institut Universitaire de France, La région Ile de France, BPI France and benefited from the facilities of MIMA2 MEB-GABI, INRA, Agroparistech, 78352 Jouy-en-Josas, France. Funding sources: CEFIPRA (Centre Franco-Indien pour la Promotion de la Recherche avancée; Grant No. 5403-1, Pathogenic Aspergillus) to JPL and VA, and Agence nationale de la recherche and Deutsche Forschungsgemeinschaft (ANR-DFG bilateral grant, AfuINTERACT) to JPL.Peer reviewedPostprin

New “haploid biofilm model” unravels IRA2 as a novel regulator of Candida albicans biofilm formation

published_or_final_versio

Complement-Mediated Differential Immune Response of Human Macrophages to Sporothrix Species Through Interaction With Their Cell Wall Peptidorhamnomannans

Funding This work was supported by Fundação de Apoio à Pesquisa do Distrito Federal (FAP-DF)/CNPq, PRONEX grant ID: (FAP-DF, 0193.001.200/2016). VA is supported by the Centre Franco-Indien pour la Promotion de la Recherche Avancée (CEFIPRA) grant No. 5403-1 and ANR-DFG AfuINF grant. IG, VA, and CS were supported by the ANR-FUNHYDRO (ANR-16S-CE110020-01) grant. NG, GB and JW are supported by the Welcome Trust (102705, 097377, 101873, 215599 and 200208) and the Medical Research Council Centre for Medical Mycology (MR/N006364/2). Acknowledgments The authors acknowledge Dr. Lars Erwig, Dr. Jude Bain, and Dr. Kevin MacKenzie of University of Aberdeen for the scientific and technical support in the video microscopy experiments. LMLB was a research fellow of Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). We acknowledge Fundação Carlos Chagas Filho de Amparo a Pesquisa do estado do Rio de Janeiro (Faperj) and Pasteur-Roux-Cantarini postdoctoral fellowship for the research fellowships given to GWPN and SSWW, respectively.Peer reviewedPublisher PD

Host Soluble Mediators: Defying the Immunological Inertness of Aspergillus fumigatus Conidia

Aspergillus fumigatus produce airborne spores (conidia), which are inhaled in abundant quantity. In an immunocompromised population, the host immune system fails to clear the inhaled conidia, which then germinate and invade, leading to pulmonary aspergillosis. In an immunocompetent population, the inhaled conidia are efficiently cleared by the host immune system. Soluble mediators of the innate immunity, that involve the complement system, acute-phase proteins, antimicrobial peptides and cytokines, are often considered to play a complementary role in the defense of the fungal pathogen. In fact, the soluble mediators are essential in achieving an efficient clearance of the dormant conidia, which is the morphotype of the fungus upon inhalation by the host. Importantly, harnessing the host soluble mediators challenges the immunological inertness of the dormant conidia due to the presence of the rodlet and melanin layers. In the review, we summarized the major soluble mediators in the lung that are involved in the recognition of the dormant conidia. This knowledge is essential in the complete understanding of the immune defense against A. fumigatus

Soluble mediators in anti-fungal immunity

International audienceAlthough soluble mediators of our innate immune system have a substantial impact on invading microbes, their role against fungal pathogens has been underexplored. Constituting the humoral immunity, soluble mediators comprise the complement system, collectins, acute-phase proteins, antibodies and antimicrobial peptides. These components can prevent fungal infection either by directly interacting with invading microbes, leading to their aggregation (microbistatic), destruction (microbicidal) or linking them to cellular immunity. The composition of soluble-mediator varies with human body-fluids, resulting in different antifungal mechanisms. Moreover, cellular immune system deploys both oxidative and non-oxidative mechanisms to destroy extracellular or internalized fungal pathogens; however, cellular immune activation is mainly influenced as well as regulated by soluble mediators. This review outlines the antifungal mechanism employed, directly or indirectly, by soluble mediators, and in response, the evading strategies of the fungal pathogens

A novel antifungal for Candida infections : its in vitro and in vivo efficacy and proposed mechanism of action

Candida is the major fungal pathogen in humans that causes infections from superficial mucosal to systemic mycoses. In recent years, the incidence of Candida infections has increased due to the growing body of immunocompromised host populations. In addition, shifting of species distribution and the emergence of antifungal resistance have caused frequent treatment failure. These key issues highlight an urgent need for new antifungals. In such a quest, this research involved a high-throughput screening of a library of 50,240 small molecules for yeast-to-hypha transition inhibitors, to identify and characterize novel small molecules with antifungal properties. From the highthroughput screening, 20 novel small molecules were identified as yeast-to-hypha inhibitors. Their antifungal and anti-biofilm properties were further examined with a wide range of Candida species. Following the extensive screening assays, SM21, which demonstrated the most potent antifungal activity, was selected as the final hit compound. Subsequently, SM21 was evaluated comprehensively for its in vitro and in vivo efficacy. In vitro, SM21 displayed strong inhibition of yeast-to-hypha transition at low concentrations and under hyphae-inducing conditions for a wide range of reference and clinical Candida strains. Moreover, SM21 exhibited anti-biofilm activity and also anti-adhesion activity of Candida on denture acrylic surfaces. With regard to the high prevalence of denture stomatitis, a new denture material incorporating SM21 was produced and evaluated. The SM21-incorporated denture material exhibited anti-adhesion activity and steadily released SM21 in a time-dependent manner. SM21 was also shown to be non-cytotoxic in vitro and in vivo. In vivo efficacy of SM21 was examined in systemic and oral candidiasis mouse models. SM21 treatment was successful in reducing mortality rate and fungal burden of the organs in the systemic candidiasis mouse model. SM21 treatment significantly reduced tongue lesions in the oral candidiasis mouse model. Lastly, the mechanism of action of SM21 was examined by transcriptomics (microarray) and proteomics approaches (label-free quantitative mass spectrometry). The expression of genes and proteins involved in the synthesis of components of the Candida cell wall and plasma membrane were significantly modulated by SM21. Hence, it was proposed that SM21 targets both the Candida cell wall and plasma membrane. In conclusion, the newly discovered small molecule, SM21, which possesses potent in vitro and in vivo efficacy, appears to be potentially a promising agent in managing Candida infections.published_or_final_versionDentistryDoctoralDoctor of Philosoph

Wnt-β-Catenin Signaling in Human Dendritic Cells Mediates Regulatory T-Cell Responses to Fungi via the PD-L1 Pathway

International audienceThe signaling pathways activated following interaction between dendritic cells (DCs) and a pathogen determine the polarization of effector T-cell and regulatory T-cell (Treg) responses to the infection. Several recent studies, mostly in the context of bacterial infections, have shown that the Wnt/b-catenin pathway plays a major role in imparting tolerogenic features in DCs and in promotion of Treg responses. However, the significance of the Wnt/b-catenin pathway's involvement in regulating the immune response to the fungal species is not known. Using Aspergillus fumigatus, a ubiquitous airborne opportunistic fungal species, we show here that fungi activate the Wnt/b-catenin pathway in human DCs and are critical for mediating the immunosuppressive Treg responses. Pharmacological inhibition of this pathway in DCs led to inhibition of maturation-associated molecules and interleukin 10 (IL-10) secretion without affecting the majority of the inflammatory cytokines. Furthermore, blockade of Wnt signaling in DCs suppressed DC-mediated Treg responses in CD4 1 T cells and downregulated both tumor necrosis factor alpha (TNF-a) and IL-10 responses in CD8 1 T cells. Mechanistically, induction of b-catenin pathway by A. fumigatus required C-type lectin receptors and promoted Treg polarization via the induction of programmed death-ligand 1 on DCs. Further investigation on the identity of fungal molecular patterns has revealed that the cell wall polysaccharides b-(1, 3)-glucan and a-(1, 3)-glucan, but not chitin, possess the capacity to activate the b-catenin pathway. Our data suggest that the Wnt/b-catenin pathway is a potential therapeutic target to selectively suppress the Treg response and to sustain the protective Th1 response in the context of invasive aspergillosis caused by A. fumigatus

Proteomic Analysis of Humoral Immune Components in Bronchoalveolar Lavage of Patients Infected or Colonized by Aspergillus fumigatus

International audienceHumoral immune components have been individually studied in the context of interaction of host with , a major airborne fungal pathogen. However, a global view of the multitude and complex nature of humoral immune components is needed to bring new insight into host- interaction. Therefore, we undertook comparative proteomic analysis of the bronchoalveolar lavage fluid collected from individuals infected or colonized with versus controls, to identify those alveolar humoral components affected upon infection. Complement proteins C1q, C8 beta-chain, factor-H, ficolin-1, ficolin-2, mannan binding lectin serine peptidase 2, pentraxin-3 and the surfactant protein-D were identified as the major humoral immune components affected by infection and colonization. Based on this observation, we hypothesize that crosstalk between these humoral components is essential during host- interaction giving new specific leads to study for better understanding the pathogenesis. Furthermore, the affected humoral components could be potential diagnostic markers of infection or colonization

Treatment of Cyclosporin A retains host defense against invasive pulmonary aspergillosis in a non-immunosuppressive murine model by preserving the myeloid cell population

Cyclosporin A (CsA) is widely used as an immunosuppressive agent for organ transplant recipients. CsA inhibits calcineurin, which is highly conserved in mammals and fungi, and thus affects both types of organism. In mammals, the immunosuppressive effect of CsA is via hampering T cell activation. In fungi, the growth inhibitory effect of CsA is via interference with hyphal growth. The aim of this study was to determine whether CsA renders mice susceptible to invasive pulmonary aspergillosis (IPA) and whether it can protect immunosuppressed mice from infection. We therefore examined both the antifungal and the immunosuppressive activity of CsA in immunosuppressed and in immunocompetent mice infected with Aspergillus fumigatus to model IPA. We found that daily injections of CsA could not produce an antifungal effect sufficient to rescue immunosuppressed mice from lethal IPA. However, a 100% survival rate was obtained in nonimmunosuppressed mice receiving daily CsA, indicating that CsA did not render the mice vulnerable to IPA. The lymphocyte subset was significantly suppressed by CsA, while the myeloid subset was not. Therefore, we speculate that CsA does not impair the host defense against IPA since the myeloid cells are preserved