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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 (31 December 2021) | Viewed by 60793

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Special Issue Editor

Dr. Sara Gago

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Guest Editor

Division of Infection, Immunity & Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester, UK
Interests: aspergillosis; host–pathogen interaction; fungal disease mechanisms; diagnosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The incidence of mould infections in immunocompromised patients, including those living with HIV or receiving immunosuppressive drugs, is a growing health concern. However, there is increasing evidence demonstrating that mould infections also have a negative impact on other groups of patients suffering from chronic (e.g., asthma, cystic fibrosis, or COPD) or severe (e.g., influenza) respiratory conditions. The development of fungal disease is strongly determined by the status of the host immune defences. Major scientific advances in the last few decades have allowed for investigation of how particular immune cells interact with mould pathogens. Stimulation of the host immune system by fungal spores, germlings, and hyphae has contributed to defining new pathogenicity drivers and to uncovering critical aspects of mechanisms of host–pathogen interaction. Furthermore, an understanding of host signalling pathways, which are dysregulated in response to mould pathogens, alongside deciphering differences in the antifungal response across the variety of high-risk populations will provide a basis for the development of new therapeutic and diagnostic strategies. The aim of this Special Issue is to focus on the mechanistic and clinical impact of mould–host interactions. Topics include, but are not limited to, mould–immune cell interactions, host and pathogen factors contributing to mould diseases, antifungal immunity, and pathogenicity drivers of mould disease.

Dr. Sara Gago
Guest Editor

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Keywords

mould infections
host–pathogen interactions
mechanisms of fungal disease

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Published Papers (11 papers)

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Research

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18 pages, 3073 KiB

Open AccessArticle

Characterisation of Aspergillus fumigatus Endocytic Trafficking within Airway Epithelial Cells Using High-Resolution Automated Quantitative Confocal Microscopy

by Nagwa Ben-Ghazzi, Sergio Moreno-Velásquez, Constanze Seidel, Darren Thomson, David W. Denning, Nick D. Read, Paul Bowyer and Sara Gago

J. Fungi 2021, 7(6), 454; https://doi.org/10.3390/jof7060454 - 7 Jun 2021

Cited by 12 | Viewed by 4246

Abstract

The precise characterization of the mechanisms modulating Aspergillus fumigatus survival within airway epithelial cells has been impaired by the lack of live-cell imaging technologies and user-friendly quantification approaches. Here we described the use of an automated image analysis pipeline to estimate the proportion of A. fumigatus spores taken up by airway epithelial cells, those contained within phagolysosomes or acidified phagosomes, along with the fungal factors contributing to these processes. Coupling the use of fluorescent A. fumigatus strains and fluorescent epithelial probes targeting lysosomes, acidified compartments and cell membrane, we found that both the efficacy of lysosome recruitment to phagosomes and phagosome acidification determines the capacity of airway epithelial cells to contain A. fumigatus growth. Overall, the capability of the airway epithelium to prevent A. fumigatus survival was higher in bronchial epithelial than alveolar epithelial cells. Certain A. fumigatus cell wall mutants influenced phagosome maturation in airway epithelial cells. Taken together, this live-cell 4D imaging approach allows observation and measurement of the very early processes of A. fumigatus interaction within live airway epithelial monolayers. Full article

(This article belongs to the Special Issue Host Response to Mould Pathogens)

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27 pages, 6656 KiB

Open AccessArticle

Expression Patterns in Reductive Iron Assimilation and Functional Consequences during Phagocytosis of Lichtheimia corymbifera, an Emerging Cause of Mucormycosis

by Felicia Adelina Stanford, Nina Matthies, Zoltán Cseresnyés, Marc Thilo Figge, Mohamed I. Abdelwahab Hassan and Kerstin Voigt

J. Fungi 2021, 7(4), 272; https://doi.org/10.3390/jof7040272 - 3 Apr 2021

Cited by 11 | Viewed by 3398

Abstract

Iron is an essential micronutrient for most organisms and fungi are no exception. Iron uptake by fungi is facilitated by receptor-mediated internalization of siderophores, heme and reductive iron assimilation (RIA). The RIA employs three protein groups: (i) the ferric reductases (Fre5 proteins), (ii) the multicopper ferroxidases (Fet3) and (iii) the high-affinity iron permeases (Ftr1). Phenotyping under different iron concentrations revealed detrimental effects on spore swelling and hyphal formation under iron depletion, but yeast-like morphology under iron excess. Since access to iron is limited during pathogenesis, pathogens are placed under stress due to nutrient limitations. To combat this, gene duplication and differential gene expression of key iron uptake genes are utilized to acquire iron against the deleterious effects of iron depletion. In the genome of the human pathogenic fungus L. corymbifera, three, four and three copies were identified for FRE5, FTR1 and FET3 genes, respectively. As in other fungi, FET3 and FTR1 are syntenic and co-expressed in L. corymbifera. Expression of FRE5, FTR1 and FET3 genes is highly up-regulated during iron limitation (Fe-), but lower during iron excess (Fe+). Fe- dependent upregulation of gene expression takes place in LcFRE5 II and III, LcFTR1 I and II, as well as LcFET3 I and II suggesting a functional role in pathogenesis. The syntenic LcFTR1 I–LcFET3 I gene pair is co-expressed during germination, whereas LcFTR1 II- LcFET3 II is co-expressed during hyphal proliferation. LcFTR1 I, II and IV were overexpressed in Saccharomyces cerevisiae to represent high and moderate expression of intracellular transport of Fe3+, respectively. Challenge of macrophages with the yeast mutants revealed no obvious role for LcFTR1 I, but possible functions of LcFTR1 II and IVs in recognition by macrophages. RIA expression pattern was used for a new model of interaction between L. corymbifera and macrophages. Full article

(This article belongs to the Special Issue Host Response to Mould Pathogens)

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17 pages, 1355 KiB

Open AccessArticle

Polymorphisms within the TNFSF4 and MAPKAPK2 Loci Influence the Risk of Developing Invasive Aspergillosis: A Two-Stage Case Control Study in the Context of the aspBIOmics Consortium

by Jose Manuel Sánchez-Maldonado, Ana Moñiz-Díez, Rob ter Horst, Daniele Campa, Antonio José Cabrera-Serrano, Manuel Martínez-Bueno, María del Pilar Garrido-Collado, Francisca Hernández-Mohedo, Laura Fernández-Puerta, Miguel Ángel López-Nevot, Cristina Cunha, Pedro Antonio González-Sierra, Jan Springer, Michaela Lackner, Laura Alcazar-Fuoli, Luana Fianchi, José María Aguado, Livio Pagano, Elisa López-Fernández, Esther Clavero, Leonardo Potenza, Mario Luppi, Lucia Moratalla, Carlos Solano, Antonio Sampedro, Manuel Cuenca-Estrella, Cornelia Lass-Flörl, PCRAGA Study Group, Federico Canzian, Juergen Loeffler, Yang Li, Hermann Einsele, Mihai G. Netea, Lourdes Vázquez, Agostinho Carvalho, Manuel Jurado and Juan Sainz Show full author list Hide full author list

J. Fungi 2021, 7(1), 4; https://doi.org/10.3390/jof7010004 - 23 Dec 2020

Cited by 4 | Viewed by 3744

Abstract

Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4_rs7526628T/T genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4_rs7526628T allele showed decreased serum levels of TNFSF14 protein (p = 0.0027), and that their macrophages had a decreased fungicidal activity (p = 0.048). In addition, we observed that each copy of the MAPKAPK2_rs12137965G allele increased the risk of IA by 60% (p = 0.0017), whereas each copy of the MAPKAPK2_rs17013271T allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2_rs12137965G allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood (p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2_rs17013271T allele had decreased numbers of CD27-IgM-IgD- B cells (p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells (p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk. Full article

(This article belongs to the Special Issue Host Response to Mould Pathogens)

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Review

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22 pages, 15074 KiB

Open AccessReview

Novel Insights into Aspergillus fumigatus Pathogenesis and Host Response from State-of-the-Art Imaging of Host–Pathogen Interactions during Infection

by Sébastien C. Ortiz, Katie Pennington, Darren D. Thomson and Margherita Bertuzzi

J. Fungi 2022, 8(3), 264; https://doi.org/10.3390/jof8030264 - 4 Mar 2022

Cited by 11 | Viewed by 7329

Abstract

Aspergillus fumigatus spores initiate more than 3,000,000 chronic and 300,000 invasive diseases annually, worldwide. Depending on the immune status of the host, inhalation of these spores can lead to a broad spectrum of disease, including invasive aspergillosis, which carries a 50% mortality rate overall; however, this mortality rate increases substantially if the infection is caused by azole-resistant strains or diagnosis is delayed or missed. Increasing resistance to existing antifungal treatments is becoming a major concern; for example, resistance to azoles (the first-line available oral drug against Aspergillus species) has risen by 40% since 2006. Despite high morbidity and mortality, the lack of an in-depth understanding of A. fumigatus pathogenesis and host response has hampered the development of novel therapeutic strategies for the clinical management of fungal infections. Recent advances in sample preparation, infection models and imaging techniques applied in vivo have addressed important gaps in fungal research, whilst questioning existing paradigms. This review highlights the successes and further potential of these recent technologies in understanding the host–pathogen interactions that lead to aspergillosis. Full article

(This article belongs to the Special Issue Host Response to Mould Pathogens)

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18 pages, 1282 KiB

Open AccessReview

Aspergillus fumigatus—Host Interactions Mediating Airway Wall Remodelling in Asthma

by Sara Namvar, Briony Labram, Jessica Rowley and Sarah Herrick

J. Fungi 2022, 8(2), 159; https://doi.org/10.3390/jof8020159 - 6 Feb 2022

Cited by 14 | Viewed by 5127

Abstract

Asthma is a chronic heterogeneous respiratory condition that is mainly associated with sensitivity to airborne agents such as pollen, dust mite products and fungi. Key pathological features include increased airway inflammation and airway wall remodelling. In particular, goblet cell hyperplasia, combined with excess mucus secretion, impairs clearance of the inhaled foreign material. Furthermore, structural changes such as subepithelial fibrosis and increased smooth muscle hypertrophy collectively contribute to deteriorating airway function and possibility of exacerbations. Current pharmacological therapies focused on airway wall remodelling are limited, and as such, are an area of unmet clinical need. Sensitisation to the fungus, Aspergillus fumigatus, is associated with enhanced asthma severity, bronchiectasis, and hospitalisation. How Aspergillus fumigatus may drive airway structural changes is unclear, although recent evidence points to a central role of the airway epithelium. This review provides an overview of the airway pathology in patients with asthma and fungal sensitisation, summarises proposed airway epithelial cell–fungal interactions and discusses the initiation of a tissue remodelling response. Related findings from in vivo animal models are included given the limited analysis of airway pathology in patients. Lastly, an important role for Aspergillus fumigatus-derived proteases in triggering a cascade of damage-repair events through upregulation of airway epithelial-derived factors is proposed. Full article

(This article belongs to the Special Issue Host Response to Mould Pathogens)

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12 pages, 816 KiB

Open AccessReview

Azole-Resistance Development; How the Aspergillus fumigatus Lifecycle Defines the Potential for Adaptation

by Jianhua Zhang, Alfons J. M. Debets, Paul E. Verweij and Eveline Snelders

J. Fungi 2021, 7(8), 599; https://doi.org/10.3390/jof7080599 - 24 Jul 2021

Cited by 12 | Viewed by 9301

Abstract

In order to successfully infect or colonize human hosts or survive changing environments, Aspergillus fumigatus needs to adapt through genetic changes or phenotypic plasticity. The genomic changes are based on the capacity of the fungus to produce genetic variation, followed by selection of the genotypes that are most fit to the new environment. Much scientific work has focused on the metabolic plasticity, biofilm formation or the particular genetic changes themselves leading to adaptation, such as antifungal resistance in the host. Recent scientific work has shown advances made in understanding the natural relevance of parasex and how both the asexual and sexual reproduction can lead to tandem repeat elongation in the target gene of the azoles: the cyp51A gene. In this review, we will explain how the fungus can generate genetic variation that can lead to adaptation. We will discuss recent advances that have been made in the understanding of the lifecycle of A. fumigatus to explain the differences observed in speed and type of mutations that are generated under different environments and how this can facilitate adaptation, such as azole-resistance selection. Full article

(This article belongs to the Special Issue Host Response to Mould Pathogens)

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14 pages, 626 KiB

Open AccessReview

Breakdown of Symbiosis in Radiation-Induced Oral Mucositis

by Gianluca Ingrosso, Simonetta Saldi, Simona Marani, Alicia Y. W. Wong, Matteo Bertelli, Cynthia Aristei and Teresa Zelante

J. Fungi 2021, 7(4), 290; https://doi.org/10.3390/jof7040290 - 12 Apr 2021

Cited by 18 | Viewed by 5894

Abstract

Oral mucositis is an acute side effect of radiation therapy that is especially common with head and neck cancer treatment. In recent years, several studies have revealed the predisposing factors for mucositis, leading to the pre-treatment of patients to deter the development of opportunistic oral fungal infections. Although many clinical protocols already advise the use of probiotics to counteract inflammation and fungal colonization, preclinical studies are needed to better delineate the mechanisms by which a host may acquire benefits via co-evolution with oral microbiota, probiotics, and fungal commensals, such as Candida albicans, especially during acute inflammation. Here, we review the current understanding of radiation therapy-dependent oral mucositis in terms of pathology, prevention, treatment, and related opportunistic infections, with a final focus on the oral microbiome and how it may be important for future therapy. Full article

(This article belongs to the Special Issue Host Response to Mould Pathogens)

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20 pages, 2735 KiB

Open AccessReview

The Host Immune Response to Scedosporium/Lomentospora

by Idoia Buldain, Leire Martin-Souto, Aitziber Antoran, Maialen Areitio, Leire Aparicio-Fernandez, Aitor Rementeria, Fernando L. Hernando and Andoni Ramirez-Garcia

J. Fungi 2021, 7(2), 75; https://doi.org/10.3390/jof7020075 - 22 Jan 2021

Cited by 9 | Viewed by 5122

Abstract

Infections caused by the opportunistic pathogens Scedosporium/Lomentospora are on the rise. This causes problems in the clinic due to the difficulty in diagnosing and treating them. This review collates information published on immune response against these fungi, since an understanding of the mechanisms involved is of great interest in developing more effective strategies against them. Scedosporium/Lomentospora cell wall components, including peptidorhamnomannans (PRMs), α-glucans and glucosylceramides, are important immune response activators following their recognition by TLR2, TLR4 and Dectin-1 and through receptors that are yet unknown. After recognition, cytokine synthesis and antifungal activity of different phagocytes and epithelial cells is species-specific, highlighting the poor response by microglial cells against L. prolificans. Moreover, a great number of Scedosporium/Lomentospora antigens have been identified, most notably catalase, PRM and Hsp70 for their potential medical applicability. Against host immune response, these fungi contain evasion mechanisms, inducing host non-protective response, masking fungal molecular patterns, destructing host defense proteins and decreasing oxidative killing. In conclusion, although many advances have been made, many aspects remain to be elucidated and more research is necessary to shed light on the immune response to Scedosporium/Lomentospora. Full article

(This article belongs to the Special Issue Host Response to Mould Pathogens)

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14 pages, 4065 KiB

Open AccessReview

Host Immune Defense upon Fungal Infections with Mucorales: Pathogen-Immune Cell Interactions as Drivers of Inflammatory Responses

by Dolly E. Montaño and Kerstin Voigt

J. Fungi 2020, 6(3), 173; https://doi.org/10.3390/jof6030173 - 17 Sep 2020

Cited by 25 | Viewed by 6168

Abstract

During the last few decades, mucormycosis has emerged as one of the most common fungal infections, following candidiasis and aspergillosis. The fungal order responsible for causing mucormycosis is the Mucorales. The main hallmarks of this infection include the invasion of blood vessels, infarction, thrombosis, and tissue necrosis, which are exhibited at the latest stages of the infection. Therefore, the diagnosis is often delayed, and the rapid progression of the infection severely endangers the life of people suffering from diabetes mellitus, hematological malignancies, or organ transplantation. Given the fact that mortality rates for mucormycosis range from 40 to 80%, early diagnosis and novel therapeutic strategies are urgently needed to battle the infection. However, compared to other fungal infections, little is known about the host immune response against Mucorales and the influence of inflammatory processes on the resolution of the infection. Hence, in this review, we summarized our current understanding of the interplay among pro-inflammatory cytokines, chemokines, and the host-immune cells in response to mucoralean fungi, as well as their potential use for immunotherapies. Full article

(This article belongs to the Special Issue Host Response to Mould Pathogens)

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18 pages, 284 KiB

Open AccessReview

Advances in Fungal Peptide Vaccines

by Leandro B. R. Da Silva, Carlos P. Taborda and Joshua D. Nosanchuk

J. Fungi 2020, 6(3), 119; https://doi.org/10.3390/jof6030119 - 25 Jul 2020

Cited by 22 | Viewed by 4470

Abstract

Vaccination is one of the greatest public health achievements in the past century, protecting and improving the quality of life of the population worldwide. However, a safe and effective vaccine for therapeutic or prophylactic treatment of fungal infections is not yet available. The lack of a vaccine for fungi is a problem of increasing importance as the incidence of diverse species, including Paracoccidioides, Aspergillus, Candida, Sporothrix, and Coccidioides, has increased in recent decades and new drug-resistant pathogenic fungi are emerging. In fact, our antifungal armamentarium too frequently fails to effectively control or cure mycoses, leading to high rates of mortality and morbidity. With this in mind, many groups are working towards identifying effective and safe vaccines for fungal pathogens, with a particular focus of generating vaccines that will work in individuals with compromised immunity who bear the major burden of infections from these microbes. In this review, we detail advances in the development of vaccines for pathogenic fungi, and highlight new methodologies using immunoproteomic techniques and bioinformatic tools that have led to new vaccine formulations, like peptide-based vaccines. Full article

(This article belongs to the Special Issue Host Response to Mould Pathogens)

Other

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4 pages, 11401 KiB

Open AccessCase Report

Autopsy Proven Pulmonary Mucormycosis Due to Rhizopus microsporus in a Critically Ill COVID-19 Patient with Underlying Hematological Malignancy

by Christoph Zurl, Martin Hoenigl, Eduard Schulz, Stefan Hatzl, Gregor Gorkiewicz, Robert Krause, Philipp Eller and Juergen Prattes

J. Fungi 2021, 7(2), 88; https://doi.org/10.3390/jof7020088 - 27 Jan 2021

Cited by 77 | Viewed by 4787

Abstract

Viral infections can cause acute respiratory distress syndrome (ARDS), consequently leading to susceptibility for secondary pulmonary infections. Over the past few weeks, a number of studies have reported on secondary pulmonary aspergillosis complicating severe COVID-19. We report the case of a 53-year old [...] Read more.

(This article belongs to the Special Issue Host Response to Mould Pathogens)

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