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Dual transcriptome of the immediate neutrophil and Candida albicans interplay
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). HKI, Leibniz Inst Nat Product Res & Infect Biol, Jena, Germany. (Constantin Urban)
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Lund Univ, Div Med Prot Chem, Dept Translat Med, Malmo, Sweden.
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2017 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 18, 696Article in journal (Refereed) Published
Abstract [en]

Background: Neutrophils are traditionally considered transcriptionally inactive. Compared to other immune cells, little is known about their transcriptional profile during interaction with pathogens. Methods: We analyzed the meta-transcriptome of the neutrophil-Candida albicans interplay and the transcriptome of C. albicans challenged with neutrophil extracellular traps (NETs) by RNA-Seq, considering yeast and hypha individually in each approach. Results: The neutrophil response to C. albicans yeast and hyphae was dominated by a morphotype-independent core response. However, 11 % of all differentially expressed genes were regulated in a specific manner when neutrophils encountered the hyphal form of C. albicans. While involving genes for transcriptional regulators, receptors, and cytokines, the neutrophil core response lacked typical antimicrobial effectors genes. Genes of the NOD-like receptor pathway, including NLRP3, were enriched. Neutrophil-and NET-provoked responses in C. albicans differed. At the same time, the Candida transcriptome upon neutrophil encounter and upon NET challenge included genes from various metabolic processes and indicate a mutual role of the regulators Tup1p, Efg1p, Hap43p, and Cap1p. Upon challenge with neutrophils and NETs, the overall Candida response was partially morphotype-specific. Yet again, actual oppositional regulation in yeasts and hyphae was only detected for the arginine metabolism in neutrophil-infecting C. albicans. Conclusions: Taken together, our study provides a comprehensive and quantitative transcript profile of the neutrophil-C. albicans interaction. By considering the two major appearances of both, neutrophils and C. albicans, our study reveals yet undescribed insights into this medically relevant encounter. Hence, our findings will facilitate future research and potentially inspire novel therapy developments.

Place, publisher, year, edition, pages
2017. Vol. 18, 696
Keyword [en]
Candida, Neutrophils, Dual transcriptome, Extracellular traps, NOD-like receptor pathway, Nutritional immunity, Morphotype
National Category
Microbiology in the medical area
Research subject
Clinical Bacteriology
Identifiers
URN: urn:nbn:se:umu:diva-102836DOI: 10.1186/s12864-017-4097-4ISI: 000409208200002OAI: oai:DiVA.org:umu-102836DiVA: diva2:810435
Note

Originally published in manuscript form with title [RNA-Seq transcription profile of the neutrophil: Candida albicans in vitro interaction]

Errata BMC Genomics (2017) 18:696 DOI: 10.1186/s12864-017-4097-4

Available from: 2015-05-07 Created: 2015-05-07 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Neutrophils versus Pathogenic Fungi: through the magnifying glass of nutritional immunity
Open this publication in new window or tab >>Neutrophils versus Pathogenic Fungi: through the magnifying glass of nutritional immunity
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neutrophils are among the first white blood cells recruited to the site of infection once microbial pathogens enter the host organism. At site, they perform a well-orchestrated chain of processes that aims to kill the microbial invader. Most prominent, neutrophils engulf microbes to inactivate them intracellularly, a process called phagocytosis. Alternatively, neutrophils can release neutrophil extracellular traps (NETs). NETs consist of chromatin decorated with antimicrobial effector proteins – a structure that can entangle bacteria and fungi. Neutrophils are crucial during fungal infections. This is reflected in the increased risk of fungal infections resulting of neutropenia. The concept of nutritional immunity describes every infection as a battle for resources. Those are mostly metal trace elements.

For a long time, neutrophils were seen as powerful, but “mindless”, killers with a limited set of actions and no transcriptional capacity, but this view is in the flux.

In the presented thesis, it was my goal to gain new insights into the interplay of neutrophils and fungi – with special attention to metal-nutritional aspects.

We compared human neutrophils lacking the ability to undergo NETosis, due to a non-functional NADPH complex, and neutrophils from the same person that were “cured” by gene therapy. We investigated those NETs and found that their inhibitory activity towards the mold A. nidulans depends on calprotectin, a known zinc-chelator.

Considering the high influx of neutrophils, we wanted to unravel the neutrophils’ contribution to the metal milieu at the site of infection and trace element changes resulting from NETosis. By combining synchrotron radiation XRF and ICP-MS, we analyzed the neutrophil metallome and the spatial element distribution in activated neutrophils and NETs. Most strikingly, we found neutrophils to be exceptionally high in Fe and the process of NETosis to be reducing available Zn in the surrounding and the early phagosome, possibly by the formation of Zn-rich vesicles.

Using RNA-sequencing, we analyzed the interplay of the C. albicans and neutrophils face-to-face. We dissected their transcriptional profile and revealed a manifold response in neutrophils that include cytokine induction and cellular rearrangement. We further were the firsts to explore the transcriptional response of C. albicans to NETs. Our data indicates a distinct response compared to intact neutrophils or other known stress triggers. Metal homeostasis was affected in Candida in both set-ups.

In summary, this thesis provides new insights into the interaction of fungal pathogens with neutrophils and emphasizes the impact of nutritional aspects on this interplay. A deeper understanding of the nutritional immunity during fungal infection might open up new strategies to tackle fungal infections – a growing threat worldwide.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2015. 63 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1716
Keyword
neutrophils, Candida albicans, nutritional immunity, metallome, Zn, Fe
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-102837 (URN)978-91-7601-261-1 (ISBN)
Public defence
2015-06-05, E04, byggnad 6E, NUS, Norrlands universitetssjukhus, Umeå, 11:14 (English)
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Supervisors
Available from: 2015-05-13 Created: 2015-05-07 Last updated: 2015-05-19Bibliographically approved

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Niemiec, Maria JoannaErmert, DavidShankar, MadhuLopes, Jose PedroUrban, Constantin F.
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