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A5

Overview

Immunomodulatory functions of ITAM- and ITIM-coupled receptors (C-type lectins/CTLs and carcinoembryonic antigen-related cell adhesion molecules/CEACAMs) for C. albicans -induced immune responses

Programme: Collaborative Research Center / Transregio 124 "Pathogenic fungi and their human host: Networks of Interaction - FungiNet"

SEEK ID: https://funginet.hki-jena.de/projects/23

Public web page: http://www.funginet.de/project-a5.html

Organisms: Aspergillus fumigatus, Candida albicans, Homo sapiens

INF PALs: No PALs for this Project

Project created: 21st Jul 2015

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Peter Großmann programme_administrator: inactive since 2020-06-01

Projects: FungiNet total, INF, A1, A2, A3, A4 (E), A5, A6, B1, B3 (E), B4, B5, C1, C2, C3, C4 (E), C5, C6 (E), Z1, Z2, FungiNet A - Aspergillus projects, FungiNet B - Bioinformatics projects, FungiNet C - Candida projects, B2

Institutions: Leibniz-Institute for Natural Product Research and Infection Biology Hans Knöll Institute (HKI)

https://orcid.org/0000-0001-6106-724X
Esther Klaile

Projects: A5, FungiNet A - Aspergillus projects, FungiNet total

Institutions: Friedrich Schiller University Jena, Center for Innovation Competence (ZIK) Septomics

https://orcid.org/0000-0001-7389-6862
Tilman Klassert

Projects: A5, FungiNet A - Aspergillus projects, FungiNet C - Candida projects, FungiNet total

Institutions: Friedrich Schiller University Jena, Center for Innovation Competence (ZIK) Septomics

DFG Reviewer

Projects: FungiNet total, FungiNet A - Aspergillus projects, FungiNet B - Bioinformatics projects, FungiNet C - Candida projects, A1, A2, A3, A4 (E), A5, A6, B1, B2, B3 (E), B4, B5, C1, C2, C3, C4 (E), C5, C6 (E), INF, Z1, Z2

Institutions: Leibniz-Institute for Natural Product Research and Infection Biology Hans Knöll Institute (HKI)

Maja Rey adminproject_administratorasset_housekeeper

Projects: INF, FungiNet total, A1, A2, FungiNet A - Aspergillus projects, A3, A4 (E), A5, A6, FungiNet C - Candida projects, C1, C2, C3, C4 (E), C5, C6 (E), FungiNet B - Bioinformatics projects, B3 (E)

Institutions: HITS Heidelberger Institut für Theoretische Studien gGmbH

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Metabolic modeling predicts specific gut bacteria as key determinants for Candida albicans colonization levels.
INF, A5, C1, C2, B5

Abstract (Expand)

Candida albicans is a leading cause of life-threatening hospital-acquired infections and can lead to Candidemia with sepsis-like symptoms and high mortality rates. We reconstructed a genome-scale C. … albicans metabolic model to investigate bacterial-fungal metabolic interactions in the gut as determinants of fungal abundance. We optimized the predictive capacity of our model using wild type and mutant C. albicans growth data and used it for in silico metabolic interaction predictions. Our analysis of more than 900 paired fungal-bacterial metabolic models predicted key gut bacterial species modulating C. albicans colonization levels. Among the studied microbes, Alistipes putredinis was predicted to negatively affect C. albicans levels. We confirmed these findings by metagenomic sequencing of stool samples from 24 human subjects and by fungal growth experiments in bacterial spent media. Furthermore, our pairwise simulations guided us to specific metabolites with promoting or inhibitory effect to the fungus when exposed in defined media under carbon and nitrogen limitation. Our study demonstrates that in silico metabolic prediction can lead to the identification of gut microbiome features that can significantly affect potentially harmful levels of C. albicans.

Authors: Mohammad Mirhakkak, Sascha Schäuble, Tilman Klassert, S. Brunke, Philipp Brandt, D. Loos, R. V. Uribe, F. Senne de Oliveira Lino, Y. Ni, Slavena Vylkova, Hortense Slevogt, Bernhard Hube, Esther Weiß, M. O. A. Sommer, Gianni Panagiotou

Date Published: 15th Dec 2020

Journal: ISME J

Proteome analysis of bronchoalveolar lavage fluids reveals host and fungal proteins highly expressed during invasive pulmonary aspergillosis in mice and humans.
INF, A5, C5

Abstract (Expand)

Invasive pulmonary aspergillosis (IPA) is a severe infection that is difficult to diagnose due to the ubiquitous presence of fungal spores, the underlying diseases of risk patients, and limitations of … currently available markers. In this study, we performed a comprehensive liquid chromatography tandem mass spectrometry (LC-MS/MS)-based identification of host and fungal proteins expressed during IPA in mice and humans. The proteomic analysis of bronchoalveolar lavage samples of individual IPA and control cases allowed the description of common host factors that had significantly increased abundance in both infected animals and IPA patients compared to their controls. Although increased levels of these individual host proteins might not be sufficient to distinguish bacterial from fungal infection, a combination of these markers might be beneficial to improve diagnosis. We also identified 16 fungal proteins that were specifically detected during infection and may be valuable candidates for biomarker evaluation.

Authors: S. Machata, Wolfgang Müller, R. Lehmann, Patricia Sieber, Gianni Panagiotou, A. Carvalho, C. Cunha, K. Lagrou, J. Maertens, Hortense Slevogt, Ilse Jacobsen

Date Published: 12th Oct 2020

Journal: Virulence

Functional surface proteomic profiling reveals the host heat-shock protein A8 as a mediator of Lichtheimia corymbifera recognition by murine alveolar macrophages.
A1, A5, B4, Z2, A6

Abstract (Expand)

Mucormycosis is an emergent, fatal fungal infection of humans and warm-blooded animals caused by species of the order Mucorales. Immune cells of the innate immune system serve as the first line of … defence against inhaled spores. Alveolar macrophages were challenged with the mucoralean fungus Lichtheimia corymbifera and subjected to biotinylation and streptavidin enrichment procedures followed by LC-MS/MS analyses. A total of 28 host proteins enriched for binding to macrophage-L. corymbifera interaction. Among those, the HSP70-family protein Hspa8 was found to be predominantly responsive to living and heat-killed spores of a virulent and an attenuated strain of L. corymbifera. Confocal scanning laser microscopy of infected macrophages revealed colocalization of Hspa8 with phagocytosed spores of L. corymbifera. The amount of detectable Hspa8 was dependent on the multiplicity of infection. Incubation of alveolar macrophages with an anti-Hspa8 antibody prior to infection reduced their capability to phagocytose spores of L. corymbifera. In contrast, anti-Hspa8 antibodies did not abrogate the phagocytosis of Aspergillus fumigatus conidia by macrophages. These results suggest an important contribution of the heat-shock family protein Hspa8 in the recognition of spores of the mucoralean fungus L. corymbifera by host alveolar macrophages and define a potential immunomodulatory therapeutic target.

Authors: M. I. A. Hassan, J. M. Kruse, Thomas Krüger, H. M. Dahse, Z. Cseresnyes, M. G. Blango, Hortense Slevogt, F. Horhold, V. Ast, R. Konig, Marc Thilo Figge, Olaf Kniemeyer, Axel Brakhage, Kerstin Voigt

Date Published: 26th Jun 2020

Journal: Environ Microbiol

Unaltered Fungal Burden and Lethality in Human CEACAM1-Transgenic Mice During Candida albicans Dissemination and Systemic Infection.
FungiNet total, A5

Abstract (Expand)

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1, CD66a) is a receptor for Candida albicans. It is crucial for the immune response of intestinal epithelial cells to this opportunistic … pathogen. Moreover, CEACAM1 is of importance for the mucosal colonization by different bacterial pathogens. We therefore studied the influence of the human CEACAM1 receptor in human CEACAM1-transgenic mice on the C. albicans colonization and infection utilizing a colonization/dissemination and a systemic infection mouse model. Our results showed no alterations in the host response between the transgenic mice and the wild-type littermates to the C. albicans infections. Both mouse strains showed comparable C. albicans colonization and mycobiota, similar fungal burdens in various organs, and a similar survival in the systemic infection model. Interestingly, some of the mice treated with anti-bacterial antibiotics (to prepare them for C. albicans colonization via oral infection) also showed a strong reduction in endogenous fungi instead of the normally observed increase in fungal numbers. This was independent of the expression of human CEACAM1. In the systemic infection model, the human CEACAM1 expression was differentially regulated in the kidneys and livers of Candida-infected transgenic mice. Notably, in the kidneys, a total loss of the largest human CEACAM1 isoform was observed. However, the overwhelming immune response induced in the systemic infection model likely covered any CEACAM1-specific effects in the transgenic animals. In vitro studies using bone marrow-derived neutrophils from both mouse strains also revealed no differences in their reaction to C. albicans. In conclusion, in contrast to bacterial pathogens interacting with CEACAM1 on different mucosal surfaces, the human CEACAM1-transgenic mice did not reveal a role of human CEACAM1 in the in vivo candidiasis models used here. Further studies and different approaches will be needed to reveal a putative role of CEACAM1 in the host response to C. albicans.

Authors: Esther Klaile, M. M. Muller, C. Zubiria-Barrera, S. Brehme, Tilman Klassert, M. Stock, A. Durotin, T. D. Nguyen, S. Feer, B. B. Singer, Peter Zipfel, Sven Rudolphi, Ilse Jacobsen, Hortense Slevogt

Date Published: 19th Dec 2019

Journal: Front Microbiol

The Interaction of Human Pathogenic Fungi With C-Type Lectin Receptors.
A5

Abstract (Expand)

Fungi, usually present as commensals, are a major cause of opportunistic infections in immunocompromised patients. Such infections, if not diagnosed or treated properly, can prove fatal. However, in … most cases healthy individuals are able to avert the fungal attacks by mounting proper antifungal immune responses. Among the pattern recognition receptors (PRRs), C-type lectin receptors (CLRs) are the major players in antifungal immunity. CLRs can recognize carbohydrate ligands, such as beta-glucans and mannans, which are mainly found on fungal cell surfaces. They induce proinflammatory immune reactions, including phagocytosis, oxidative burst, cytokine, and chemokine production from innate effector cells, as well as activation of adaptive immunity via Th17 responses. CLRs such as Dectin-1, Dectin-2, Mincle, mannose receptor (MR), and DC-SIGN can recognize many disease-causing fungi and also collaborate with each other as well as other PRRs in mounting a fungi-specific immune response. Mutations in these receptors affect the host response and have been linked to a higher risk in contracting fungal infections. This review focuses on how CLRs on various immune cells orchestrate the antifungal response and on the contribution of single nucleotide polymorphisms in these receptors toward the risk of developing such infections.

Authors: S. Goyal, J. C. Castrillon-Betancur, Esther Klaile, Hortense Slevogt

Date Published: 20th Jun 2018

Journal: Front Immunol

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