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Advances Against Aspergillosis and Mucormycosis 2022

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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 May 2022) | Viewed by 38126

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Special Issue Editors

Dr. Gabriele Sass

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Guest Editor

California Institute for Medical Research, 2260 Clove Dr, San Jose, CA 95128, USA
Interests: intermicrobial interactions; drug discovery
Special Issues, Collections and Topics in MDPI journals

Dr. Jatin M. Vyas

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Guest Editor

Department of Medicine, Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02114, USA
Interests: host-pathogen interactions; innate immune; fungal pathogens

Dr. Inderpaul Sehgal

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Guest Editor

Department of Pulmonary Medicine, Postgraduate Institute of Medical Education & Research, Chandigarh, India
Interests: chronic pulmonary aspergillosis; acute respiratory distress syndrome; invasive and non-invasive mechanical ventilation

Special Issue Information

Dear Colleagues,

We are excited to once again assemble many of the leading clinicians and scientists from around the world for the 10th Advances Against Aspergillosis and Mucormycosis conference, which will be held virtually on 2–3 February, 2022.

This conference has now clearly established itself as the premier forum for detailed and dedicated discussion of all aspects of Aspergillus and Mucorales infection and research. The Aspergillus and Mucorales fields are in a state of rapid advancement in terms of translational, immunologic, epidemiologic, diagnostic, and therapeutic research.

We are pleased to announce the publication of a Conference Supplement, including papers from the invited speakers, in the Journal of Fungi. There are three Guest Editors, drawn from the faculty, who will be leading the 10th such Supplement. These Supplements are one of the foundations of the repository of knowledge about these microbes.

This meeting is another chance to gather the world’s aspergillosis and mucormycosis experts in one venue. A fundamental tenet of this colloquium continues to be to engender collaborative relationships amongst clinicians, scientists, and industry to further advance the field.

When this 10th meeting convenes, it will represent the 20th year of Advances Against Aspergillosis activity. All nine previous international meetings were overwhelmingly successful, with attendance varying from 334 to 533 and attendees hailing from 28 to 49 countries and approximately 200 submitted abstracts per meeting.

The Scientific Committee membership and the Program are available at: www.AAAM2022.org

David W. Denning
David A. Stevens
William J. Steinbach
AAAM2022 Organizers

Dr. Gabriele Sass
Dr. Jatin Mahesh Vyas
Dr. Inderpaul Sehgal
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.

Published Papers (12 papers)

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Research

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18 pages, 4608 KiB

Open AccessArticle

Macrophage Lysosomal Alkalinization Drives Invasive Aspergillosis in a Mouse Cystic Fibrosis Model of Airway Transplantation

by Efthymia Iliana Matthaiou, Wayland Chiu, Carol Conrad and Joe Hsu

J. Fungi 2022, 8(7), 751; https://doi.org/10.3390/jof8070751 - 20 Jul 2022

Cited by 1 | Viewed by 2591

Abstract

Cystic fibrosis (CF) lung transplant recipients (LTRs) exhibit a disproportionately high rate of life-threatening invasive aspergillosis (IA). Loss of the cystic fibrosis transmembrane conductance regulator (CFTR^-/-) in macrophages (mφs) has been associated with lyosomal alkalinization. We hypothesize that this alkalinization would persist in the iron-laden post-transplant microenvironment increasing the risk of IA. To investigate our hypothesis, we developed a murine CF orthotopic tracheal transplant (OTT) model. Iron levels were detected by immunofluorescence staining and colorimetric assays. Aspergillus fumigatus (Af) invasion was evaluated by Grocott methenamine silver staining. Phagocytosis and killing of Af conidia were examined by flow cytometry and confocal microscopy. pH and lysosomal acidification were measured by LysoSensor^TM and Lysotracker^TM, respectively. Af was more invasive in the CF airway transplant recipient compared to the WT recipient (p < 0.05). CFTR^-/- mφs were alkaline at baseline, a characteristic that was increased with iron-overload. These CFTR^-/- mφs were unable to phagocytose and kill Af conidia (p < 0.001). Poly(lactic-co-glycolic acid) (PLGA) nanoparticles acidified lysosomes, restoring the CFTR^-/- mφs’ ability to clear conidia. Our results suggest that CFTR^-/- mφs’ alkalinization interacts with the iron-loaded transplant microenvironment, decreasing the CF-mφs’ ability to kill Af conidia, which may explain the increased risk of IA. Therapeutic pH modulation after transplantation could decrease the risk of IA. Full article

(This article belongs to the Special Issue Advances Against Aspergillosis and Mucormycosis 2022)

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10 pages, 586 KiB

Open AccessArticle

Estimated Incidence and Prevalence of Serious Fungal Infections in Morocco

by Badre Eddine Lmimouni, Christophe Hennequin, Richard O. S. Penney and David W. Denning

J. Fungi 2022, 8(4), 414; https://doi.org/10.3390/jof8040414 - 17 Apr 2022

Cited by 3 | Viewed by 2956

Abstract

Few data are published from Morocco on fungal disease, although numerous case reports attest to a wide range of conditions in the country. Here, we estimate for the first time the incidence and prevalence of serious fungal diseases in the country. Detailed literature searches in English and French were conducted for all serious fungal infections. Demographic and individual underlying condition prevalence or annual incidence were obtained from UNAIDS (HIV), WHO (TB) and other international sources. Deterministic modelling was then applied to estimate fungal disease burden. Morocco’s population in 2021 was 36,561,800. Multiple publications describe various fungal diseases, but epidemiological studies are rare. The most frequent serious fungal infections were tinea capitis (7258/100,000) and recurrent vulvovaginal candidiasis (2794/100,000 females). Chronic pulmonary aspergillosis is also common at a prevalence of 19,290 (53/100,000) because of the relatively high rate of tuberculosis. The prevalence of asthma in adults exceeds one million, of whom fungal asthma (including allergic bronchopulmonary aspergillosis (ABPA)) probably affects 42,150 (115/100,000). Data are scant on candidaemia (estimated at 5/100,000), invasive aspergillosis (estimated at 4.1/100,000), HIV-related complications such as cryptococcal meningitis and Pneumocystis pneumonia and mucormycosis. Fungal keratitis is estimated at 14/100,000). Mycetoma and chromoblastomycosis are probably rare. Fungal disease is probably common in Morocco and diagnostic capacity is good in the teaching hospitals. These estimates need confirmation with methodologically robust epidemiological studies. Full article

(This article belongs to the Special Issue Advances Against Aspergillosis and Mucormycosis 2022)

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13 pages, 4439 KiB

Open AccessArticle

Efficacy of LD Bio Aspergillus ICT Lateral Flow Assay for Serodiagnosis of Chronic Pulmonary Aspergillosis

by Animesh Ray, Mohit Chowdhury, Janya Sachdev, Prayas Sethi, Ved Prakash Meena, Gagandeep Singh, Immaculata Xess, Surabhi Vyas, Maroof Ahmad Khan, Sanjeev Sinha, David W. Denning, Naveet Wig and Sushil Kumar Kabra

J. Fungi 2022, 8(4), 400; https://doi.org/10.3390/jof8040400 - 14 Apr 2022

Cited by 10 | Viewed by 3291

Abstract

Background: The diagnosis of CPA relies on the detection of the IgG Aspergillus antibody, which is not freely available, especially in resource-poor settings. Point-of-care tests like LDBio Aspergillus ICT lateral flow assay, evaluated in only a few studies, have shown promising results for the diagnosis of CPA. However, no study has compared the diagnostic performances of LDBio LFA in setting of tuberculosis endemic countries and have compared it with that of IgG Aspergillus. Objectives: This study aimed to evaluate the diagnostic performances of LDBio LFA in CPA and compare it with existing the diagnostic algorithm utilising ImmunoCAP IgG Aspergillus. Methods: Serial patients presenting with respiratory symptoms (cough, haemoptysis, fever, etc.) for >4 weeks were screened for eligibility. Relevant investigations, including direct microscopy and culture of respiratory secretions, IgG Aspergillus, chest imaging, etc., were done according to existing algorithm. Serums of all patients were tested by LDBio LFA and IgG Aspergillus (ImmunoCAP Asp IgG) and their diagnostic performances were compared. Results: A total of 174 patients were included in the study with ~66.7% patients having past history of tuberculosis. A diagnosis of CPA was made in 74 (42.5%) of patients. The estimated sensitivity and specificity of LDBio LFA was 67.6% (95% CI: 55.7–78%) and 81% (95% CI: 71.9–88.2%), respectively, which increased to 73.3% (95% CI: 60.3–83.9%) and 83.9% (95% CI: 71.7–92.4%), respectively, in patients with a past history of tuberculosis. The sensitivity and specificity of IgG Aspergillus was 82.4% (95% CI: 71.8–90.3%) and 82% (95% CI: 73.1–89%); 86.7% (95% CI: 75.4–94.1%) and 80.4% (95% CI: 67.6–89.8%), in the whole group and those with past history of tuberculosis, respectively. Conclusions: LDBio LFA is a point-of-care test with reasonable sensitivity and specificity. However, further tests may have to be done to rule-in or rule-out the diagnosis of CPA in the appropriate setting. Full article

(This article belongs to the Special Issue Advances Against Aspergillosis and Mucormycosis 2022)

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7 pages, 1474 KiB

Open AccessCommunication

Taking a Closer Look: Clinical and Histopathological Characteristics of Culture-Positive versus Culture-Negative Pulmonary Mucormycosis

by Amy Spallone, Cesar A. Moran, Sebastian Wurster, Dierdre B. Axell-House and Dimitrios P. Kontoyiannis

J. Fungi 2022, 8(4), 380; https://doi.org/10.3390/jof8040380 - 8 Apr 2022

Cited by 3 | Viewed by 1609

Abstract

The cultural recovery of Mucorales from hyphae-laden tissue is poor, and the clinical implications of culture positivity are scarcely studied. Therefore, we compared clinical and histopathological characteristics of culture-positive and culture-negative histology-proven pulmonary mucormycosis cases among cancer patients. Histology specimens were blindly reviewed by a thoracic pathologist and graded on four histopathologic features: hyphal quantity, tissue necrosis, tissue invasion, and vascular invasion. Twenty cases with a corresponding fungal culture were identified; five were culture-positive, and fifteen were culture-negative. Although no statistically significant differences were found, culture-positive patients were more likely to exhibit a high burden of necrosis and have a high burden of hyphae but tended to have less vascular invasion than culture-negative patients. In terms of clinical characteristics, culture-positive patients were more likely to have acute myeloid leukemia (60% vs. 27%, p = 0.19), a history of hematopoietic cell transplant (80% vs. 53%, p = 0.31), severe lymphopenia (absolute lymphocyte count ≤ 500/µL, 100% vs. 73%, p = 0.36), and monocytopenia (absolute monocyte count ≤100/µL, 60% vs. 20%, p = 0.11). Forty-two-day all-cause mortality was comparable between culture-positive and culture-negative patients (60% and 53%, p = 0.80). This pilot study represents the first comprehensive histopathological scoring method to examine the relationship between histopathologic features, culture positivity, and clinical features of pulmonary mucormycosis. Full article

(This article belongs to the Special Issue Advances Against Aspergillosis and Mucormycosis 2022)

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15 pages, 2859 KiB

Open AccessArticle

Protein Kinase A Regulates Autophagy-Associated Proteins Impacting Growth and Virulence of Aspergillus fumigatus

by E. Keats Shwab, Praveen R. Juvvadi, Shareef K. Shaheen, John Allen IV, Greg Waitt, Erik J. Soderblom, Yohannes G. Asfaw, M. Arthur Moseley and William J. Steinbach

J. Fungi 2022, 8(4), 354; https://doi.org/10.3390/jof8040354 - 30 Mar 2022

Cited by 1 | Viewed by 2192

Abstract

Cellular recycling via autophagy-associated proteins is a key catabolic pathway critical to invasive fungal pathogen growth and virulence in the nutrient-limited host environment. Protein kinase A (PKA) is vital for the growth and virulence of numerous fungal pathogens. However, the underlying basis for its regulation of pathogenesis remains poorly understood in any species. Our Aspergillus fumigatus PKA-dependent whole proteome and phosphoproteome studies employing advanced mass spectroscopic approaches identified numerous previously undefined PKA-regulated proteins in catabolic pathways. Here, we demonstrate reciprocal inhibition of autophagy and PKA activity, and identify 16 autophagy-associated proteins as likely novel PKA-regulated effectors. We characterize the novel PKA-phosphoregulated sorting nexin Atg20, and demonstrate its importance for growth, cell wall stress response, and virulence of A. fumigatus in a murine infection model. Additionally, we identify physical and functional interaction of Atg20 with previously characterized sorting nexin Atg24. Furthermore, we demonstrate the importance of additional uncharacterized PKA-regulated putative autophagy-associated proteins to hyphal growth. Our data presented here indicate that PKA regulates the autophagy pathway much more extensively than previously known, including targeting of novel effector proteins with fungal-specific functions important for invasive disease. Full article

(This article belongs to the Special Issue Advances Against Aspergillosis and Mucormycosis 2022)

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14 pages, 2772 KiB

Open AccessArticle

Targeted Delivery of Antifungal Liposomes to Rhizopus delemar

by Quanita J. Choudhury, Suresh Ambati, Zachary A. Lewis and Richard B. Meagher

J. Fungi 2022, 8(4), 352; https://doi.org/10.3390/jof8040352 - 30 Mar 2022

Cited by 7 | Viewed by 2837

Abstract

Mucormycosis (a.k.a. zygomycosis) is an often-life-threatening disease caused by fungi from the ancient fungal division Mucoromycota. Globally, there are nearly a million people with the disease. Rhizopus spp., and R. delemar (R. oryzae, R. arrhizus) in particular, are responsible for most of the diagnosed cases. Pulmonary, rhino-orbito-cerebral, and invasive mucormycosis are most effectively treated with amphotericin B (AmB) and particularly with liposomal formulations (e.g., AmBisome^®). However, even after antifungal therapy, there is still a 50% mortality rate. Hence, there is a critical need to improve therapeutics for mucormycosis. Targeting AmB-loaded liposomes (AmB-LLs) with the pathogen receptor Dectin-1 (DEC1-AmB-LLs) to the beta-glucans expressed on the surface of Aspergillus fumigatus and Candida albicans lowers the effective dose required to kill cells relative to untargeted AmB-LLs. Because Dectin-1 is an immune receptor for R. delemar infections and may bind it directly, we explored the Dectin-1-mediated delivery of liposomal AmB to R. delemar. DEC1-AmB-LLs bound 100- to 1000-fold more efficiently to the exopolysaccharide matrix of R. delemar germlings and mature hyphae relative to AmB-LLs. DEC1-AmB-LLs delivering sub-micromolar concentrations of AmB were an order of magnitude more efficient at inhibiting and/or killing R. delemar than AmB-LLs. Targeted antifungal drug-loaded liposomes have the potential to improve the treatment of mucormycosis. Full article

(This article belongs to the Special Issue Advances Against Aspergillosis and Mucormycosis 2022)

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Review

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15 pages, 776 KiB

Open AccessReview

Clinical Aspergillus Signatures in COPD and Bronchiectasis

by Pei Yee Tiew, Kai Xian Thng and Sanjay H. Chotirmall

J. Fungi 2022, 8(5), 480; https://doi.org/10.3390/jof8050480 - 5 May 2022

Cited by 13 | Viewed by 4693

Abstract

Pulmonary mycoses remain a global threat, causing significant morbidity and mortality. Patients with airways disease, including COPD and bronchiectasis, are at increased risks of pulmonary mycoses and its associated complications. Frequent use of antibiotics and corticosteroids coupled with impaired host defenses predispose patients to fungal colonization and airway persistence, which are associated with negative clinical consequences. Notably, Aspergillus species remain the best-studied fungal pathogen and induce a broad spectrum of clinical manifestations in COPD and bronchiectasis ranging from colonization and sensitization to more invasive disease. Next-generation sequencing (NGS) has gained prominence in the field of respiratory infection, and in some cases is beginning to act as a viable alternative to traditional culture. NGS has revolutionized our understanding of airway microbiota and in particular fungi. In this context, it permits the identification of the previously unculturable, fungal composition, and dynamic change within microbial communities of the airway, including potential roles in chronic respiratory disease. Furthermore, inter-kingdom microbial interactions, including fungi, in conjunction with host immunity have recently been shown to have important clinical roles in COPD and bronchiectasis. In this review, we provide an overview of clinical Aspergillus signatures in COPD and bronchiectasis and cover the current advances in the understanding of the mycobiome in these disease states. The challenges and limitations of NGS will be addressed. Full article

(This article belongs to the Special Issue Advances Against Aspergillosis and Mucormycosis 2022)

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6 pages, 228 KiB

Open AccessReview

Recent Developments in the Diagnosis of Mucormycosis

by Eric Dannaoui

J. Fungi 2022, 8(5), 457; https://doi.org/10.3390/jof8050457 - 28 Apr 2022

Cited by 15 | Viewed by 2073

Abstract

Mucormycosis is a potentially fatal infection that presents in different clinical forms and occurs in patients with various risk factors. Recently, the COVID-19 epidemic has been responsible for an increase in the incidence of mucormycosis, particularly in India. As with other invasive filamentous fungal infections, there are no specific clinical or radiological signs, and we have fewer diagnostic tools available than for other invasive fungal infections. Therefore, the diagnosis of Mucormycosis remains difficult. Nevertheless, for optimal management, early and accurate diagnosis is important. According to the latest recommendations, diagnosis is based on direct examination of clinical specimens, and/or histopathology, and culture. There are also molecular tools for direct detection from clinical specimens, but these techniques are moderately recommended. The main problems with these molecular techniques are that, until now, they were not very well standardized; there was a great heterogeneity of DNA targets and methods, which resulted in variable sensitivity. It is in this field that most advances have been made in the last two years. Indeed, recent studies have evaluated the performance and kinetics of Mucorales qPCR in serum and have shown good sensitivity and specificity. Large inter-laboratory evaluations of qPCR in serum have also been performed and have demonstrated good qualitative and quantitative reproducibility. These new results suggest the use of Mucorales qPCR as part of the diagnostic strategy for mucormycosis. One way to achieve better reproducibility could be to use commercial methods. Currently, there are at least three commercial qPCRs for Mucorales (MucorGenius from PathoNostics, MycoGenie from Ademtech, and Fungiplex from Bruker) that can be used to test serum, respiratory samples, or biopsies. However, to date, there has been little evaluation of these methods. Overall, Mucorales PCR in tissue samples, in respiratory samples, and in serum is promising and its addition as a diagnostic tool in the definitions of invasive mucormycosis should be discussed. Full article

(This article belongs to the Special Issue Advances Against Aspergillosis and Mucormycosis 2022)

10 pages, 676 KiB

Open AccessReview

Fungal Priming: Prepare or Perish

by Ety Harish and Nir Osherov

J. Fungi 2022, 8(5), 448; https://doi.org/10.3390/jof8050448 - 25 Apr 2022

Cited by 9 | Viewed by 2897

Abstract

Priming (also referred to as acclimation, acquired stress resistance, adaptive response, or cross-protection) is defined as an exposure of an organism to mild stress that leads to the development of a subsequent stronger and more protective response. This memory of a previously encountered stress likely provides a strong survival advantage in a rapidly shifting environment. Priming has been identified in animals, plants, fungi, and bacteria. Examples include innate immune priming and transgenerational epigenetic inheritance in animals and biotic and abiotic stress priming in plants, fungi, and bacteria. Priming mechanisms are diverse and include alterations in the levels of specific mRNAs, proteins, metabolites, and epigenetic changes such as DNA methylation and histone acetylation of target genes. Full article

(This article belongs to the Special Issue Advances Against Aspergillosis and Mucormycosis 2022)

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7 pages, 611 KiB

Open AccessReview

Mechanistic Basis of Super-Infection: Influenza-Associated Invasive Pulmonary Aspergillosis

by Keven Mara Robinson

J. Fungi 2022, 8(5), 428; https://doi.org/10.3390/jof8050428 - 22 Apr 2022

Cited by 5 | Viewed by 2674

Abstract

Influenza infection is a risk factor for invasive pulmonary aspergillosis in both immunocompetent and immunocompromised hosts. The purpose of this review is to highlight the epidemiology of influenza-associated invasive pulmonary aspergillosis and the mechanistic studies that have been performed to delineate how influenza [...] Read more.

(This article belongs to the Special Issue Advances Against Aspergillosis and Mucormycosis 2022)

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9 pages, 570 KiB

Open AccessReview

Prevalence of COVID-19-Associated Pulmonary Aspergillosis: Critical Review and Conclusions

by Matthias Egger, Linda Bussini, Martin Hoenigl and Michele Bartoletti

J. Fungi 2022, 8(4), 390; https://doi.org/10.3390/jof8040390 - 12 Apr 2022

Cited by 35 | Viewed by 3896

Abstract

First reports of cases and case series of COVID-19-associated pulmonary aspergillosis (CAPA) emerged during the first months of the pandemic. Prevalence rates varied widely due to the fact that CAPA was, and still remains, challenging to diagnose in patients with COVID-19-associated acute respiratory failure (ARF). The clinical picture and radiological findings of CAPA are unspecific and can resemble those of severe COVID-19. Hence, mycological evidence became a key component in establishing a diagnosis. However, blood tests lack sensitivity in early treatable phases of CAPA and once positive, mortality has been shown to exceed 80% despite systemic antifungal therapy. The primarily airway invasive growth in non-neutropenic patients and the late occurrence of angioinvasion in the course of disease may mainly account for these diagnostic obstacles. Testing of bronchoalveolar lavage (BAL) is therefore crucial in the diagnostic process, but was rarely performed during the early phase of the pandemic, which potentially interfered with the accuracy of reported prevalence. Current guidelines recommend treatment of CAPA during its early airway invasive phase, which may result in some overtreatment (i.e., treatment in patients that may not develop angioinvasive infection) and adverse drug events, yet there is no viable alternative approach. Timely treatment of cases needs to be ensured for patients with mycological evidence of CAPA in the lower respiratory tract given the independent contribution of CAPA to devastating mortality rates of around 50% that have been shown in multiple studies. Here, we review the evolution of reported CAPA prevalence and the role of CAPA as an important opportunistic infection affecting COVID-19 patients in intensive care units (ICUs). Full article

(This article belongs to the Special Issue Advances Against Aspergillosis and Mucormycosis 2022)

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7 pages, 601 KiB

Open AccessReview

Sulfur Metabolism as a Promising Source of New Antifungal Targets

by Jorge Amich

J. Fungi 2022, 8(3), 295; https://doi.org/10.3390/jof8030295 - 13 Mar 2022

Cited by 10 | Viewed by 4252

Abstract

Fungal infections are a growing threat to human health. Despite their clinical relevance, there is a surprisingly limited availability of clinically approved antifungal agents, which is seriously aggravated by the recent appearance and fast spread of drug resistance. It is therefore clear that there is an urgent need for novel and efficient antifungals. In this context, metabolism is recognized as a promising source for new antifungal targets and, indeed, there are new drugs in development that target metabolic pathways. Fungal sulfur metabolism is particularly interesting, as many of its processes are essential for viability and/or pathogenicity and it shows substantial differences with human metabolism. This short-review will summarize our current knowledge of sulfur-related genes and routes that are important for Aspergillus fumigatus virulence, which consequently could be pursued for drug development. Full article

(This article belongs to the Special Issue Advances Against Aspergillosis and Mucormycosis 2022)

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