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Neutrophils Versus Pathogenic Fungi Through the Magnifying Glass of Nutritional Immunity

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Neutrophils Versus Pathogenic Fungi Through the Magnifying Glass of Nutritional Immunity Neutrophils versus Pathogenic Fungi through the magnifying glass of nutritional immunity Maria Joanna Niemiec Doctoral thesis Department of Molecular Biology Molecular Infection Medicine Sweden (MIMS) Umeå University Umeå, 2015 Responsible publisher under Swedish law: the Dean of the Medical Faculty This work is protected by the Swedish Copyright Legislation (Act 1960:729) ISBN: 978-91-7601-261-1 ISSN: 0346-6612 Elektronisk version tillgänglig på http://umu.diva-portal.org/ Printed by: Print & Media Umeå, Sweden 2015 To all those who were always convinced this moment would come. Table of Contents Table of Contents i Publications included in this thesis iii Publications not included in this thesis iv Abstract v Clarifications vii Introduction & Background 1 1. Neutrophils 1 1.1 The innate immune system - overview 1 1.2 Professional phagocytes 3 1.3 Neutrophils – from bone marrow to the site of infection 5 1.4 NETosis – neutrophil functionality post mortem 10 1.5 Neutrophil disorders 12 2. Human fungal pathogens 14 2.1 The fungal threat 14 2.2 The yeast Candida albicans and other Candida ssp. 15 2.3 The mold Aspergillus nidulans and other Aspergillus ssp. 16 2.4 Fungal defense strategies against neutrophil killing 17 2.5 Impact of fungal morphology during pathogenesis 19 3. Nutritional immunity 22 3.1 The third branch of the human immune system – major concepts 22 3.2 Zinc during fungal infections 23 3.3 Iron, copper, and manganese during fungal infections 25 Methodological remarks 28 Neutrophil isolation 28 Fungal strains 28 Metal consistency 28 Synchrotron radiation X-ray fluorescence 29 In vitro infections for RNA-sequencing 29 Aims 31 Results & Discussion 33 Paper I 33 NET calprotectin is an effector during A. nidulans inhibition 33 NET inhibition is reversible by Zn supplementation 34 Paper II 36 NETosis reduces Zn availability in the surrounding 36 NETs contain Fe, but not Zn 37 Neutrophils are exceptionally high in Fe 37 Neutrophil nucleus, granules and void vacuoles show characteristic element profiles 39 i Paper III 42 Neutrophil antimicrobial effectors are not induced by C. albicans 42 Neutrophil transcriptional response to C. albicans contains few metal retaining genes 44 C. albicans response to neutrophils and NETs includes metal acquisition genes 46 Conclusions & Outlook 49 Acknowledgements 51 References 53 ii Publications included in this thesis Paper I Restoration of anti-Aspergillus defense by neutrophil extracellular traps in human chronic granulomatous disease after gene therapy is calprotectin- dependent. Bianchi M* & Niemiec MJ*, Siler U, Urban CF and Reichenbach J. Journal of Allergy and Clinical Immunology, 2011. * equal contribution Paper II Trace element landscape of resting and activated human neutrophils on the sub-micrometer level. Niemiec MJ, De Samber B, Garrevoet J, Vergucht E, Vekemans B, De Rycke R, Björn E, Sandblad L, Wellenreuther G, Falkenberg G, Cloetens P, Vincze L & Urban CF. Metallomics, 2015. Paper III RNA-Seq transcription profile of the neutrophil – Candida albicans in vitro interaction. Niemiec MJ, Grumaz C, Mills I, Ermert D, Desel C, Sohn K & Urban CF. Manuscript. Those articles will be referred to in this thesis as paper I, II, and III. iii Publications not included in this thesis Paper IV Candida albicans escapes mouse neutrophils. Ermert D* & Niemiec MJ*, Röhm M, Glenthøj A, Borregaard N, Urban CF. Journal of Leukocyte Biology, 2013. * equal contributions Paper V Malaria-enhanced neutrophil-dependent clearance of S. pneumoniae in an in vivo co-infection model. Nelson M, Niemiec MJ, Fahlgren A, Nahrevanian S, Urban CF, Bergström S & Normark J. Manuscript. iv Abstract Neutrophils are among the first white blood cells recruited to the site of in- fection once microbial pathogens enter the host organism. At site, they per- form 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 entan- gle 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. While neutrophils were seen for a long time as powerful, but “mindless”, killers with a limited set of actions and no transcriptional capacity, 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 Aspergillus nidulans depends on calprotectin, a known zinc-chelator. Considering the high influx of neutrophils, we wanted to unravel the neutro- phils’ contribution to the metal milieu at the site of infection and trace ele- ment 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. v Using RNA-sequencing, we analyzed the interplay of the Candida albicans and neutrophils face-to-face. We dissected their transcriptional profile and revealed a complex response in neutrophils that include cytokine induction and cellular rearrangement. We further were the firsts to explore the tran- scriptional 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. vi Clarifications CAT catalase CD cluster of differentiation CGD chronic granulomatous disease CLR C-type lectin receptor CR complement receptor Ctr Cu transporter DC dendritic cell DEG differentially expressed gene ERK extracellular signal-regulated kinases, = MAPK ET extracellular traps FcγR Fc (fragment crystallizable) γ receptor Fet ferrous transporter FPR formylated peptide receptor Fre ferric reductase Ftr Fe transporter G-CSF granulocyte-colony stimulating factor GPX glutathione peroxidase GUT gastrointestinally induced transition ICAM intracellular adhesion molecule ICP-MS inductively coupled plasma mass spectrometry Ig immunoglobulin IL interleukin IRAK interleukin-1 receptor-associated kinase LAD leukocyte adhesion deficiency MAC membrane attack complex MBL mannan-binding lectin MEK = MAPKK or MAP2K, Mitogen-activated protein kinase kinase MMP matrix metalloproteinase MPO myeloperoxidase MR mannose receptor MYD88 myeloid differentiation primary response gene 88 NADPH nicotinamide adenine dinucleotide phosphate NETs neutrophil extracellular traps NLR nod-like receptor NLRP3 NOD-like receptor family, pyrin domain containing 3 NO nitric oxide p.i. post infection PAD peptidylarginine deiminases PMN polymorphonuclear cell PSGL-1 P-selectin glycoprotein ligand-1 RLH RIG-like helicases RNS reactive nitrogen species ROS reactive oxygen species SCN severe congenital neutropenia SOD superoxide dismutase SR-XRF synchrotron radiation X-ray fluorescence TLR toll-like receptor TNF tumor necrosis factor WHIM Warts, Hypogammaglobulinemia, Infections, and Myelokathexis syndrome ZnT Zn transporter Zrt Zn-regulated transporter vii viii Introduction & Background 1. Neutrophils Neutrophils are the most abundant white blood cells. With numbers up to 1011 generated every day, they constitute 60-80 % of all nucleus-containing blood cells. Neutrophils mature in the bone marrow under the control of G- CSF and belong to the myeloid lineage of hematopoietic cells. After leaving the bone marrow to enter circulation, 95 % of mature neutrophils are post- mitotic. As professional phagocytes, they are assigned to be part of the innate immune system [1]. 1.1 The innate immune system - overview The human immune system is traditionally divided into two major branches: the adaptive and the innate immune system. As indicated by their names, the innate immune system is present from the very beginning of life and needs no further training, while the adaptive immune system can learn and, very importantly, memorize. Due to these properties, the innate immune re- sponse is fast, but rather unspecific, and the adaptive immune system is slower, but pathogen-specific. While the innate immune response can occur immediately, the adaptive immune response takes between 3-4 days to be fully engaged [2]. Both branches of the immune system communicate with each other, and new findings of recent years indicate that the strict separa- tion of the two is not entirely correct [3]. For instance, activated innate im-
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