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Phagocytosis of Neonatal Pathogens by Peripheral Blood Neutrophils and Monocytes from Newborn Preterm and Term Infants

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Phagocytosis of Neonatal Pathogens by Peripheral Blood Neutrophils and Monocytes from Newborn Preterm and Term Infants nature publishing group Basic Science Investigation Articles Phagocytosis of neonatal pathogens by peripheral blood neutrophils and monocytes from newborn preterm and term infants Amy Prosser1, Julie Hibbert1, Tobias Strunk1,2, Chooi Heen Kok2, Karen Simmer2, Peter Richmond1, David Burgner1,3,4 and Andrew Currie2,5 BACKGROUND: Deficiencies in phagocytosis may contrib- Very preterm infants (<30 wks gestational age (GA)) ute to the increased susceptibility of infants to early life infec- are extremely susceptible to bacterial infection, with risk tions. Data on phagocytosis of the major neonatal pathogens inversely correlated with birth weight and GA (3,4). Early- Staphylococcus epidermidis (SE), Staphylococcus aureus (SA), and late-onset sepsis (occurring before and after 72 h, and Escherichia coli (EC) by preterm infant leukocytes are respectively) remain important causes of morbidity and inconsistent. mortality (4,5). The commonest pathogen group in pre- METHODS: Cord and <24-h peripheral blood were collected term infants is coagulase-negative staphylococci, of which from very preterm (<30.1 wks gestational age (GA)) and term Staphylococcus epidermidis (SE) is the predominant species. (37–42 wks GA) infants. Monocyte and neutrophil phagocy- Coagulase-negative staphylococci are responsible for ~50% tosis of pHrodo-labeled SE, SA, and EC were analyzed using a of late-onset sepsis and 7–12% of early-onset sepsis episodes small-volume flow cytometry assay, with simultaneous charac- (4–6). Escherichia coli (EC), Staphylococcus aureus (SA) and terization of surface activation marker expression. Group B Streptococcus (GBS) account for the majority of RESULTS: Preterm infants had lower proportions of mono- non–coagulase-negative staphylococci infections in preterm cytes and neutrophils capable of phagocytosis than term infants (5,7,8). infants, but preterm infant phagocytes had higher phagocytic Deficiencies of innate immune functions, including phago- capacity. Phagocytosis was strongly correlated between cord cytosis, cytokine production, and complement activity, have and <24-h peripheral blood. Supplementation with exog- been reported in preterm infants and are suggested to con- enous complement significantly increased phagocytosis of tribute to their heightened susceptibility to bacterial infec- EC but not of SE or SA. Monocyte human leukocyte antigen tion (9,10). However, the data, particularly for deficiencies (HLA)-DR expression was lower in preterm infants but did not in phagocytosis, are inconsistent (11). There are no definitive correlate with phagocytosis. comparisons of phagocytosis between adults and neonates; CONCLUSION: There is no defect in phagocytosis by mono- studies have identified positive (12,13), negative (14), and neu- cytes and neutrophils from preterm compared with term tral (11,13) trends in functionality between the groups (15). infants, although preterm infants possess fewer phagocytes, Similarly, the reported correlation between GA and phagocy- possibly contributing to susceptibility to bacterial infec- tosis functionality is inconsistent (12,16). Discrepancies are tion. Further investigation into the development of postnatal also evident when comparing specific cell types, including phagocytic competence is warranted. monocytes and neutrophils (12–15). Characterization of innate immune responses to common hagocytosis is an essential component of innate immune neonatal pathogens is essential to inform translational stud- Presponses to pathogens, encompassing recognition, bind- ies aiming to reduce the disease burden. However, immune ing, engulfment, and degradation of particles such as bacteria. studies of preterm cells is challenging, as blood samples Although primarily an innate immune process, degradation from preterm infants (with a blood volume of <50 ml (17)) and processing of microbes during phagocytosis for presenta- are limited in volume. Previous studies of preterm phago- tion via major histocompatibility complexes is also a crucial cytic responses to bacterial infection have largely used cord link to adaptive immune system responses (1). Individuals blood, as comparatively large volumes (5–30 ml) are readily with phagocytic defects (e.g., Wiskott–Aldrich syndrome (2)) obtained. However, characterization of postnatal peripheral are at an increased risk of bacterial infection. blood is essential; there are few data on changes in innate 1School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia; 2University of Western Australia Centre for Neonatal Research and Education, Perth, Western Australia, Australia; 3Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia; 4Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia; 5School of Veterinary & Life Sciences, Murdoch University, Perth, Western Australia, Australia. Correspondence: Andrew Currie ([email protected]) Received 21 June 2012; accepted 27 March 2013; advance online publication 16 October 2013. doi:10.1038/pr.2013.145 Copyright © 2013 International Pediatric Research Foundation, Inc. Volume 74 | Number 5 | November 2013 Pediatric Research 503 Articles Prosser et al. immune function in the immediate postnatal period and RESULTS it is unclear whether cord blood data are representative of Detection of Phagocytosis With pHrodo-Labeled Bacteria Using peripheral blood responses. Whole Blood To enable analysis of very preterm peripheral blood, we The phagocytosis assay conditions used for neonatal samples developed and optimized a small-volume, whole-blood were initially optimized for time, dose, and minimum blood assay utilizing a pH-sensitive dye pHrodo to detect mono- volume requirement using peripheral blood from healthy cyte and neutrophil phagocytic functionality. The formation adult volunteers (data not shown). Incubation of preterm of the phagosome around an ingested entity during phago- infant whole blood with pHrodo-labeled bacteria, under opti- cytosis relies on low pH for bactericidal functions and anti- mal conditions, resulted in a marked shift in fluorescence of gen processing and presentation (1,18). pHrodo is a highly phagocytic cells clearly detectable above the background of pH-sensitive succinimidyl ester dye that fluoresces dramati- unstimulated blood (Figure 1b,1d). Both phagocyte popula- cally when exposed to low pH (<4.0). Phagocytosis is there- tions (monocytes and neutrophils) were readily identified in fore detectable and quantifiable when the phagosome forms, preterm infant samples using a combination of anti-CD14 and acidifies, around ingested pHrodo-labeled bacteria, staining and side-scatter properties (Figure 1a). The per- minimizing high background fluorescence of cell-bound, centage of pHrodo+ cells and the associated median pHrodo but uningested, bacteria (18,19). fluorescence intensity (MFI) of phagocytic cells were readily Our aims are to (i) describe this novel technique, (ii) determined. As expected, nonphagocytic lymphocytes did not compare monocyte and neutrophil phagocytic capacity in fluoresce (Figure 1c). Blocking of phagocytosis in adult blood cord and peripheral blood, (iii) examine the effect of GA by preincubation with 20 μg/ml cytochalasin D (CD) was on phagocytosis by monocytes and neutrophils of common observed although complete abrogation of phagocytosis was neonatal pathogens SE, SA, and EC, and (iv) investigate cor- not achieved (data not shown). Confocal microscopy of adult relations between cellular activation marker expression and blood with pHrodo-labeled SE, with or without the addition phagocytosis activity. of CD showed low levels of fluorescence of bacteria associated ab 250 K 100 200 K 80 65.2 150 K 60 SSC-A 100 K % Of max 40 8.68 50 K 20 23 00 0 100 1,000 10,000 1 × 105 0 100 1,000 10,000 1 × 105 FITC-A: CD14 pHrodo cd 100 100 80 80 60 60 % Of max 40 % Of max 40 20 20 0 0 0 100 1,000 10,000 1 × 105 0 100 1,000 10,000 1 × 105 pHrodo pHrodo Figure 1. Analysis of phagocytosis using pHrodo-labeled bacteria. (a) Representative plot of an infant peripheral blood sample collected under the opti- mized phagocytosis protocol, showing inclusion gates and percentages for monocytes, neutrophils, and lymphocytes based on side-scatter area (SSC-A) and CD14 staining. (b–d) Representative histograms from (a) showing pHrodo fluorescence in the presence (solid black line) or absence (shaded grey) of pHrodo-labeled SE by neutrophils, lymphocytes, or monocytes, respectively. 504 Pediatric Research Volume 74 | Number 5 | November 2013 Copyright © 2013 International Pediatric Research Foundation, Inc. Phagocytosis in newborn whole blood Articles with CD-treated cells in comparison with bright fluorescence used as a surrogate for many preterm infant studies. We there- following phagocytic engulfment (data not shown). Assay fore investigated whether cord blood phagocytic responses are optimization was conducted using in-house pHrodo-labeled representative of peripheral blood responses of 1-day-old neo- SE; however, conditions were maintained for commercially nates. The proportion of phagocytic monocytes and neutrophils purchased pHrodo-labeled SA and EC to ensure comparability in cord and <24 h infant blood were significantly correlated during analysis. (P < 0.0001 using nonparametric Spearman correlation) directly and strongly for all bacteria tested (SE: r = 0.76 and 0.83; SA: r = Phagocytosis of Important Neonatal Pathogens by Infant 0.68 and 0.76; and EC: r = 0.70 and 0.72
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