Influences of early-onset infections on the neonatal proteome

Bodensohn, Wolfgang (2023): Influences of early-onset infections on the neonatal proteome. Dissertation, LMU München: Medizinische Fakultät

Abstract

Infection and sepsis are major causes of global morbidity and mortality in the neonatal period. Their management is challenging since initial symptoms are unspecific and the diagnostic accuracy of established blood tests is suboptimal. Proteomics, the systemic investigation of proteins by mass spectrometry (MS), may provide new blood biomarkers – single proteins or entire biological networks – facilitating early diagnosis and improving the outcome of neonatal infection and sepsis. In 2017–2019, the Dr. von Hauner Children’s Hospital Munich (LMU) and the Max Planck Institute of Biochemistry Martinsried (MPIB) conducted a large-scale proteomic observational study in neonates (n = 662). By means of a cutting-edge MS-workflow, up to 700 proteins each were measured in minimal amounts of whole blood collected on conventional filter cards. Within the broader framework of this study, I dedicated the present thesis to a subgroup of late preterm (≥ 35+0) and term infants affected by (non-culture-proven) early-onset bacterial infection (n = 20). From each of them, a pair of blood samples had been collected: a first sample as part of initial diagnostics and before the beginning of antibiotic therapy (around 10 h after birth), a second sample ca. 48 h later. I evaluated the respective protein profiles from three points of view: (1), in comparison to control samples from healthy neonates; (2), longitudinally over the two time points; (3), by comparing the severely diseased patients with the less severely affected ones. (1) S100-P was the most significantly altered protein (31-fold increased, p = 0.001). It also correlated positively with CRP (C-reactive protein) at initiation of antibiotic therapy (r = 0.73, p = 0.03). Moreover, the cytoskeletal regulator protein ACTR3 (actin-related protein 3) and the acute-phase protein HP (haptoglobin) were both 8-fold decreased (p = 0.003 & 0.0008). The DNA-binding protein hnRNPK (heterogeneous nuclear ribonucleoprotein K) showed a negative correlation with the total duration of antibiotic treatment (r = –0.76, p = 0.02). The haemostatic glycoprotein vWF (von Willebrand factor) had, unlike S100-P, a negative correlation with the initial CRP (r = –0.67, p = 0.05). (2) The protein abundances of apolipoprotein B100 & E and of ITIH3 (inter-alpha-trypsin inhibitor heavy chain H3) were most significantly lower at t1 than at t2 (all ca. 2-fold lower, q = 0.008). Moreover, complement proteins and acute-phase proteins were significantly less abundant at t1 as well, such as SERPIN-A3 & -A1 (alpha-1-anti[chymo]trypsin), ORM1 (alpha-1-acid-glycoprotein) and SAA2–4 (serum amyloid A 2–4). Among all of these, SERPIN-A3 and ORM1 reflected the dynamics towards t2 most accurately, since they did not show any longitudinal change between the two examined control groups. S100-A8 and S100-A9 (also known as calprotectin dimer) were 2-fold more abundant at t1 than at t2 (p = 0.003 & 0.01). (3) I could not identify any further potential markers, but I could reproduce some of the main findings from the two previous considerations in a low significance area. Overall, despite small to medium sample sizes the present data grants deep insight into the proteome profiles of neonatal patients affected by early-onset bacterial infection. The significant role of (apo-)lipoproteins in inflammation and sepsis was confirmed (particularly for Apo-B100). A further examination of their diagnostic (or even therapeutic) potential in neonates seems to be very promising. Moreover, protein S100-P was shown to be significantly increased in the early phase of infection. For the proteins S100-A8 & A9 (calprotectin), there are at least indications that their usage in monitoring inflammation levels could be applicable to neonatal sepsis as well. This thesis is to contribute to a more comprehensive understanding of the neonatal blood proteome. It is part of the ongoing search for the ideal set of biomarkers for neonatal infection and sepsis. Thereby, it is dedicated to an issue with room for significant improvement, for the greater good of many patients at an early point in their life.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Proteomics, Neonatology, Early-onset infection, Sepsis, Biomarker
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 27. Juli 2023
• 1. Bericht­erstatter:in: Genzel-Boroviczény, Orsolya