Juliana Campos Junqueira
Eleftherios Mylonakis- 1Department of Biosciences and Oral Diagnosis, Institute of Science and Technology, São Paulo State University/UNESP, São José dos Campos, Brazil
- 2Division of Infectious Diseases, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, United States
Editorial on the Research Topic
Candida biofilms
Biofilm formation is an important factor of Candida pathogenesis with several clinical implications. Most Candida spp. form biofilms on mucosal and skin surfaces causing different types of superficial candidiasis, as well as on implanted medical devices leading to systemic infections (Horton et al., 2020; Fan et al., 2022). The inherent biofilm resistance to available antifungal drugs results in recurrent infections, chronic persistent infections, and poor clinical outcomes (Ponde et al., 2021). The Research Topic on “Candida biofilms” includes a collection of 14 original research articles and three reviews prepared by renowned groups from Brazil, China, Germany, India, Portugal, Spain, United Kingdom, and USA. Taken together the articles in this issue give an overview on the field of Candida biofilms and provide insights on their structure and regulatory networks; interactions with the host immune defense; mechanisms involved in antifungal resistance; pathogenicity and clinical relevance; cross-kingdom interactions; and development of novel therapeutic approaches.
In this context, Böttcher et al. present a detailed study about biofilm formation of C. albicans with focus on the role of STP2, a key transcriptional regulator of extracellular amino acid signaling and metabolism. The results demonstrate that STP2 mediates the adherence, germ tube formation, metabolic adaptation, and biofilm sustainability, suggesting that regulatory responses to extracellular amino acids are not only involved with nutritional homeostasis, but also coordinate crucial factors for biofilm development. Related to this work, Wang et al. explore the complex mechanism of C. albicans to respond to environmental challenges, unveiling that SPT20 plays an important role to resist hyperosmotic stress through regulating the high osmolarity glycerol 1 mitogen activated protein kinase transduction pathway (Hog1-MAPK). Moving focus to biofilms formed by Candida glabrata, Santos et al. demonstrate that Drug:H+ antiporter 1 (DHA1) transporters, involved in the activation of efflux pumps and drug resistance, can also influence the biofilm development by affecting nutrient uptake and cellular adhesion. Taken together, these studies contribute to clarify the intertwined network of pathways involved in biofilms formed by Candida spp., making them promising targets for drug development.
Looking into the influence of biofilms on Candida-host interactions and the role of biofilm in Candida pathogenesis, Eix and Nett bring a comprehensive review on innate immune responses associated with biofilms, highlighting the key mechanisms by which Candida cells increase their resistance to phagocytosis and alter the mononuclear cell cytokine profile. The authors also examine the insights into host responses to biofilm provided by animal studies, and discuss models that explore biofilms formed on vascular catheters, dental devices, and the mucosal surfaces of rats and mice. Using a mouse model of vaginal candidiasis, Wu et al. demonstrate that C. albicans strains can form significant quantities of biotic biofilms on the vaginal epithelium. The formation of these biofilms leads to high resistance to antifungal treatment and promotes the formation of persister cells, providing new experimental evidence that extend the role of biofilms in the pathogenesis of vaginal candidiasis. Notably, the mechanisms employed by C. albicans to colonize and to form biofilms on vulvovaginal mucosa are thoroughly discussed in the article performed by Rodríguez-Cerdeira et al., who emphasize the genomic, proteomic and quorum sensing aspects of these biofilms.
In a cohort study, Pentland et al. demonstrate the clinical relevance of biofilms in voice prosthesis of patients that underwent total laryngectomy, and show that biofilms are associated with loss of device performance and its early failure. Interestingly, in most cases of prosthesis failure the investigators found polymicrobial biofilms composed mainly by Staphylococcus aureus and C. albicans. Indeed, multi-species biofilms formed by Candida and bacteria can be formed in various niches of the human body, including the oral cavity, gastrointestinal tract, vulvovaginal region, lungs, and skin (Lohse et al., 2018). The interactions established by Candida with different bacterial species have been widely studied (Barbosa et al., 2016; Kong et al., 2016; Kostoulias et al., 2016), however little is known about the possible interactions of Candida spp. with other fungi. In pioneering studies, Oliveira et al. and Garcia et al. demonstrate that C. albicans can form dual species biofilms with Paracoccidioides brasiliensis or Trichophyton rubrum, respectively. The results of both studies suggest that C. albicans and P. brasilensis or T. rubrum can coexist in the same environment and establish fungal-fungal interactions on host surfaces.
The cross-kingdom microbial interactions in biofilms have been explored as a potential resource for the identification of new antifungal molecules (Scorzoni et al., 2021). From this perspective, Santos et al. reveal that Streptococcus mutans, an important bacterium in dental biofilms, can secrete products capable of inhibiting the oral candidiasis in a murine model. In this work, the authors extracted, fractionated, and identified the fraction of the S. mutans UA159 culture (SM-F2) with strong activity against C. albicans and high efficacy in the treatment of oral candidiasis. In an innovative study, Rossoni et al. explore the antimicrobial activity of bacterial metabolic products on Candida auris, an emerging multidrug-resistant yeast. The results show that crude extract derived from the probiotic bacterium Lactobacillus paracasei 28.4 can inhibit the biofilms and persister cells of C. auris, and protect the model host Galleria mellonella from fungal infection through a direct antifungal activity as well as by modulating the host immune response. Besides to natural compounds from microbial origins, plant extracts have gained much attention with large number of bioactive compounds already isolated and identified (Singla and Dubey, 2019; Scorzoni et al., 2021). This Research Topic highlights two plant-derived natural compounds: the coumarin scopoletin (gelseminic acid) studied by Lemos et al. and the palmitic acid (hexadecenoic acid) studied by Prasath et al. Based on their results, both compounds exhibit an effective inhibition on biofilms formed by Candida tropicalis. The mechanism of action of scopoletin involves the alteration on fungal cell and plasma membrane sterols, while the action of palmitic acid seems associated with ROS-mediated mitochondrial dysfunction and regulation of ergosterol biosynthesis. Interestingly, scopoletin also showed activity against the efflux pumps at plasma membrane when combined with fluconazole, suggesting potential synergistic activity against multidrug-resistant Candida strains.
Looking at therapeutic strategies targeted to Candida biofilms, and based on the evidence that antiretroviral HIV protease inhibitors can influence the secreted aspartyl proteases (Saps) of Candida spp. (Cenci et al., 2008; Braga-Silva et al., 2010), Lohse et al. investigate the capacity of 80 protease inhibitors in preventing and treating Candida biofilms. Among the 80 protease inhibitors studied, the investigators found that gliotoxin, acivicin, TPCK and nelfinavir show effectiveness against Candida biofilms. Moreover, several protease inhibitors exhibit ability to decrease C. albicans biofilms when combined with caspofungin or amphotericin B. Reddy and Nancharaiah explore new anti-biofilm approaches using ionic liquids, a novel class of molten salts originates from the combination of cations and anions, with several applications in chemical industry. The prospecting results indicate the imidazolium ionic liquid with hexadecyl group ([C16MIM]+[Cl]−) as the most effective compound against C. albicans biofilms. The antifungal and anti-biofilm activity of imidazolium includes alterations in various cellular process, such as membrane permeability, ergosterol content, and ROS generation. Seeking alternative approaches against C. auris, Vazquez-Munoz et al. studied the use of silver nanoparticles (AgNPs) coated with polyvinylpyrrolidone (PVP) and verified strong antimicrobial activity on several C. auris strains under planktonic and biofilm growing conditions. Promisingly, this antimicrobial activity against C. auris strains is irrespective of their clade, geographical origin, or antifungal-resistant profiles.
Lastly, Vera-González and Shukla discuss the recent advances in antifungal biomaterials for combating Candida biofilm infections. This review explores the design of nanoparticles aimed at disrupting existing biofilms and presents innovative technologies that employ polymer-only coatings as well as coatings with conventional or new antifungal agents against biofilm formation. Moreover, the authors outline future perspectives in the development of biomaterials targeted for Candida biofilms, including the use of enzymes to digest the components of extracellular matrix and identification of new drug targets such as extracellular vesicles.
We hope that this Research Topic covers the key points of the development, pathogenesis, and clinical relevance of Candida biofilms, and provides an overview about the progress and challenges of new antifungal discovery that will incentivize innovation in the field of Candida biofilm pathogenesis and therapeutics.
Author contributions
JJ and EM wrote the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Barbosa, J. O., Rossoni, R. D., Vilela, S. F., de Alvarenga, J. A., Velloso Mdos, S., Prata, M. C., et al. (2016). Streptococcus mutans can modulate biofilm formation and attenuate the virulence of Candida albicans. PLoS ONE 11, e0150457. doi: 10.1371/journal.pone.0150457
Braga-Silva, L. A., Mogami, S. S., Valle, R. S., Silva-Neto, I. D., and Santos, A. L. (2010). Multiple effects of amprenavir against Candida albicans. FEMS Yeast Res. 10, 221–224. doi: 10.1111/j.1567-1364.2009.00595.x
Cenci, E., Francisci, D., Belfiori, B., Pierucci, S., Baldelli, F., Bistoni, F., et al. (2008). Tipranavir exhibits different effects on opportunistic pathogenic fungi. J. Infect. 56, 58–64. doi: 10.1016/j.jinf.2007.08.004
Fan, F., Liu, Y., Liu, Y., Lv, R., Sun, W., Ding, W., et al. (2022). Candida albicans biofilms: antifungal resistance, immune evasion, and emerging therapeutic strategies. Int. J. Antimicrob. Agents. 60, 106673. doi: 10.1016/j.ijantimicag.2022.106673
Horton, M. V., Johnson, C. J., Kernien, J. F., Patel, T. D., Lam, B. C., Cheong, J. Z. A., et al. (2020). Candida auris forms high-burden biofilms in skin niche conditions and on porcine skin. mSphere. 5. doi: 10.1128/mSphere.00910-19
Kong, E. F., Tsui, C., Kucharikova, S., Andes, D., Van Dijck, P., and Jabra-Rizk, M. A. (2016). Commensal protection of Staphylococcus aureus against antimicrobials by Candida albicans biofilm matrix. mBio. 7. doi: 10.1128/mBio.01365-16
Kostoulias, X., Murray, G. L., Cerqueira, G. M., Kong, J. B., Bantun, F., Mylonakis, E., et al. (2016). Impact of a cross-kingdom signaling molecule of Candida albicans on Acinetobacter baumannii physiology. Antimicrob. Agents Chemother. 60, 161–167. doi: 10.1128/AAC.01540-15
Lohse, M. B., Gulati, M., Johnson, A. D., and Nobile, C. J. (2018). Development and regulation of single- and multi-species Candida albicans biofilms. Nat. Rev. Microbiol. 16, 19–31. doi: 10.1038/nrmicro.2017.107
Ponde, N. O., Lortal, L., Ramage, G., Naglik, J. R., and Richardson, J. P. (2021). Candida albicans biofilms and polymicrobial interactions. Crit. Rev. Microbiol. 47, 91–111. doi: 10.1080/1040841X.2020.1843400
Scorzoni, L., Fuchs, B. B., Junqueira, J. C., and Mylonakis, E. (2021). Current and promising pharmacotherapeutic options for candidiasis. Exp. Opin. Pharmacother. 22, 867–887. doi: 10.1080/14656566.2021.1873951
Keywords: biofilms, Candida spp., candidiasis, antifungals, fungal-host interactions
Citation: Junqueira JC and Mylonakis E (2023) Editorial: Candida biofilms. Front. Microbiol. 13:1128600. doi: 10.3389/fmicb.2022.1128600
Received: 20 December 2022; Accepted: 23 December 2022;
Published: 04 January 2023.
Edited and reviewed by: Axel Cloeckaert, Institut National de recherche pour l'agriculture, l'alimentation et l'environnement (INRAE), France
Copyright © 2023 Junqueira and Mylonakis. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Juliana Campos Junqueira, 
anVsaWFuYS5qdW5xdWVpcmEmI3gwMDA0MDt1bmVzcC5icg==; Eleftherios Mylonakis, ZW15bG9uYWtpcyYjeDAwMDQwO2xpZmVzcGFuLm9yZw==