scholarly journals Mass Spectrometry-Based Proteomics of Fungal Pathogenesis, Host–Fungal Interactions, and Antifungal Development

2019 ◽  
Vol 5 (2) ◽  
pp. 52 ◽  
Author(s):  
Brianna Ball ◽  
Arianne Bermas ◽  
Duncan Carruthers-Lay ◽  
Jennifer Geddes-McAlister
Keyword(s):  
Mass Spectrometry ◽  
Fungal Pathogens ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
Treatment Options ◽  
Drug Efficacy ◽  
Global Scale ◽  
Fungal Pathogenesis ◽  
Biological Targets ◽  
Fungal Interactions

The prevalence of fungal diseases is increasing on a global scale, ranging from acute to systemic infections caused by commensal or pathogenic microorganisms, often associated with the immune status of the host. Morbidity and mortality rates remain high and our ability to treat fungal infections is challenged by a limited arsenal of antifungal agents and the emergence of drug resistant pathogens. There is a high demand for new approaches to elucidate the fungal mechanisms of pathogenesis and the interplay between host and pathogen to discover novel treatment options. Moreover, the need for improved drug efficacy and reduced host toxicity requires the identification and characterization of antifungal biological targets and molecular mechanisms of action. Mass spectrometry (MS)-based proteomics is a rapidly advancing field capable of addressing these priorities by providing comprehensive information on the dynamics of cellular processes, modifications, and interactions. In this Review, we focus on applications of MS-based proteomics in a diverse array of fungal pathogens and host systems to define and distinguish the molecular details of fungal pathogenesis and host–fungal interactions. We also explore the emerging role of MS-based proteomics in the discovery and development of novel antifungal therapies and provide insight into the future of MS-based proteomics in fungal biology.

scholarly journals Post-Translational Modifications Drive Success and Failure of Fungal–Host Interactions

2021 ◽  
Vol 7 (2) ◽  
pp. 124
Author(s):  
Charmaine Retanal ◽  
Brianna Ball ◽  
Jennifer Geddes-McAlister
Keyword(s):  
Fungal Pathogens ◽  
Fungal Infections ◽  
Treatment Options ◽  
Global Scale ◽  
Host Cells ◽  
Candida Spp ◽  
Post Translational Modifications ◽  
Fungal Host ◽  
Resistant Species

Post-translational modifications (PTMs) change the structure and function of proteins and regulate a diverse array of biological processes. Fungal pathogens rely on PTMs to modulate protein production and activity during infection, manipulate the host response, and ultimately, promote fungal survival. Given the high mortality rates of fungal infections on a global scale, along with the emergence of antifungal-resistant species, identifying new treatment options is critical. In this review, we focus on the role of PTMs (e.g., phosphorylation, acetylation, ubiquitination, glycosylation, and methylation) among the highly prevalent and medically relevant fungal pathogens, Candida spp., Aspergillus spp., and Cryptococcus spp. We explore the role of PTMs in fungal stress response and host adaptation, the use of PTMs to manipulate host cells and the immune system upon fungal invasion, and the importance of PTMs in conferring antifungal resistance. We also provide a critical view on the current knowledgebase, pose questions key to our understanding of the intricate roles of PTMs within fungal pathogens, and provide research opportunities to uncover new therapeutic strategies.

Resistance to antifungal therapies

2017 ◽  
Vol 61 (1) ◽  
pp. 157-166 ◽  
Author(s):  
Rajendra Prasad ◽  
Atanu Banerjee ◽  
Abdul Haseeb Shah
Keyword(s):  
Fungal Pathogens ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
Therapeutic Strategies ◽  
Antifungal Resistance ◽  
Antifungal Drugs ◽  
Therapeutic Interventions ◽  
Medical Professionals ◽  
Comprehensive Understanding ◽  
Novel Targets

The evolution of antifungal resistance among fungal pathogens has rendered the limited arsenal of antifungal drugs futile. Considering the recent rise in the number of nosocomial fungal infections in immunocompromised patients, the emerging clinical multidrug resistance (MDR) has become a matter of grave concern for medical professionals. Despite advances in therapeutic interventions, it has not yet been possible to devise convincing strategies to combat antifungal resistance. Comprehensive understanding of the molecular mechanisms of antifungal resistance is essential for identification of novel targets that do not promote or delay emergence of drug resistance. The present study discusses features and limitations of the currently available antifungals, mechanisms of antifungal resistance and highlights the emerging therapeutic strategies that could be deployed to combat MDR.

Fungal infections in solid organ transplantation

2017 ◽  
Author(s):  
Darius Armstrong James ◽  
Anand Shah ◽  
Anna Reed
Keyword(s):  
Organ Transplantation ◽  
Fungal Infections ◽  
Wide Spectrum ◽  
Treatment Options ◽  
Solid Organ Transplantation ◽  
Invasive Disease ◽  
Global Scale ◽  
Molecular Diagnostic ◽  
Individual Risk ◽  
Solid Organ

Fungal infections are a significant and life-threatening complication of organ transplantation, on a global scale. Risk varies according to transplant type, with liver, lung, and small bowel transplant recipients being at particular risk. Whilst invasive candidiasis is the most common fungal infection in organ transplantation overall, aspergillosis is a particular problem in lung transplantation. In addition, a wide spectrum of fungi may cause invasive disease in organ transplantation, consequently diagnosis and treatment can be challenging. Key challenges are to understand individual risk for infection, appropriate prophylactic strategies, and molecular diagnostic approaches. Treatment options are complicated by drug–drug interactions with transplant therapy, as well as intrinsic allograft dysfunction seen in many patients. In this chapter, we review the epidemiology, risk factors, diagnosis, and management of fungal infections in solid organ transplantation.

scholarly journals EQUAL Score Scedosporiosis/Lomentosporiosis 2021: a European Confederation of Medical Mycology (ECMM) tool to quantify guideline adherence

2021 ◽  
Author(s):  
Jannik Stemler ◽  
Michaela Lackner ◽  
Sharon C -A Chen ◽  
Martin Hoenigl ◽  
Oliver A Cornely
Keyword(s):  
Fungal Pathogens ◽  
Fungal Infections ◽  
Treatment Options ◽  
Real Life ◽  
Medical Mycology ◽  
Maximum Point ◽  
Current Guideline ◽  
Level Of Evidence ◽  
Scoring Tool

Abstract Background Invasive scedosporiosis and lomentosporiosis are life-threatening fungal infections in immunocompromised patients with complex diagnostic and treatment patterns. Objectives To develop a scoring tool to facilitate and quantify adherence to current guideline recommendations for diagnosis, treatment and follow-up of invasive scedosporiosis and lomentosporiosis. Methods Experts from European Confederation of Medical Mycology (ECMM) excellence centres reviewed current guidelines for scedosporiosis and lomentosporiosis. Recommendations for diagnosis, treatment and follow-up were summarized, assembled and weighted according to their strength of recommendation and level of evidence (strongly recommended = 3 points; moderately recommended = 2 points; marginally recommended = 1 point; recommended against = 0 points). Additional items considered of high importance for clinical management were also weighted. Results A total of 170 recommendations were identified. A 21-item tool was developed and embedded into the EQUAL score card. Nine items for diagnosis with 18 achievable points were assembled. For treatment, three general recommendation items with a maximal score of 9 were identified, while for specific antifungal treatment the two fungal pathogens were separated. Three and four items were established for scedosporiosis and lomentosporiosis, respectively, with a maximum achievable score of 3 due to the separation of different treatment options with the maximum point value of 3 for voriconazole-based treatment. Follow-up comprised two items (4 points maximum). Key recommendations for clinical outcome were weighted accordingly. Conclusions We propose the EQUAL Score Scedosporiosis/Lomentosporiosis to quantify adherence to current guideline recommendations for management of these rare infections. The score remains to be validated in real-life patient cohorts and correlated with patient outcome.

scholarly journals Comparative Genome Sequence Analyses of Geographic Samples of Aspergillus fumigatus—Relevance for Amphotericin B Resistance

2020 ◽  
Vol 8 (11) ◽  
pp. 1673
Author(s):  
Yuying Fan ◽  
Yue Wang ◽  
Jianping Xu
Keyword(s):  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Fungal Pathogens ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
High Rate ◽  
Whole Genome ◽  
Nucleotide Polymorphisms ◽  
Genome Sequences ◽  
Resistant Strains

Amphotericin B (AMB) is a major fungicidal polyene agent that has a broad spectrum of action against invasive fungal infections. AMB is typically used as the last-line drug against serious and life-threatening infections when other drugs have failed to eliminate the fungal pathogens. Recently, AMB resistance in Aspergillus fumigatus has become more evident. For example, a high rate of AMB resistance (96%) was noted in the A. fumigatus population in Hamilton, Ontario, Canada. AMB-resistant strains have also been found in other countries. However, the mechanism of AMB resistance remains largely unknown. Here, we investigated the potential genes and mutations associated with AMB resistance using whole-genome sequences and examined AMB resistance distribution among genetic populations. A total of 196 whole-genome sequences representing strains from 11 countries were examined. Analyses of single nucleotide polymorphisms (SNPs) at the whole-genome level revealed that these strains belonged to three divergent genetic clusters, with the majority (90%) of AMB resistant strains located in one of the three clusters, Cluster 2. Our analyses identified over 60 SNPs significantly associated with AMB resistance. Together, these SNPs represent promising candidates from which to investigate the putative molecular mechanisms of AMB resistance and for their potential use in developing rapid diagnostic markers for clinical screening of AMB resistance in A. fumigatus.

scholarly journals Steryl Glycosides in Fungal Pathogenesis: An Understudied Immunomodulatory Adjuvant

2020 ◽  
Vol 6 (1) ◽  
pp. 25 ◽  
Author(s):  
Tyler G. Normile ◽  
Kyle McEvoy ◽  
Maurizio Del Poeta
Keyword(s):  
Immune Response ◽  
Fungal Infections ◽  
Treatment Options ◽  
Host Immune Response ◽  
Novel Treatment ◽  
Wide Range ◽  
Efficacious Vaccine ◽  
Lipid Compounds ◽  
Fungal Interactions

Invasive fungal infections pose an increasing threat to human hosts, especially in immunocompromised individuals. In response to the increasing morbidity and mortality of fungal infections, numerous groups have shown great strides in uncovering novel treatment options and potential efficacious vaccine candidates for this increasing threat due to the increase in current antifungal resistance. Steryl glycosides are lipid compounds produced by a wide range of organisms, and are largely understudied in the field of pathogenicity, especially to fungal infections. Published works over the years have shown these compounds positively modulating the host immune response. Recent advances, most notably from our lab, have strongly indicated that steryl glycosides have high efficacy in protecting the host against lethal Cryptococcal infection through acting as an immunoadjuvant. This review will summarize the keystone studies on the role of steryl glycosides in the host immune response, as well as elucidate the remaining unknown characteristics and future perspectives of these compounds for the host–fungal interactions.

scholarly journals Glycobiology of Human Fungal Pathogens: New Avenues for Drug Development

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1348 ◽  
Author(s):  
Danielle J. Lee ◽  
Holly O’Donnell ◽  
Françoise H. Routier ◽  
Joe Tiralongo ◽  
Thomas Haselhorst
Keyword(s):  
Cell Wall ◽  
Immune System ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Treatment Options ◽  
Fungal Spores ◽  
Fungal Species ◽  
Cell Wall Polysaccharides ◽  
Fungal Cell ◽  
Sugar Transporters

Invasive fungal infections (IFI) are an increasing threat to the developing world, with fungal spores being ubiquitous and inhaled every day. Some fungal species are commensal organisms that are part of the normal human microbiota, and, as such, do not pose a threat to the immune system. However, when the natural balance of this association is disturbed or the host’s immune system is compromised, these fungal pathogens overtake the organism, and cause IFI. To understand the invasiveness of these pathogens and to address the growing problem of IFI, it is essential to identify the cellular processes of the invading organism and their virulence. In this review, we will discuss the prevalence and current options available to treat IFI, including recent reports of drug resistance. Nevertheless, the main focus of this review is to describe the glycobiology of human fungal pathogens and how various components of the fungal cell wall, particularly cell wall polysaccharides and glycoconjugates, are involved in fungal pathogenicity, their biosynthesis and how they can be potentially exploited to develop novel antifungal treatment options. We will specifically describe the nucleotide sugar transporters (NSTs) that are important in fungal survival and suggest that the inhibition of fungal NSTs may potentially be useful to prevent the establishment of fungal infections.

Supportive Care

Hematology ◽  
2004 ◽  
Vol 2004 (1) ◽  
pp. 372-389 ◽  
Author(s):  
John R. Wingard ◽  
W. Garrett Nichols ◽  
George B. McDonald
Keyword(s):  
Fungal Pathogens ◽  
Fungal Infections ◽  
Treatment Options ◽  
Hematologic Malignancies ◽  
Respiratory Viruses ◽  
Antifungal Prophylaxis ◽  
Diagnostic Methods ◽  
Sinusoidal Obstruction Syndrome ◽  
Advantages And Disadvantages ◽  
Prevention And Treatment

Abstract To optimize treatment outcomes for hematologic malignancies, minimizing the consequences of treatment complications requires as much skill as the choice of the treatment itself. Myelosuppression and immunosuppression are frequent complications and have potentially serious infectious consequences. Invasive fungal infections and infections from respiratory viruses are increasing in frequency and have life-threatening potential. Damage to vital organs, especially the liver, is another important concern. In this chapter, the scope of invasive fungal and respiratory viral infections, recent insights into the pathogenesis of hepatic sinusoidal injury, and recent developments that impact prevention and treatment approaches for these complications are described. In Section I, Dr. John Wingard describes the advantages and disadvantages of various treatment options for invasive infections by the two chief fungal pathogens, Candida and Aspergillus. Adjunctive therapies and practical considerations that clinicians should weigh in choosing one or another of the various agents are discussed. The studies that have evaluated antifungal prophylaxis and empirical treatment strategies are reviewed. Finally, new approaches such as combination therapy, new diagnostics, and efforts to bolster host immunity are considered. In Section II, Dr. W. Garrett Nichols describes the epidemiology of community-acquired respiratory viruses (CRV) in patients with hematologic malignancies. Risk factors, clinical syndromes, and possible indirect effects of CRV infections are discussed. Treatment and prevention options are reviewed. In Section III, Dr. George McDonald describes sinusoidal obstruction syndrome (once known as hepatic veno-occlusive disease). Recent insights into pathogenesis are described. Diagnostic criteria and the advantages and disadvantages of various diagnostic methods are reviewed and prognosis is considered. Prevention and treatment options are discussed.

scholarly journals Crosstalk Between Autophagy and Hypoxia-Inducible Factor-1α in Antifungal Immunity

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2150 ◽  
Author(s):  
Tim Quäschling ◽  
Dirk Friedrich ◽  
George S. Deepe ◽  
Jan Rupp
Keyword(s):  
Immune Response ◽  
Immune Cells ◽  
Fungal Pathogens ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
Hypoxia Inducible Factor ◽  
Canonical Pathway ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Hypoxia Inducible Factor 1Α

Modern medicine is challenged by several potentially severe fungal pathogens such as Aspergillus fumigatus, Candida albicans, or Histoplasma capsulatum. Though not all fungal pathogens have evolved as primary pathogens, opportunistic pathogens can still cause fatal infections in immuno-compromised patients. After infection with these fungi, the ingestion and clearance by innate immune cells is an important part of the host immune response. Innate immune cells utilize two different autophagic pathways, the canonical pathway and the non-canonical pathway, also called microtubule-associated protein 1A/1B-light chain 3 (LC3) -associated pathway (LAP), to clear fungal pathogens from the intracellular environment. The outcome of autophagy-related host immune responses depends on the pathogen and cell type. Therefore, the understanding of underlying molecular mechanisms of autophagy is crucial for the development and improvement of antifungal therapies. One of those molecular mechanisms is the interaction of the transcription-factor hypoxia-inducible factor 1α (HIF-1α) with the autophagic immune response. During this review, we will focus on a comprehensive overview of the role of autophagy and HIF-1α on the outcome of fungal infections.

scholarly journals The Quiet and Underappreciated Rise of Drug-Resistant Invasive Fungal Pathogens

2020 ◽  
Vol 6 (3) ◽  
pp. 138 ◽  
Author(s):  
Amir Arastehfar ◽  
Cornelia Lass-Flörl ◽  
Rocio Garcia-Rubio ◽  
Farnaz Daneshnia ◽  
Macit Ilkit ◽  
...  
Keyword(s):  
Fungal Pathogens ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Fungal Species ◽  
Antifungal Resistance ◽  
Candida Auris ◽  
Recent Emergence ◽  
Invasive Infections

Human fungal pathogens are attributable to a significant economic burden and mortality worldwide. Antifungal treatments, although limited in number, play a pivotal role in decreasing mortality and morbidities posed by invasive fungal infections (IFIs). However, the recent emergence of multidrug-resistant Candida auris and Candida glabrata and acquiring invasive infections due to azole-resistant C. parapsilosis, C. tropicalis, and Aspergillus spp. in azole-naïve patients pose a serious health threat considering the limited number of systemic antifungals available to treat IFIs. Although advancing for major fungal pathogens, the understanding of fungal attributes contributing to antifungal resistance is just emerging for several clinically important MDR fungal pathogens. Further complicating the matter are the distinct differences in antifungal resistance mechanisms among various fungal species in which one or more mechanisms may contribute to the resistance phenotype. In this review, we attempt to summarize the burden of antifungal resistance for selected non-albicansCandida and clinically important Aspergillus species together with their phylogenetic placement on the tree of life. Moreover, we highlight the different molecular mechanisms between antifungal tolerance and resistance, and comprehensively discuss the molecular mechanisms of antifungal resistance in a species level.

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