Ilse D. Jacobsen

National Center for Advancing Translational Sciences

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Bernhard Hube

Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI)

Axel A. Brakhage

Friedrich Schiller University Jena

Sascha Brunke

Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI)

Matthias Brock

University of Nottingham

Olaf Kniemeyer

Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI)

Oliver Kurzai

Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI)

Mario Kapitan

Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI)

Maria J. Niemiec

Friedrich Schiller University Jena

Peter F. Zipfel

Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI)

Melanie Polke

Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI)

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Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI)

201

Friedrich Schiller University Jena

167

Jena University Hospital

Leibniz Association

Schiller International University

University of Würzburg

Institut Pasteur

Medizinische Hochschule Hannover

Innsbruck Medical University

Ludwig-Maximilians-Universität München

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The Role of Host and Fungal Factors in the Commensal-to-Pathogen Transition of Candida albicans

Current Clinical Microbiology Reports (2023)

Ilse D. Jacobsen

Abstract Purpose of Review The fungus Candida albicans has evolved to live in close association with warm-blooded hosts and is found frequently on mucosal surfaces of healthy humans. As an opportunistic pathogen, C. albicans can also cause mucosal and disseminated infections (candidiasis). This review describes the features that differentiate the fungus in the commensal versus pathogenic state and the main factors underlying C. albicans commensal-to-pathogen transition. Recent Findings Adhesion, invasion, and tissue damage are critical steps in the infection process. Especially invasion and damage require transcriptional and morphological changes that differentiate C. albicans in the pathogenic from the commensal state. While the commensal-to-pathogen transition has some conserved causes and features in the oral cavity, the female urogenital tract, and the gut, site-specific differences have been identified in recent years. Summary This review highlights how specific factors in the different mucosal niches affect development of candidiasis. Recent evidence suggests that colonization of the gut is not only a risk factor for systemic candidiasis but might also provide beneficial effects to the host.

Fungal pathogen

Pathogenic fungus

Commensalism

10.1007/s40588-023-00190-w

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Citations (21)

Characterization of host-pathogen interactions in an avian whole blood model

Sravya Sreekantapuram Angela Berndt Christian Berens Stefanie Barth Ilse D. Jacobsen

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Unaltered Fungal Burden and Lethality in Human CEACAM1-Transgenic Mice During Candida albicans Dissemination and Systemic Infection

Frontiers in Microbiology (2019)

Esther Klaile Mario M. Müller Cristina Zubiría-Barrera Saskia Brehme Tilman E. Klassert

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.

Systemic candidiasis

10.3389/fmicb.2019.02703

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Use of an Actinobacillus pleuropneumoniae Multiple Mutant as a Vaccine That Allows Differentiation of Vaccinated and Infected Animals

Infection and Immunity (2006)

Alexander Maas Ilse D. Jacobsen Jochen Meens Gerald-F. Gerlach

ABSTRACT Vaccination against Actinobacillus pleuropneumoniae is hampered by the lack of vaccines inducing reliable cross-serotype protection. In contrast, pigs surviving natural infection are at least partially protected from clinical symptoms upon reinfection with any serotype. Thus, we set out to construct an attenuated A. pleuropneumoniae live vaccine allowing the differentiation of vaccinated from infected animals (the DIVA concept) by successively deleting virulence-associated genes. Based on an A. pleuropneumoniae serotype 2 prototype live negative marker vaccine (W. Tonpitak, N. Baltes, I. Hennig-Pauka, and G.-F. Gerlach, Infect. Immun. 70:7120-7125, 2002), genes encoding three enzymes involved in anaerobic respiration and the ferric uptake regulator Fur were deleted, resulting in a highly attenuated sixfold mutant; this mutant was still able to colonize the lower respiratory tract and induced a detectable immune response. Upon a single aerosol application, this mutant provided significant protection from clinical symptoms upon heterologous infection with an antigenically distinct A. pleuropneumoniae serotype 9 challenge strain and allowed the serological discrimination between infected and vaccinated groups.

Actinobacillus pleuropneumoniae

Attenuated vaccine

Heterologous

Actinobacillus

10.1128/iai.00133-06

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Citations (36)

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

Figshare (2021)

Silke Machata Mario M. Müller Roland Lehmann Patricia Sieber Gianni Panagiotou

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.

Proteome

Pulmonary aspergillosis

10.6084/m9.figshare.13078725.v3

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SreA‐mediated iron regulation in Aspergillus fumigatus

Molecular Microbiology (2008)

Markus Schrettl Sun Kim Martin Eisendle Claudia Kragl William C. Nierman

Aspergillus fumigatus, the most common airborne fungal pathogen of humans, employs two high-affinity iron uptake systems: iron uptake mediated by the extracellular siderophore triacetylfusarinine C and reductive iron assimilation. Furthermore, A. fumigatus utilizes two intracellular siderophores, ferricrocin and hydroxyferricrocin, to store iron. Siderophore biosynthesis, which is essential for virulence, is repressed by iron. Here we show that this control is mediated by the GATA factor SreA. During iron-replete conditions, SreA deficiency partially derepressed synthesis of triacetylfusarinine C and uptake of iron resulting in increased cellular accumulation of both iron and ferricrocin. Genome-wide DNA microarray analysis identified 49 genes that are repressed by iron in an SreA-dependent manner. This gene set, termed SreA regulon, includes all known genes involved in iron acquisition, putative novel siderophore biosynthetic genes, and also genes not directly linked to iron metabolism. SreA deficiency also caused upregulation of iron-dependent and antioxidative pathways, probably due to the increased iron content and iron-mediated oxidative stress. Consistently, the sreA disruption mutant displayed increased sensitivity to iron, menadion and phleomycin but retained wild-type virulence in a mouse model. As all detrimental effects of sreA disruption are restricted to iron-replete conditions these data underscore that A. fumigatus faces iron-depleted conditions during infection.

Regulon

10.1111/j.1365-2958.2008.06376.x

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Citations (237)

Functionality of the human antibody response to Candida albicans

Figshare (2021)

Melissa Wich Stephanie Greim Marta Ferreira‐Gomes Thomas Krüger Olaf Kniemeyer

Candida albicans is a common commensal on human mucosal surfaces, but can become pathogenic, e.g. if the host is immunocompromised. While neutrophils, macrophages and T cells are regarded as major players in the defense against pathogenic C. albicans, the role of B cells and the protective function of their antibodies are less well characterized. In this study, we show that human serum antibodies are able to enhance the association of human THP-1 monocyte-like cells with C. albicans cells. Human serum antibodies are also capable of inhibiting the adherence and damage dealt to epithelial cells. Furthermore, human serum antibodies impair C. albicans invasion of human oral epithelial cells by blocking induced endocytosis and consequently host cell damage. While aspartic proteases secreted by C. albicans are able to cleave human IgG, this process does not appear to affect the protective function of human antibodies. Thus, humans are equipped with a robust antibody response to C. albicans, which can enhance antifungal activities and prevent fungal-mediated epithelial damage.

Antibody response

10.6084/m9.figshare.17288352

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Lichtheimia Species Exhibit Differences in Virulence Potential

PLoS ONE (2012)

Volker Schwartze Kerstin Hoffmann Ildikó Nyilasi Tamás Papp Csaba Vágvölgyi

Although the number of mucormycosis cases has increased during the last decades, little is known about the pathogenic potential of most mucoralean fungi. Lichtheimia species represent the second and third most common cause of mucormycosis in Europe and worldwide, respectively. To date only three of the five species of the genus have been found to be involved in mucormycosis, namely L. corymbifera, L. ramosa and L. ornata. However, it is not clear whether the clinical situation reflects differences in virulence between the species of Lichtheimia or whether other factors are responsible. In this study the virulence of 46 strains of all five species of Lichtheimia was investigated in chicken embryos. Additionally, strains of the closest-related genus Dichotomocladium were tested. Full virulence was restricted to the clinically relevant species while all strains of L. hyalospora, L. sphaerocystis and Dichotomocladium species were attenuated. Although virulence differences were present in the clinically relevant species, no connection between origin (environmental vs clinical) or phylogenetic position within the species was observed. Physiological studies revealed no clear connection of stress resistance and carbon source utilization with the virulence of the strains. Slower growth at 37°C might explain low virulence of L. hyalospora, L. spaherocystis and Dichotomocladium; however, similarly slow growing strains of L. ornata were fully virulent. Thus, additional factors or a complex interplay of factors determines the virulence of strains. Our data suggest that the clinical situation in fact reflects different virulence potentials in the Lichtheimiaceae.

Mycology

10.1371/journal.pone.0040908

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Citations (44)

Differential role of NK cells against Candida albicans infection in immunocompetent or immunocompromised mice

European Journal of Immunology (2014)

Jessica Quintin Jessica Voigt Robbert van der Voort Ilse D. Jacobsen Ineke Verschueren

Little is known regarding the role of NK cells during primary and secondary disseminated Candida albicans infection. We assessed the role of NK cells for host defense against candidiasis in immunocompetent, as well as immunodeficient, hosts. Surprisingly, depletion of NK cells in immunocompetent WT mice did not increase susceptibility to systemic candidiasis, suggesting that NK cells are redundant for antifungal defense in otherwise immunocompetent hosts. NK‐cell‐depleted mice were found to be protected as a consequence of attenuation of systemic inflammation. In contrast, the absence of NK cells in T/B/NK‐cell‐deficient NSG (NOD SCID gamma) mice led to an increased susceptibility to both primary and secondary systemic C. albicans infections compared with T/B‐cell‐deficient SCID mice. In conclusion, this study demonstrates that NK cells are an essential and nonredundant component of anti‐ C. albicans host defense in immunosuppressed hosts with defective T/B‐lymphocyte immunity, while contributing to hyperinflammation in immunocompetent hosts. The discovery of the importance of NK cells in hosts with severe defects of adaptive immunity might have important consequences for the design of adjunctive immunotherapeutic approaches in systemic C. albicans infections targeting NK‐cell function.

10.1002/eji.201343828

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Pathogenicity mechanisms and host response during oral Candida albicans infections

Expert Review of Anti-infective Therapy (2014)

Betty Hebecker Julian R. Naglik Bernhard Hube Ilse D. Jacobsen

Oral candidiasis remains one of the most common forms of Candida infections and occurs if the balance between host, Candida and microbiota is disturbed, e.g., by broad spectrum antibiotics or immunosuppression. In recent years, identification of fungal factors contributing to host cell damage and new insights into host defense mechanisms have significantly extended our understanding of the pathogenesis of oral candidiasis. In this review, we will provide an overview of the pathogenicity mechanisms during oral Candida infections and discuss some approaches by which this knowledge could be transferred into therapeutic approaches.

Immunosuppression

Host factors

Host response

Pathogenesis

10.1586/14787210.2014.916210

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Citations (88)