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Gene Expression Profiling at Birth Characterizing the Preterm Infant with Early Onset Infection

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J Mol Med (2017) 95:169–180 DOI 10.1007/s00109-016-1466-4 ORIGINAL ARTICLE Gene expression profiling at birth characterizing the preterm infant with early onset infection Anne Hilgendorff1,2 & Anita Windhorst 3,4 & Manuel Klein5 & Svetlin Tchatalbachev3 & Christine Windemuth-Kieselbach6 & Joachim Kreuder2 & Matthias Heckmann7 & Anna Gkatzoflia2 & Harald Ehrhardt2 & Josef Mysliwietz8 & Michael Maier3 & Benjamin Izar3,9 & Andre Billion3 & Ludwig Gortner10 & Trinad Chakraborty3 & Hamid Hossain3 Received: 26 August 2015 /Revised: 9 August 2016 /Accepted: 18 August 2016 /Published online: 30 August 2016 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract with EOI could be further differentiated into two subclasses Early onset infection (EOI) in preterm infants <32 weeks ges- and were distinguished by the magnitude of the expression of tational age (GA) is associated with a high mortality rate and genes involved in both neutrophil and T cell activation. A the development of severe acute and long-term complications. hallmark activity for both subclasses of EOI was a common The pathophysiology of EOI is not fully understood and clin- suppression of genes involved in natural killer (NK) cell func- ical and laboratory signs of early onset infections in this pa- tion, which was independent from NK cell numbers. tient cohort are often not conclusive. Thus, the aim of this Significant results were recapitulated in an independent vali- study was to identify signatures characterizing preterm infants dation cohort. Gene expression profiling may enable early and with EOI by using genome-wide gene expression (GWGE) more precise diagnosis of EOI in preterm infants. analyses from umbilical arterial blood of preterm infants. This prospective cohort study was conducted in preterm in- Key message fants <32 weeks GA. GWGE analyses using CodeLink hu- & Gene expression (GE) profiling at birth characterizes pre- man microarrays were performed from umbilical arterial term infants with EOI. blood of preterm infants with and without EOI. GWGE anal- & GE analysis indicates dysregulation of NK cell activity. yses revealed differential expression of 292 genes in preterm & NK cell activity at birth may be a useful marker to improve infants with EOI as compared to infants without EOI. Infants early diagnosis of EOI. Anne Hilgendorff and Anita Windhorst contributed equally to the study. Electronic supplementary material The online version of this article (doi:10.1007/s00109-016-1466-4) contains supplementary material, which is available to authorized users. * Hamid Hossain 4 Institute for Medical Informatics, Justus-Liebig-University Giessen, [email protected] Giessen, Germany 5 Hospital Barmherzige Brueder, Regensburg, Germany 1 Department of Neonatology, Grosshadern, Ludwig-Maximilian 6 Institute of Medical Biometry and Epidemiology, University Munich, Germany and the Comprehensive Pneumology Philipps-University Marburg, Marburg, Germany Center, Helmholtz Zentrum Muenchen, Munich, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany 7 Department of Neonatology and Pediatric Intensive Care, University Medicine, Greifswald, Germany 2 Department of Pediatrics and Neonatology, Justus-Liebig University 8 Giessen, Germany, Member of the German Center for Lung Research Institute for Molecular Immunology, Helmholtz Center Munich, (DZL), Giessen, Germany Munich, Germany 9 Broad Institute of MIT and Harvard, Cambridge, MA, USA 3 Institute for Medical Microbiology, Justus-Liebig University Giessen, Member of the German Center for Infection Research 10 Department of Pediatrics and Neonatology, University of Saarland, (DZIF), Schubertstr. 81, 35392 Giessen, Germany Homburg, Germany 170 J Mol Med (2017) 95:169–180 Keywords Neonatal sepsis . Gene expression profiling Patients were allocated to one of the two following groups: (I) EOI and (II) non-EOI (no signs of infection in the first 72 h of life). EOI was diagnosed if the infant showed both a pathologic Introduction ratio of immature to total granulocytes (IT ratio ≥ 0.2 as deter- mined by manual counts) and/or a pathologic white blood cell Preterm birth (PTB) remains a major problem in perinatal medi- count paralleled or followed by an increase in CRP ≥ 6mg/lin cine and accounts for 75 % of the perinatal mortality and 50 % of the first 72 h of life [7, 10–14]. These laboratory signs had to be the perinatal morbidity [1]. Early onset infections (EOI) in PTB are accompanied by at least three of the following clinical signs associated with significant morbidity and a mortality rate of 15– suggestive of bacterial infection in the new born infants: pallor, 50 %, especially in very immature preterm infants [2, 3]. Although gray skin color, capillary refill >3 s, requiring volume resuscita- clinical and experimental studies continue to provide valuable in- tion or substitution of any catecholamines, dyspnea, tachypnea, sight into processes leading to EOI and its attendant complications requiring respiratory support or supplemental oxygen, increased [4, 5], biological pathways relevant to the complex pathophysiol- thermal instability, unexplained hypo- and hyperglycemia, feed- ogy of EOI remain poorly understood. This is reflected in the ing difficulties, bilious reflux and abdominal distension, increas- limitations of early diagnostic markers and the absence of targeted ing incidence of apnea and/or bradycardia, lethargy, irritability, treatment approaches in this high-risk patient cohort. Clinical signs and increased or decreased muscle tone [2, 15]. All patients who are ambiguous and difficult to interpret in the absence of reliable did not meet the criteria for the EOI were considered as non-EOI. early biochemical markers [6–8]. The gold standard of blood The characteristics and clinical parameters in the first 72 h of life culture-proven sepsis severely underestimates the rate of severe of the patient cohort are given in Table 1 (exploration cohort). P infections in newborns and especially preterm infants, as the diag- values were calculated using Fisher’s exact test for qualitative nostic approach is complicated by maternal antibiotic therapy and parameters and Wilcoxon U test for quantitative parameters. hampered by small blood volumes [2, 9]. As outcome and prog- The comprehensive monitoring of the perinatal course is fur- nosis of EOI mainly depend on early and efficient treatment, sen- ther defined in Supplemental Materials and Methods. The study sitive and specific indicators of EOI are crucial at the earliest stage has been approved by the legal ethical committee (File 79/01, of disease. University of Giessen, Germany). In this prospective cohort study, we applied gene expres- sion profiling from umbilical arterial blood of preterm infants Blood sampling, RNA isolation, and microarrays <32 weeks of gestational age to provide comprehensive bio- logical information and identify biological pathways relevant Blood for standard laboratory analyses including WBC and for the development of EOI in order to enable the identifica- blood samples for transcriptome analyses were obtained from tion of early diagnostic markers. an indwelling umbilical artery catheter immediately after birth. WBCs were repeated upon clinical indication in the later postna- tal course as a possible indicator of developing (congenital and Material and methods nosocomial) infections. Details of the microarray experiments and data analysis can be found in Supplemental Materials and Patients Methods. Briefly, 250–300 μl of umbilical arterial blood was obtained Newborn infants <32 weeks gestational age (GA) were prospec- immediately after birth from an indwelling umbilical artery cath- tively included in this study. eter and directly transferred to 750–900 μl of the PAXgene Depending on the availability of diagnostic criteria at birth, Blood RNA System (PreAnalytiX, Heidelberg, Germany). infants were pro- or retrospectively excluded when one of the RNA isolation was performed according to the manufacturer’s following diagnoses was present: premature rupture of mem- recommendations (PreAnalytiX). RNA was hybridized on branes ≥3 weeks prior to birth leading to oligo- or anhydramnios, CodeLink UniSet Human 10 K Bioarrays (GE Healthcare) using severe congenital malformations, diagnosis of severe metabolic the CodeLink Expression Assay Kit (GE Healthcare) and sam- disorders, prepartum treatment of the mother with cytostatic or ples processed using CodeLink Expression Software V4.1 (GE immunosuppressive medication other than for lung maturation, Healthcare). and postnatal treatment with corticosteroids in a dose ≥1 mg/kg body weight. Analysis of C-reactive protein (CRP), whole white Gene expression analysis blood count (WBC), and microbiological examination of blood cultures, swabs, urine, and stool samples were carried out in the In order to account for confounding effects of WBCs on the first 72 h of life. Patients were clinically re-evaluated in short transcriptome pattern, we evaluated differences between EOI intervals and continuously monitored for vital signs, i.e., heart and non-EOI preterm infants in their differential WBCs at rate, blood pressure, microcirculation, and breathing pattern. birth by using the Wilcoxon rank-sum test. Missing data from J Mol Med (2017) 95:169–180 171 Table 1 Neonatal characteristics of preterm infants EOI Non-EOI (control) P value n 16 8 GA (weeks) 29 (24–30) 31 (29–31) 0.008 Birth weight (g) 1085 (590–1730) 1445 (900–1760)
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  • Effect of NKG2C Absence on Natural Killer Cell Phenotype and Function in Human

    Effect of NKG2C Absence on Natural Killer Cell Phenotype and Function in Human

    Effect of NKG2C Absence on Natural Killer Cell Phenotype and Function in Human Immunodeficiency Virus/Cytomegalovirus Co-infection ©Emilie M. Comeau A thesis submitted to the School of Graduate Studies in partial fulfillment of the requirements for the degree of Master of Science in Medicine Division of BioMedical Science Immunology and Infectious Diseases Faculty of Medicine, Memorial University of Newfoundland St. John’s, Newfoundland May 2018 Abstract Natural killer (NK) cells expressing NKG2C and CD57 expand following human cytomegalovirus (CMV) infection. This NK cell subset downregulates FcεR1γ and acquires enhanced capacity to mediate antibody-dependent cellular cytotoxicity (ADCC). Expansion of these differentiated NK cells is exaggerated in human immunodeficiency virus (HIV) infection. Individuals lacking the gene encoding NKG2C have diminished resistance to HIV, but it remains unclear whether differentiation into NK cells with superior ADCC is impaired in NKG2Cnull individuals. Therefore, our objective was to investigate if CMV-driven NK cell differentiation into enhanced killers is impaired in NKG2Cnull HIV-infected individuals. Phenotypic (CD57+, FcεR1γ-) and functional (IFN- γ, TNF-α induction and cytotoxicity) NK cell responses were compared between NKG2Cnull and matched NKG2C-expressing individuals by flow cytometry following stimulation through natural cytotoxicity receptors (using K562 cells) or CD16 (using monoclonal antibody, 3G8). Cytotoxicity was measured in 51Chromium release assays against anti-CD16-coated P815 cells (redirected lysis) and anti-human leukocyte antigen (HLA) class I antibody-coated C1R cells (classical ADCC). Antibodies were titrated to determine concentrations producing half maximal responses (EC50) to compare sensitivity. Our data indicate highly similar CMV-driven NK cell differentiation in terms of both general phenotype and function, regardless of NKG2C genotype.