“Behavior” of Fungi—A Themed Issue in Honor of Dr. Peter N. Lipke

A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Fungal Pathogens".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 13832

Special Issue Editor

College of Medicine, University of Arizona, Tucson, AZ, USA
Interests: HIV; candida adherence; kissing bug behavior; chagas

Special Issue Information

Dear Colleagues,

This Special Edition of Pathogens is in honor of Dr. Peter N. Lipke, for his many contributions to our knowledge of the “behavior” of fungi. Early in his career, he elucidated mechanisms of Saccharomyces cerevisiae agglutination, a cell–cell interaction leading to sexual exchange. He focused on components of the cell wall and their roles in this very “social interaction”. Decades later, he turned his attention to Candida albicans. He has shown us how this even more social yeast aggregates by exploiting amyloid sequences in cell surface proteins. This discovery has led to knowledge of biofilm formation and consequent fungal adhesion to human proteins and tissues. This “sociologist” of yeasts is himself is a most congenial man. His many trainees join him and his wife, Anne (who ran his lab), and their many sons and daughters in a journey to understand different ways of belonging to biofilms and families. These studies include consequences of behavior in both small and large organisms. Consequences include benign ones like food and drink (bread, beer, and wine), as well as malign ones such as C. albicans infections.

Prof. Dr. Stephen A. Klotz
Guest Editor

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Keywords

  • fungal cell wall
  • fungal pheromones
  • yeast aggregation
  • fungal functional amyloids
  • fungal glycoproteins

Published Papers (7 papers)

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Research

18 pages, 4799 KiB  
Article
Novelty Search Promotes Antigenic Diversity in Microbial Pathogens
by Brandon Ely, Winston Koh, Eamen Ho, Tasmina M. Hassan, Anh V. Pham and Weigang Qiu
Pathogens 2023, 12(3), 388; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens12030388 - 28 Feb 2023
Viewed by 1582
Abstract
Driven by host–pathogen coevolution, cell surface antigens are often the fastest evolving parts of a microbial pathogen. The persistent evolutionary impetus for novel antigen variants suggests the utility of novelty-seeking algorithms in predicting antigen diversification in microbial pathogens. In contrast to traditional genetic [...] Read more.
Driven by host–pathogen coevolution, cell surface antigens are often the fastest evolving parts of a microbial pathogen. The persistent evolutionary impetus for novel antigen variants suggests the utility of novelty-seeking algorithms in predicting antigen diversification in microbial pathogens. In contrast to traditional genetic algorithms maximizing variant fitness, novelty-seeking algorithms optimize variant novelty. Here, we designed and implemented three evolutionary algorithms (fitness-seeking, novelty-seeking, and hybrid) and evaluated their performances in 10 simulated and 2 empirically derived antigen fitness landscapes. The hybrid walks combining fitness- and novelty-seeking strategies overcame the limitations of each algorithm alone, and consistently reached global fitness peaks. Thus, hybrid walks provide a model for microbial pathogens escaping host immunity without compromising variant fitness. Biological processes facilitating novelty-seeking evolution in natural pathogen populations include hypermutability, recombination, wide dispersal, and immune-compromised hosts. The high efficiency of the hybrid algorithm improves the evolutionary predictability of novel antigen variants. We propose the design of escape-proof vaccines based on high-fitness variants covering a majority of the basins of attraction on the fitness landscape representing all potential variants of a microbial antigen. Full article
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18 pages, 2701 KiB  
Article
In Silico Analysis of a Drosophila Parasitoid Venom Peptide Reveals Prevalence of the Cation–Polar–Cation Clip Motif in Knottin Proteins
by Joseph Arguelles, Jenny Lee, Lady V. Cardenas, Shubha Govind and Shaneen Singh
Pathogens 2023, 12(1), 143; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens12010143 - 14 Jan 2023
Cited by 1 | Viewed by 2329
Abstract
As generalist parasitoid wasps, Leptopilina heterotoma are highly successful on many species of fruit flies of the genus Drosophila. The parasitoids produce specialized multi-strategy extracellular vesicle (EV)-like structures in their venom. Proteomic analysis identified several immunity-associated proteins, including the knottin peptide, LhKNOT, [...] Read more.
As generalist parasitoid wasps, Leptopilina heterotoma are highly successful on many species of fruit flies of the genus Drosophila. The parasitoids produce specialized multi-strategy extracellular vesicle (EV)-like structures in their venom. Proteomic analysis identified several immunity-associated proteins, including the knottin peptide, LhKNOT, containing the structurally conserved inhibitor cysteine knot (ICK) fold, which is present in proteins from diverse taxa. Our structural and docking analysis of LhKNOT’s 36-residue core knottin fold revealed that in addition to the knottin motif itself, it also possesses a Cation–Polar–Cation (CPC) clip. The CPC clip motif is thought to facilitate antimicrobial activity in heparin-binding proteins. Surprisingly, a majority of ICKs tested also possess the CPC clip motif, including 75 bona fide plant and arthropod knottin proteins that share high sequence and/or structural similarity with LhKNOT. Like LhKNOT and these other 75 knottin proteins, even the Drosophila Drosomycin antifungal peptide, a canonical target gene of the fly’s Toll-NF-kappa B immune pathway, contains this CPC clip motif. Together, our results suggest a possible defensive function for the parasitoid LhKNOT. The prevalence of the CPC clip motif, intrinsic to the cysteine knot within the knottin proteins examined here, suggests that the resultant 3D topology is important for their biochemical functions. The CPC clip is likely a highly conserved structural motif found in many diverse proteins with reported heparin binding capacity, including amyloid proteins. Knottins are targets for therapeutic drug development, and insights into their structure–function relationships will advance novel drug design. Full article
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12 pages, 2179 KiB  
Article
Triazine-Based Small Molecules: A Potential New Class of Compounds in the Antifungal Toolbox
by Karen A. Conrad, Hyunjeong Kim, Mohammad Qasim, Amel Djehal, Aaron D. Hernday, Laurent Désaubry and Jason M. Rauceo
Pathogens 2023, 12(1), 126; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens12010126 - 12 Jan 2023
Cited by 1 | Viewed by 1605
Abstract
Invasive fungal infections caused by Candida species remain a significant public health problem worldwide. The increasing prevalence of drug-resistant infections and a limited arsenal of antifungal drugs underscore the need for novel interventions. Here, we screened several classes of pharmacologically active compounds against [...] Read more.
Invasive fungal infections caused by Candida species remain a significant public health problem worldwide. The increasing prevalence of drug-resistant infections and a limited arsenal of antifungal drugs underscore the need for novel interventions. Here, we screened several classes of pharmacologically active compounds against mammalian diseases for antifungal activity. We found that the synthetic triazine-based compound melanogenin (Mel) 56 is fungicidal in Candida albicans laboratory and clinical strains with minimal inhibitory concentrations of 8–16 µg/mL. Furthermore, Mel56 has general antifungal activity in several non-albicans Candida species and the non-pathogenic yeast Saccharomyces cerevisiae. Surprisingly, Mel56 inhibited the yeast-to-hyphae transition at sublethal concentrations, revealing a new role for triazine-based compounds in fungi. In human cancer cell lines, Mel56 targets the inner mitochondrial integral membrane prohibitin proteins, PHB1 and PHB2. However, Mel56 treatment did not impact C. albicans mitochondrial activity, and antifungal activity was similar in prohibitin single, double, and triple homozygous mutant strains compared to the wild-type parental strain. These results suggests that Mel56 has a novel mechanism-of-action in C. albicans. Therefore, Mel56 is a promising antifungal candidate warranting further analyses. Full article
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19 pages, 3063 KiB  
Article
[PRION+] States Are Associated with Specific Histone H3 Post-Translational Modification Changes
by Samantha N. Cobos, Chaim Janani, Gabriel Cruz, Navin Rana, Elizaveta Son, Rania Frederic, Jailene Paredes Casado, Maliha Khan, Seth A. Bennett and Mariana P. Torrente
Pathogens 2022, 11(12), 1436; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens11121436 - 29 Nov 2022
Viewed by 1594
Abstract
Prions are proteins able to take on alternative conformations and propagate them in a self-templating process. In Saccharomyces cerevisiae, prions enable heritable responses to environmental conditions through bet-hedging mechanisms. Hence, [PRION+] states may serve as an atypical form of epigenetic [...] Read more.
Prions are proteins able to take on alternative conformations and propagate them in a self-templating process. In Saccharomyces cerevisiae, prions enable heritable responses to environmental conditions through bet-hedging mechanisms. Hence, [PRION+] states may serve as an atypical form of epigenetic control, producing heritable phenotypic change via protein folding. However, the connections between prion states and the epigenome remain unknown. Do [PRION+] states link to canonical epigenetic channels, such as histone post-translational modifications? Here, we map out the histone H3 modification landscape in the context of the [SWI+] and [PIN+] prion states. [SWI+] is propagated by Swi1, a subunit of the SWI/SNF chromatin remodeling complex, while [PIN+] is propagated by Rnq1, a protein of unknown function. We find [SWI+] yeast display decreases in the levels of H3K36me2 and H3K56ac compared to [swi] yeast. In contrast, decreases in H3K4me3, H3K36me2, H3K36me3 and H3K79me3 are connected to the [PIN+] state. Curing of the prion state by treatment with guanidine hydrochloride restored histone PTM to [prion] state levels. We find histone PTMs in the [PRION+] state do not match those in loss-of-function models. Our findings shed light into the link between prion states and histone modifications, revealing novel insight into prion function in yeast. Full article
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10 pages, 3476 KiB  
Article
The Paradoxical Effects of Serum Amyloid-P Component on Disseminated Candidiasis
by Stephen A. Klotz and Peter N. Lipke
Pathogens 2022, 11(11), 1304; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens11111304 - 06 Nov 2022
Cited by 3 | Viewed by 1089
Abstract
Serum amyloid P component (SAP) may play an important role in human fungal diseases. SAP binds to functional amyloid on the fungal surface and masks fungi from host immune processes, skewing the macrophage population from the pro-inflammatory M1 to the quiescent M2 type. [...] Read more.
Serum amyloid P component (SAP) may play an important role in human fungal diseases. SAP binds to functional amyloid on the fungal surface and masks fungi from host immune processes, skewing the macrophage population from the pro-inflammatory M1 to the quiescent M2 type. We assessed the role of SAP in a murine model of disseminated candidiasis. Mice were injected with human SAP subcutaneously (SQ) followed by intravenous injection of Candida albicans. Male, BALBcJ mice were administered 2 mg human SAP or the homologous human pro-inflammatory pentraxin CRP, SQ on day −1 followed by 1 mg on days 0 thru 4; yeast cells were administered intravenously on day 0. Mice not receiving a pentraxin were morbid on day 1, surviving 4–7 days. Mice administered SAP survived longer than mice receiving yeast cells alone (p < 0.022), although all mice died. Mice given CRP died faster than mice receiving yeast cells alone (p < 0.017). Miridesap is a molecule that avidly binds SAP, following which the complex is broken down by the liver. Miridesap administered in the drinking water removed SAP from the serum and yeast cells and significantly prolonged the life of mice (p < 0.020). Some were “cured” of candidiasis. SAP administered early in the septic process provided short-lived benefit to mice, probably by blunting cytokine secretion associated with disseminated candidiasis. The most important finding was that removal of SAP with miridesap led to prolonged survival by removing SAP and preventing its dampening effects on the host immune response. Full article
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8 pages, 782 KiB  
Article
Blocking Serum Amyloid-P Component from Binding to Macrophages and Augmenting Fungal Functional Amyloid Increases Macrophage Phagocytosis of Candida albicans
by Stephen A. Klotz, Nicole Bradley and Peter N. Lipke
Pathogens 2022, 11(9), 1000; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens11091000 - 01 Sep 2022
Cited by 4 | Viewed by 1412
Abstract
Candida-macrophage interactions are important immune defense responses associated with disseminated and deep-seated candidiasis in humans. Cells of Candida spp. express functional amyloids on their surfaces during the pathogenesis of disseminated candidiasis. These amyloids become decorated with serum amyloid P-component (SAP) that binds [...] Read more.
Candida-macrophage interactions are important immune defense responses associated with disseminated and deep-seated candidiasis in humans. Cells of Candida spp. express functional amyloids on their surfaces during the pathogenesis of disseminated candidiasis. These amyloids become decorated with serum amyloid P-component (SAP) that binds to Candida cells and macrophages and downregulates the cellular and cytokine response to the fungi. In this report, further characterization of the interactions of SAP and fungal functional amyloid are demonstrated. Blocking the binding of SAP to macrophage FcγR1 receptors increases phagocytosis of yeast cells; seeding a pro-amyloid-forming peptide on the yeast cell surface also increases phagocytosis of yeasts by macrophages; and, lastly, miridesap, a small palindromic molecule, prevents binding of SAP to yeasts and removes SAP that is bound to C. albicans thus, potentially increasing phagocytosis of yeasts by macrophages. Some, or all, of these interventions may be useful in boosting the host immune response to disseminated candidiasis. Full article
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28 pages, 4333 KiB  
Article
Mycobacterium abscessus Mutants with a Compromised Functional Link between the Type VII ESX-3 System and an Iron Uptake Mechanism Reliant on an Unusual Mycobactin Siderophore
by Glennon V. Bythrow, Manal F. Farhat, Keith Levendosky, Poornima Mohandas, Gabrielle A. Germain, Barney Yoo and Luis E. N. Quadri
Pathogens 2022, 11(9), 953; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens11090953 - 23 Aug 2022
Cited by 8 | Viewed by 3196
Abstract
The opportunistic pathogen Mycobacterium abscessus subsp. abscessus (Mab) has become an emerging public health threat due to the increasing number of Mab-associated chronic pulmonary disease cases. Treatment requires multiple drug courses and is often combined with surgical resection. Cure rates [...] Read more.
The opportunistic pathogen Mycobacterium abscessus subsp. abscessus (Mab) has become an emerging public health threat due to the increasing number of Mab-associated chronic pulmonary disease cases. Treatment requires multiple drug courses and is often combined with surgical resection. Cure rates are only ~50% due to treatment failure and comorbidities. Deeper understanding of the biology of Mab is required to illuminate potential avenues for the development of better therapeutics against Mab infections. The ESX-3 type VII protein secretion system of Mab has an important role in host inflammatory and pathological responses during infection. In this work, we demonstrate a functional link between ESX-3 and an iron uptake system based on an unusual mycobactin-type siderophore (designated MBT Ab) and exploit this link to implement a large screen for transposon mutants with an impaired ESX-3. Most mutants we identified carry insertions in genes encoding predicted ESX-3 secretion machinery components or potential ESX-3 substrates. The mutants overproduce MBT Ab, a trait consistent with an iron uptake defect. Our characterization of MBT Ab revealed structural features reminiscent of nocardial mycobactin-like compounds with cytotoxicity. This finding raises the possibility that MBT Ab may play roles in pathogenesis unlinked to iron homeostasis. The mutants generated herein will facilitate research to better understand the role of ESX-3 and its interplay with the siderophore system. Full article
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