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Antifungal Immunity and Fungal Vaccine Development

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A special issue of Journal of Fungi (ISSN 2309-608X). This special issue belongs to the section "Fungal Pathogenesis and Disease Control".

Deadline for manuscript submissions: closed (10 February 2021) | Viewed by 49494

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Special Issue Editors

Prof. Dr. Hector M. Mora-Montes

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Guest Editor

Department of Biology, Division of Natural Sciences, University of Guanajuato, Guanajuato, Mexico
Interests: fungal cell wall; virulence factors; host–fungus interaction
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Thomas Lehrnbecher

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Guest Editor

Division of Pediatric Hematology and Oncology, Hospital for Children and Adolescents, Johann Wolfgang Goethe University, Frankfurt, Germany
Interests: invasive fungal infections in immunocompromised children; fungal-host interaction; immunotherapy against invasive fungal infections

Special Issue Information

Dear Colleagues,

Fungi are a vast group of heterotrophic organisms that can grow in a wide repertoire of ecological niches. Even though it is estimated that there are more than 3.6 million species, only 120,000 have been identified and parts of their biology described. Thus far, about 300 fungal species have evolved strategies to be pathogenic to humans, and these are the main focus of medical mycology.

Fungal infections are a significant burden to the human, representing about 15% of hospital-acquired infections, and a recurrent problem to ambulant immunosuppressed patients and people living on the margins of society. Thus far, we have limited knowledge about the underlying mechanisms of the host–fungus interaction and the molecular determinants of pathogenicity for most of the pathogenic species. This has been translated into a limited number of therapeutic drugs to control fungal pathogens. In addition, natural or acquired drug resistance of fungal isolates is now a common problem faced by physicians.

Therefore, greater efforts are still required to find therapeutic alternatives to curve these pathogens. In the last two decades, basic aspects of the fungal immune sensing have been described, and we have now a detailed panorama of the ligand-receptor interactions that lead to the activation of immune effectors for pathogen control. Despite this knowledge, no vaccine against a fungal pathogen is currently available and the immunomodulatory alternatives put in practice are extremely limited. To raise awareness among the community about the importance of this issue and to highlight the current progress in this field, we offer this Special Issue on antifungal immunity and fungal vaccine development.

Prof. Dr. Hector M. Mora-Montes
Prof. Dr. Thomas Lehrnbecher
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. Journal of Fungi is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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

mycosis
host-fungus interaction
immunity
vaccine
immunomodulation

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Published Papers (10 papers)

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Research

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14 pages, 1855 KiB

Open AccessArticle

Natural Killer Cell Line NK-92-Mediated Damage of Medically Important Fungi

by Stanislaw Schmidt, Marie Luckowitsch, Michael Hogardt and Thomas Lehrnbecher

J. Fungi 2021, 7(2), 144; https://doi.org/10.3390/jof7020144 - 17 Feb 2021

Cited by 6 | Viewed by 2927

Abstract

Invasive fungal disease (IFD) in hematopoietic stem cell transplantation is associated with high morbidity and mortality. As the antifungal host response determines risk and outcome of IFD, there is growing interest in adoptive immunotherapy using T cells or natural killer (NK) cells. Although the NK-92 cell line has been tested as anticancer therapy in clinical trials, data on the antifungal activity of NK-92 cells are lacking. Here, we show that the NK-92 cell line exhibits considerable fungal damage on all medically important fungi tested, such as different species of Aspergillus, Candida, mucormycetes, and Fusarium. The extent of fungal damage differs across various species of mucormycetes and Fusarium, whereas it is comparable across different species of Aspergillus and Candida. Interferon (IFN)-γ levels in the supernatant were lower when NK-92 cells are co-incubated with Aspergillus fumigatus, Candida albicans, or Rhizopus arrhizus compared to the levels when NK-92 cells are incubated alone. Different to primary human NK cells, no increase of perforin levels in the supernatant was observed when the fungi were added to NK-92 cells. Our in vitro data demonstrated that the NK-92 cell line could be a feasible tool for antifungal immunotherapy, but data of animal models are warranted prior to clinical trials. Full article

(This article belongs to the Special Issue Antifungal Immunity and Fungal Vaccine Development)

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22 pages, 2651 KiB

Open AccessArticle

A Candida parapsilosis Overexpression Collection Reveals Genes Required for Pathogenesis

by Sára E. Pál, Renáta Tóth, Joshua D. Nosanchuk, Csaba Vágvölgyi, Tibor Németh and Attila Gácser

J. Fungi 2021, 7(2), 97; https://doi.org/10.3390/jof7020097 - 29 Jan 2021

Cited by 12 | Viewed by 2857

Abstract

Relative to the vast data regarding the virulence mechanisms of Candida albicans, there is limited knowledge on the emerging opportunistic human pathogen Candida parapsilosis. The aim of this study was to generate and characterize an overexpression mutant collection to identify and explore virulence factors in C. parapsilosis. With the obtained mutants, we investigated stress tolerance, morphology switch, biofilm formation, phagocytosis, and in vivo virulence in Galleria mellonella larvae and mouse models. In order to evaluate the results, we compared the data from the C. parapsilosis overexpression collection analysis to the results derived from previous deletion mutant library characterizations. Of the 37 overexpression C. parapsilosis mutants, we identified eight with altered phenotypes compared to the controls. This work is the first report to identify CPAR2_107240, CPAR2_108840, CPAR2_302400, CPAR2_406400, and CPAR2_602820 as contributors to C. parapsilosis virulence by regulating functions associated with host-pathogen interactions and biofilm formation. Our findings also confirmed the role of CPAR2_109520, CPAR2_200040, and CPAR2_500180 in pathogenesis. This study was the first attempt to use an overexpression strategy to systematically assess gene function in C. parapsilosis, and our results demonstrate that this approach is effective for such investigations. Full article

(This article belongs to the Special Issue Antifungal Immunity and Fungal Vaccine Development)

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14 pages, 3971 KiB

Open AccessArticle

Cellular and Molecular Response of Macrophages THP-1 during Co-Culture with Inactive Trichophyton rubrum Conidia

by Gabriela Gonzalez Segura, Bruna Aline Cantelli, Kamila Peronni, Pablo Rodrigo Sanches, Tatiana Takahasi Komoto, Elen Rizzi, Rene Oliveira Beleboni, Wilson Araújo da Silva Junior, Nilce Maria Martinez-Rossi, Mozart Marins and Ana Lúcia Fachin

J. Fungi 2020, 6(4), 363; https://doi.org/10.3390/jof6040363 - 12 Dec 2020

Cited by 10 | Viewed by 3802

Abstract

Trichophyton rubrum is causing an increasing number of invasive infections, especially in immunocompromised and diabetic patients. The fungal invasive infectious process is complex and has not yet been fully elucidated. Therefore, this study aimed to understand the cellular and molecular mechanisms during the interaction of macrophages and T. rubrum. For this purpose, we used a co-culture of previously germinated and heat-inactivated T. rubrum conidia placed in contact with human macrophages cell line THP-1 for 24 h. This interaction led to a higher level of release of interleukins IL-6, IL-2, nuclear factor kappa beta (NF-κB) and an increase in reactive oxygen species (ROS) production, demonstrating the cellular defense by macrophages against dead fungal elements. Cell viability assays showed that 70% of macrophages remained viable during co-culture. Human microRNA expression is involved in fungal infection and may modulate the immune response. Thus, the macrophage expression profile of microRNAs during co-culture revealed the modulation of 83 microRNAs, with repression of 33 microRNAs and induction of 50 microRNAs. These data were analyzed using bioinformatics analysis programs and the modulation of the expression of some microRNAs was validated by qRT-PCR. In silico analysis showed that the target genes of these microRNAs are related to the inflammatory response, oxidative stress, apoptosis, drug resistance, and cell proliferation. Full article

(This article belongs to the Special Issue Antifungal Immunity and Fungal Vaccine Development)

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12 pages, 1786 KiB

Open AccessArticle

Using Expanded Natural Killer Cells as Therapy for Invasive Aspergillosis

by Win Mar Soe, Joan Hui Juan Lim, David L. Williams, Jessamine Geraldine Goh, Zhaohong Tan, Qi Hui Sam, Sanjay H. Chotirmall, Nur A’tikah Binte Mohamed Ali, Soo Chin Lee, Ju Ee Seet, Sharada Ravikumar and Louis Yi Ann Chai

J. Fungi 2020, 6(4), 231; https://doi.org/10.3390/jof6040231 - 17 Oct 2020

Cited by 10 | Viewed by 3083

Abstract

Invasive aspergillosis (IA) is a major opportunistic fungal infection in patients with haematological malignancies. Morbidity and mortality rates are high despite anti-fungal treatment, as the compromised status of immune system prevents the host from responding optimally to conventional therapy. This raises the consideration for immunotherapy as an adjunctive treatment. In this study, we evaluated the utility of expanded human NK cells as treatment against Aspergillus fumigatus infection in vitro and in vivo. The NK cells were expanded and activated by K562 cells genetically modified to express 4-1BB ligand and membrane-bound interleukin-15 (K562-41BBL-mbIL-15) as feeders. The efficacy of these cells was investigated in A. fumigatus killing assays in vitro and as adoptive cellular therapy in vivo. The expanded NK cells possessed potent killing activity at low effector-to-target ratio of 2:1. Fungicidal activity was morphotypal-dependent and most efficacious against A. fumigatus conidia. Fungicidal activity was mediated by dectin-1 receptors on the expanded NK cells leading to augmented release of perforin, resulting in enhanced direct cytolysis. In an immunocompromised mice pulmonary aspergillosis model, we showed that NK cell treatment significantly reduced fungal burden, hence demonstrating the translational potential of expanded NK cells as adjunctive therapy against IA in immunocompromised patients. Full article

(This article belongs to the Special Issue Antifungal Immunity and Fungal Vaccine Development)

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Review

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15 pages, 821 KiB

Open AccessReview

Fungal Melanin and the Mammalian Immune System

by Sichen Liu, Sirida Youngchim, Daniel Zamith-Miranda and Joshua D. Nosanchuk

J. Fungi 2021, 7(4), 264; https://doi.org/10.3390/jof7040264 - 31 Mar 2021

Cited by 37 | Viewed by 6381

Abstract

Melanins are ubiquitous complex polymers that are commonly known in humans to cause pigmentation of our skin. Melanins are also present in bacteria, fungi, and helminths. In this review, we will describe the diverse interactions of fungal melanin with the mammalian immune system. We will particularly focus on Cryptococcus neoformans and also discuss other major melanotic pathogenic fungi. Melanin interacts with the immune system through diverse pathways, reducing the effectiveness of phagocytic cells, binding effector molecules and antifungals, and modifying complement and antibody responses. Full article

(This article belongs to the Special Issue Antifungal Immunity and Fungal Vaccine Development)

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16 pages, 1364 KiB

Open AccessReview

Immune Sensing of Candida albicans

by Ebrima Bojang, Harlene Ghuman, Pizga Kumwenda and Rebecca A. Hall

J. Fungi 2021, 7(2), 119; https://doi.org/10.3390/jof7020119 - 6 Feb 2021

Cited by 65 | Viewed by 10345

Abstract

Candida albicans infections range from superficial to systemic and are one of the leading causes of fungus-associated nosocomial infections. The innate immune responses during these various infection types differ, suggesting that the host environment plays a key role in modulating the host–pathogen interaction. In addition, C. albicans is able to remodel its cell wall in response to environmental conditions to evade host clearance mechanisms and establish infection in niches, such as the oral and vaginal mucosa. Phagocytes play a key role in clearing C. albicans, which is primarily mediated by Pathogen Associated Molecular Pattern (PAMP)–Pattern Recognition Receptor (PRR) interactions. PRRs such as Dectin-1, DC-SIGN, and TLR2 and TLR4 interact with PAMPs such as β-glucans, N-mannan and O-mannan, respectively, to trigger the activation of innate immune cells. Innate immune cells exhibit distinct yet overlapping repertoires of PAMPs, resulting in the preferential recognition of particular Candida morphotypes by them. The role of phagocytes in the context of individual infection types also differs, with neutrophils playing a prominent role in kidney infections, and dendritic cells playing a prominent role in skin infections. In this review, we provide an overview of the key receptors involved in the detection of C. albicans and discuss the differential innate immune responses to C. albicans seen in different infection types such as vulvovaginal candidiasis (VVC) and oral candidiasis. Full article

(This article belongs to the Special Issue Antifungal Immunity and Fungal Vaccine Development)

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20 pages, 1765 KiB

Open AccessReview

Immune Sensing and Potential Immunotherapeutic Approaches to Control Chromoblastomycosis

by Leandro C. D. Breda, Isabela G. Menezes, Larissa N. M. Paulo and Sandro Rogério de Almeida

J. Fungi 2021, 7(1), 3; https://doi.org/10.3390/jof7010003 - 22 Dec 2020

Cited by 7 | Viewed by 3534

Abstract

Chromoblastomycosis (CBM) is a neglected, chronic, and progressive subcutaneous mycosis caused by different species of fungi from the Herpotrichiellaceae family. CBM disease is usually associated with agricultural activities, and its infection is characterized by verrucous, erythematous papules, and atrophic lesions on the upper and lower limbs, leading to social stigma and impacts on patients’ welfare. The economic aspect of disease treatment is another relevant issue. There is no specific treatment for CBM, and different anti-fungal drug associations are used to treat the patients. However, the long period of the disease and the high cost of the treatment lead to treatment interruption and, consequently, relapse of the disease. In previous years, great progress had been made in the comprehension of the CBM pathophysiology. In this review, we discuss the differences in the cell wall composition of conidia, hyphae, and muriform cells, with a particular focus on the activation of the host immune response. We also highlight the importance of studies about the host skin immunology in CBM. Finally, we explore different immunotherapeutic studies, highlighting the importance of these approaches for future treatment strategies for CBM. Full article

(This article belongs to the Special Issue Antifungal Immunity and Fungal Vaccine Development)

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28 pages, 519 KiB

Open AccessReview

Immunotherapy against Systemic Fungal Infections Based on Monoclonal Antibodies

by Camila Boniche, Suélen Andreia Rossi, Brenda Kischkel, Filipe Vieira Barbalho, Ágata Nogueira D’Aurea Moura, Joshua D. Nosanchuk, Luiz R. Travassos and Carlos Pelleschi Taborda

J. Fungi 2020, 6(1), 31; https://doi.org/10.3390/jof6010031 - 29 Feb 2020

Cited by 36 | Viewed by 6380

Abstract

The increasing incidence in systemic fungal infections in humans has increased focus for the development of fungal vaccines and use of monoclonal antibodies. Invasive mycoses are generally difficult to treat, as most occur in vulnerable individuals, with compromised innate and adaptive immune responses. Mortality rates in the setting of our current antifungal drugs remain excessively high. Moreover, systemic mycoses require prolonged durations of antifungal treatment and side effects frequently occur, particularly drug-induced liver and/or kidney injury. The use of monoclonal antibodies with or without concomitant administration of antifungal drugs emerges as a potentially efficient treatment modality to improve outcomes and reduce chemotherapy toxicities. In this review, we focus on the use of monoclonal antibodies with experimental evidence on the reduction of fungal burden and prolongation of survival in in vivo disease models. Presently, there are no licensed monoclonal antibodies for use in the treatment of systemic mycoses, although the potential of such a vaccine is very high as indicated by the substantial promising results from several experimental models. Full article

(This article belongs to the Special Issue Antifungal Immunity and Fungal Vaccine Development)

20 pages, 689 KiB

Open AccessReview

Monoclonal Antibodies as Tools to Combat Fungal Infections

by Sebastian Ulrich and Frank Ebel

J. Fungi 2020, 6(1), 22; https://doi.org/10.3390/jof6010022 - 4 Feb 2020

Cited by 24 | Viewed by 4900

Abstract

Antibodies represent an important element in the adaptive immune response and a major tool to eliminate microbial pathogens. For many bacterial and viral infections, efficient vaccines exist, but not for fungal pathogens. For a long time, antibodies have been assumed to be of minor importance for a successful clearance of fungal infections; however this perception has been challenged by a large number of studies over the last three decades. In this review, we focus on the potential therapeutic and prophylactic use of monoclonal antibodies. Since systemic mycoses normally occur in severely immunocompromised patients, a passive immunization using monoclonal antibodies is a promising approach to directly attack the fungal pathogen and/or to activate and strengthen the residual antifungal immune response in these patients. Full article

(This article belongs to the Special Issue Antifungal Immunity and Fungal Vaccine Development)

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12 pages, 252 KiB

Open AccessReview

Immune Parameters for Diagnosis and Treatment Monitoring in Invasive Mold Infection

by Jeffrey D. Jenks, Stephen A Rawlings, Carol Garcia-Vidal, Philipp Koehler, Toine Mercier, Juergen Prattes, Cornelia Lass-Flörl, M Teresa Martin-Gomez, Dieter Buchheidt, Livio Pagano, Jean-Pierre Gangneux, Frank L. van de Veerdonk, Mihai G. Netea, Agostinho Carvalho and Martin Hoenigl

J. Fungi 2019, 5(4), 116; https://doi.org/10.3390/jof5040116 - 16 Dec 2019

Cited by 14 | Viewed by 4130

Abstract

Infections caused by invasive molds, including Aspergillus spp., can be difficult to diagnose and remain associated with high morbidity and mortality. Thus, early diagnosis and targeted systemic antifungal treatment remains the most important predictive factor for a successful outcome in immunocompromised individuals with invasive mold infections. Diagnosis remains difficult due to low sensitivities of diagnostic tests including culture and other mycological tests for mold pathogens, particularly in patients on mold-active antifungal prophylaxis. As a result, antifungal treatment is rarely targeted and reliable markers for treatment monitoring and outcome prediction are missing. Thus, there is a need for improved markers to diagnose invasive mold infections, monitor response to treatment, and assist in determining when antifungal therapy should be escalated, switched, or can be stopped. This review focuses on the role of immunologic markers and specifically cytokines in diagnosis and treatment monitoring of invasive mold infections. Full article

(This article belongs to the Special Issue Antifungal Immunity and Fungal Vaccine Development)

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