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Host-Microbe Interactions as Key Mediators in Fungal Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 14112

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Special Issue Editors

Dr. Costantini Claudio

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Guest Editor

Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Interests: immunopathology; metagenomics; metabolomics; infections
Special Issues, Collections and Topics in MDPI journals

Dr. Giorgia Renga

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Guest Editor

Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy

Dr. Vasileios Oikonomou

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Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Special Issue Information

Dear Colleagues,

Fungal diseases represent a significant health problem, with current estimates reporting over 1 billion people affected and more than 1.5 million deaths annually. Current antifungal drugs target fungi-selective components; however, their efficacy has proved to be limited in certain clinical settings, and host-directed approaches may bear the potential for innovative therapeutic strategies. An additional level of complexity is represented by the microbial communities, or microbiota, that colonize all of the surfaces of the body exposed to the external environment, and engage in reciprocal interactions with the host for mutual advantage. Dysregulation of host–microbial interactions is increasingly being associated with pathological conditions, including infectious diseases. We are now beginning to understand how fungi, either commensals or transiently interacting with the host, participate in host–microbe cross-talk and are influenced in their activity and pathogenicity.

Contributions to this Special Issue will deal with the role of host–microbe interactions in fungal diseases, the underlying mechanisms, and the potential targets for therapeutic purposes.

Dr. Costantini Claudio
Dr. Giorgia Renga
Dr. Vasileios Oikonomou
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

fungal diseases
microbiota
tolerance
antifungal drugs
host–microbe interaction
inflammation

Published Papers (5 papers)

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Research

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15 pages, 1638 KiB

Open AccessArticle

K143R Amino Acid Substitution in 14-α-Demethylase (Erg11p) Changes Plasma Membrane and Cell Wall Structure of Candida albicans

by Daria Derkacz, Przemysław Bernat and Anna Krasowska

Int. J. Mol. Sci. 2022, 23(3), 1631; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031631 - 31 Jan 2022

Cited by 7 | Viewed by 2594

Abstract

The opportunistic pathogen Candida albicans is responsible for life-threating infections in immunocompromised individuals. Azoles and polyenes are two of the most commonly used antifungals and target the ergosterol biosynthesis pathway or ergosterol itself. A limited number of clinically employed antifungals correspond to the development of resistance mechanisms. One resistance mechanism observed in clinical isolates of azole-resistant C. albicans is the introduction of point mutations in the ERG11 gene, which encodes a key enzyme (lanosterol 14-α-demethylase) on the ergosterol biosynthesis pathway. Here, we demonstrate that a point mutation K143R in ERG11 (C. albicans ERG11^K143R/K143R) contributes not only to azole resistance, but causes increased gene expression. Overexpression of ERG11 results in increased ergosterol content and a significant reduction in plasma membrane fluidity. Simultaneously, the same point mutation caused cell wall remodeling. This could be facilitated by the unmasking of chitin and β-glucan on the fungal cell surface, which can lead to recognition of the highly immunogenic β-glucan, triggering a stronger immunological reaction. For the first time, we report that a frequently occurring azole-resistance strategy makes C. albicans less susceptible to azole treatment while, at the same time, affects its cell wall architecture, potentially leading to exposure of the pathogen to a more effective host immune response. Full article

(This article belongs to the Special Issue Host-Microbe Interactions as Key Mediators in Fungal Diseases)

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13 pages, 4095 KiB

Open AccessArticle

A Shifted Composition of the Lung Microbiota Conditions the Antifungal Response of Immunodeficient Mice

by Emilia Nunzi, Giorgia Renga, Melissa Palmieri, Giuseppe Pieraccini, Marilena Pariano, Claudia Stincardini, Fiorella D’Onofrio, Ilaria Santarelli, Marina Maria Bellet, Andrea Bartoli, Claudio Costantini and Luigina Romani

Int. J. Mol. Sci. 2021, 22(16), 8474; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168474 - 06 Aug 2021

Cited by 3 | Viewed by 1904

Abstract

The microbiome, i.e., the communities of microbes that inhabit the surfaces exposed to the external environment, participates in the regulation of host physiology, including the immune response against pathogens. At the same time, the immune response shapes the microbiome to regulate its composition and function. How the crosstalk between the immune system and the microbiome regulates the response to fungal infection has remained relatively unexplored. We have previously shown that strict anaerobes protect from infection with the opportunistic fungus Aspergillus fumigatus by counteracting the expansion of pathogenic Proteobacteria. By resorting to immunodeficient mouse strains, we found that the lung microbiota could compensate for the lack of B and T lymphocytes in Rag1^–/– mice by skewing the composition towards an increased abundance of protective anaerobes such as Clostridia and Bacteroidota. Conversely, NSG mice, with major defects in both the innate and adaptive immune response, showed an increased susceptibility to infection associated with a low abundance of strict anaerobes and the expansion of Proteobacteria. Further exploration in a murine model of chronic granulomatous disease, a primary form of immunodeficiency characterized by defective phagocyte NADPH oxidase, confirms the association of lung unbalance between anaerobes and Proteobacteria and the susceptibility to aspergillosis. Consistent changes in the lung levels of short-chain fatty acids between the different strains support the conclusion that the immune system and the microbiota are functionally intertwined during Aspergillus infection and determine the outcome of the infection. Full article

(This article belongs to the Special Issue Host-Microbe Interactions as Key Mediators in Fungal Diseases)

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11 pages, 2367 KiB

Open AccessArticle

Lactate Like Fluconazole Reduces Ergosterol Content in the Plasma Membrane and Synergistically Kills Candida albicans

by Jakub Suchodolski, Jakub Muraszko, Przemysław Bernat and Anna Krasowska

Int. J. Mol. Sci. 2021, 22(10), 5219; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105219 - 14 May 2021

Cited by 11 | Viewed by 2479

Abstract

Candida albicans is an opportunistic pathogen that induces vulvovaginal candidiasis (VVC), among other diseases. In the vaginal environment, the source of carbon for C. albicans can be either lactic acid or its dissociated form, lactate. It has been shown that lactate, similar to the popular antifungal drug fluconazole (FLC), reduces the expression of the ERG11 gene and hence the amount of ergosterol in the plasma membrane. The Cdr1 transporter that effluxes xenobiotics from C. albicans cells, including FLC, is delocalized from the plasma membrane to a vacuole under the influence of lactate. Despite the overexpression of the CDR1 gene and the increased activity of Cdr1p, C. albicans is fourfold more sensitive to FLC in the presence of lactate than when glucose is the source of carbon. We propose synergistic effects of lactate and FLC in that they block Cdr1 activity by delocalization due to changes in the ergosterol content of the plasma membrane. Full article

(This article belongs to the Special Issue Host-Microbe Interactions as Key Mediators in Fungal Diseases)

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14 pages, 5067 KiB

Open AccessArticle

Fructose Induces Fluconazole Resistance in Candida albicans through Activation of Mdr1 and Cdr1 Transporters

by Jakub Suchodolski and Anna Krasowska

Int. J. Mol. Sci. 2021, 22(4), 2127; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042127 - 21 Feb 2021

Cited by 11 | Viewed by 2345

Abstract

Candida albicans is a pathogenic fungus that is increasingly developing multidrug resistance (MDR), including resistance to azole drugs such as fluconazole (FLC). This is partially a result of the increased synthesis of membrane efflux transporters Cdr1p, Cdr2p, and Mdr1p. Although all these proteins can export FLC, only Cdr1p is expressed constitutively. In this study, the effect of elevated fructose, as a carbon source, on the MDR was evaluated. It was shown that fructose, elevated in the serum of diabetics, promotes FLC resistance. Using C. albicans strains with green fluorescent protein (GFP) tagged MDR transporters, it was determined that the FLC-resistance phenotype occurs as a result of Mdr1p activation and via the increased induction of higher Cdr1p levels. It was observed that fructose-grown C. albicans cells displayed a high efflux activity of both transporters as opposed to glucose-grown cells, which synthesize Cdr1p but not Mdr1p. Additionally, it was concluded that elevated fructose serum levels induce the de novo production of Mdr1p after 60 min. In combination with glucose, however, fructose induces Mdr1p production as soon as after 30 min. It is proposed that fructose may be one of the biochemical factors responsible for Mdr1p production in C. albicans cells. Full article

(This article belongs to the Special Issue Host-Microbe Interactions as Key Mediators in Fungal Diseases)

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Review

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14 pages, 858 KiB

Open AccessReview

The Environmental Effects on Virulence Factors and the Antifungal Susceptibility of Cryptococcus neoformans

by Mahek Momin and Ginny Webb

Int. J. Mol. Sci. 2021, 22(12), 6302; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126302 - 11 Jun 2021

Cited by 5 | Viewed by 3966

Abstract

Cryptococcus neoformans is a facultative intracellular pathogen responsible for fungal meningoencephalitis primarily in immunocompromised individuals. It has become evident the pathogenicity of C. neoformans is dependent on the fungal cell’s environment. The differential expression of virulence factors, based on the cell’s environmental conditions, is one mechanism allowing for the environmental control of the pathogenic ability of C. neoformans. Here, we discuss how these virulence factors (including melanin, the polysaccharide capsule, and Antiphagocytic protein 1) have been shown to be differentially expressed dependent on the cell’s environment. The genetics and signaling pathways leading to the environmental-dependent regulation of virulence factors will also be examined. Susceptibility to antifungal therapeutics is also regulated by the environment, and thus affects the pathogenic abilities of C. neoformans and disease outcomes. This review will also examine the role of the C. neoformans’s environment on antifungal susceptibilities, and the genetics and signaling pathways responsible for these susceptibility alterations. By examining the complex interplay between the environment and the pathogenicity of C. neoformans, we have a better understanding of the intricacies of the pathogen–environment interaction and how to exploit this interaction to develop the most effective treatment protocols. Full article

(This article belongs to the Special Issue Host-Microbe Interactions as Key Mediators in Fungal Diseases)

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