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2. Candida pathogens induce protective mitochondria-associated type I interferon signalling and a damage-driven response in vaginal epithelial cells

Author

Barcelona Supercomputing Center, Pekmezovic, Marina, Hovhannisyan, Hrant, Gresnigt, Mark S., Iracane, Elise, Oliveira Pacheco, João, Siscar Lewin, Sofía, Seemann, Eric, Qualmann, Britta, Kalkreuter, Till, Müller, Sylvia, Kamradt, Thomas, Mogavero, Selene, Brunke, Sascha, Butler, Geraldine, Gabaldón, Toni, Hube, Bernhard, Barcelona Supercomputing Center, Pekmezovic, Marina, Hovhannisyan, Hrant, Gresnigt, Mark S., Iracane, Elise, Oliveira Pacheco, João, Siscar Lewin, Sofía, Seemann, Eric, Qualmann, Britta, Kalkreuter, Till, Müller, Sylvia, Kamradt, Thomas, Mogavero, Selene, Brunke, Sascha, Butler, Geraldine, Gabaldón, Toni, and Hube, Bernhard

Abstract

Vaginal candidiasis is an extremely common disease predominantly caused by four phylogenetically diverse species: Candida albicans; Candida glabrata; Candida parapsilosis; and Candida tropicalis. Using a time course infection model of vaginal epithelial cells and dual RNA sequencing, we show that these species exhibit distinct pathogenicity patterns, which are defined by highly species-specific transcriptional profiles during infection of vaginal epithelial cells. In contrast, host cells exhibit a homogeneous response to all species at the early stages of infection, which is characterized by sublethal mitochondrial signalling inducing a protective type I interferon response. At the later stages, the transcriptional response of the host diverges in a species-dependent manner. This divergence is primarily driven by the extent of epithelial damage elicited by species-specific mechanisms, such as secretion of the toxin candidalysin by C. albicans. Our results uncover a dynamic, biphasic response of vaginal epithelial cells to Candida species, which is characterized by protective mitochondria-associated type I interferon signalling and a species-specific damage-driven response., M.P., H.H., E.I., J.O.P., T.G., G.B. and B.H. received funding from the European Union Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant no. 642095 (OPATHY). B.H. also received support from the German Research Foundation within the Collaborative Research Centre/Transregio 124 FungiNet (project C1). M.S.G. was supported by the German Research Foundation Emmy Noether Programme (project no. 434385622/GR 5617/1-1). We acknowledge the support of the Spanish Ministry of Science, Innovation and Universities (grant no. PGC2018-099921-B-I00) to the European Molecular Biology Laboratory partnership, the Centro de Excelencia Severo Ochoa and the CERCA Programme/Generalitat de Catalunya. We thank C. Kämnitz from the Electron Microscopy Center in Jena for the sample preparation for TEM. The schematic models in Figs. 4–6 were created with images adapted from Servier Medical Art (Servier)., Peer Reviewed, Postprint (author's final draft)

Published
2021

6. The role of Candida albicans transcription factor RLM1 in response to carbon adaptation

Author

Oliveira-Pacheco, João, Alves, R., Costa-Barbosa, Augusto, Rodrigues, Bruno Cerqueira, Silva, Patrícia Pereira, Paiva, Sandra, Silva, Sónia Carina, Henriques, Mariana, Pais, Célia, Sampaio, Paula, and Universidade do Minho

Subjects
0301 basic medicine, Microbiology (medical), media_common.quotation_subject, 030106 microbiology, lcsh:QR1-502, Microbiology, lcsh:Microbiology, Cell wall, 03 medical and health sciences, Immune system, C. albicans, Secretion, Internalization, Candida albicans, Original Research, media_common, 2. Zero hunger, lactate, Science & Technology, Ciências Naturais::Ciências Biológicas, biology, Chemistry, Biofilm, carbon adaptation, biology.organism_classification, candidiasis, cell wall remodeling, Corpus albicans, 3. Good health, Cell biology, Interleukin 10, 030104 developmental biology, alternative carbon sources, RLM1
Abstract

Candida albicans is the main causative agent of candidiasis and one of the most frequent causes of nosocomial infections worldwide. In order to establish an infection, this pathogen supports effective stress responses to counter host defenses and adapts to changes in the availability of important nutrients, such as alternative carbon sources. These stress responses have clear implications on the composition and structure of Candida cell wall. Therefore, we studied the impact of lactate, a physiologically relevant carbon source, on the activity of C. albicans RLM1 transcriptional factor. RLM1 is involved in the cell wall integrity pathway and plays an important role in regulating the flow of carbohydrates into cell wall biosynthesis pathways. The role of C. albicans RLM1 in response to lactate adaptation was assessed in respect to several virulence factors, such as the ability to grow under cell wall damaging agents, filament, adhere or form biofilm, as well as to immune recognition. The data showed that growth of C. albicans cells in the presence of lactate induces the secretion of tartaric acid, which has the potential to modulate the TCA cycle on both the yeast and the host cells. In addition, we found that adaptation of C. albicans cells to lactate reduces their internalization by immune cells and consequent % of killing, which could be correlated with a lower exposure of the cell wall -glucans. In addition, absence of RLM1 has a minor impact on internalization, compared with the wild-type and complemented strains, but it reduces the higher efficiency of lactate grown cells at damaging phagocytic cells and induces a high amount of IL-10, rendering these cells more tolerable to the immune system. The data suggests that RLM1 mediates cell wall remodeling during carbon adaptation, impacting their interaction with immune cells., This study was supported by the Portuguese National Funding Agency for Science, Research and Technology FCT. RA received FCT Ph.D. fellowship (PD/BD/113813/2015) and AC-B received FCT Ph.D. fellowship SFRH/BD/133513/2017. The work on CBMA was supported by FEDER through POFC-COMPETE and by FCT through strategic funding UID/BIA/04050/2013. The work on CEB was supported by Pest-OE/EQB/LA0023/2013, from FCT, "BioHealth - Biotechnology and Bioengineering approaches to improve health quality," Ref. NORTE-07-0124-FEDER-000027, co-funded by the Programa Operacional Regional do Norte (ON.2 - O Novo Norte), QREN, FEDER, and the project "Consolidating Research Expertise and Resources on Cellular and Molecular Biotechnology at CEB/IBB," Ref. FCOMP-01-0124-FEDER-027462., info:eu-repo/semantics/publishedVersion

Published
2018

11. Population genomics of the pathogenic yeast Candida tropicalis identifies hybrid isolates in environmental samples.

Author

O'Brien, Caoimhe E., Oliveira-Pacheco, João, Ó Cinnéide, Eoin, Haase, Max A. B., Hittinger, Chris Todd, Rogers, Thomas R., Zaragoza, Oscar, Bond, Ursula, and Butler, Geraldine

Subjects
*CANDIDA tropicalis, *ENVIRONMENTAL sampling, *CANDIDEMIA, *GENOMICS, *PHENOTYPES, *SPECIES diversity, *HETEROZYGOSITY
Abstract

Candida tropicalis is a human pathogen that primarily infects the immunocompromised. Whereas the genome of one isolate, C. tropicalis MYA-3404, was originally sequenced in 2009, there have been no large-scale, multi-isolate studies of the genetic and phenotypic diversity of this species. Here, we used whole genome sequencing and phenotyping to characterize 77 isolates of C. tropicalis from clinical and environmental sources from a variety of locations. We show that most C. tropicalis isolates are diploids with approximately 2–6 heterozygous variants per kilobase. The genomes are relatively stable, with few aneuploidies. However, we identified one highly homozygous isolate and six isolates of C. tropicalis with much higher heterozygosity levels ranging from 36–49 heterozygous variants per kilobase. Our analyses show that the heterozygous isolates represent two different hybrid lineages, where the hybrids share one parent (A) with most other C. tropicalis isolates, but the second parent (B or C) differs by at least 4% at the genome level. Four of the sequenced isolates descend from an AB hybridization, and two from an AC hybridization. The hybrids are MTLa/α heterozygotes. Hybridization, or mating, between different parents is therefore common in the evolutionary history of C. tropicalis. The new hybrids were predominantly found in environmental niches, including from soil. Hybridization is therefore unlikely to be associated with virulence. In addition, we used genotype-phenotype correlation and CRISPR-Cas9 editing to identify a genome variant that results in the inability of one isolate to utilize certain branched-chain amino acids as a sole nitrogen source. Author summary: Candida tropicalis is an important fungal pathogen, which is particularly common in the Asia-Pacific and Latin America. There is currently very little known about the diversity of genotype and phenotype of C. tropicalis isolates. By carrying out a phylogenomic analysis of 77 isolates, we find that C. tropicalis genomes range from very homozygous to highly heterozygous. We show that the heterozygous isolates are hybrids, most likely formed by mating between different parents. Unlike other Candida species, the hybrids are more common in environmental than in clinical niches, suggesting that for this species, hybridization is not associated with virulence. We also explore the range of phenotypes, and we identify a genomic variant that is required for growth on valine and isoleucine as sole nitrogen sources. [ABSTRACT FROM AUTHOR]

Published
2021
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