Protein Oxidation Biomarkers and Myeloperoxidase Activation in Cerebrospinal Fluid in Childhood Bacterial Meningitis

Abstract

The immunological response in bacterial meningitis (BM) causes the formation of reactive oxygen and nitrogen species (ROS, RNS) and activates myeloperoxidase (MPO), an inflammatory enzyme. Thus, structural oxidative and nitrosative damage to proteins and DNA occurs. We aimed to asses these events in the cerebrospinal fluid (CSF) of pediatric BM patients. Phenylalanine (Phe), para-tyrosine (p-Tyr), nucleoside 2′-deoxiguanosine (2dG), and biomarkers of ROS/RNS-induced protein and DNA oxidation: ortho-tyrosine (o-Tyr), 3-chlorotyrosine (3Cl-Tyr), 3-nitrotyrosine (3NO₂-Tyr) and 8-oxo-2′-deoxyguanosine (8OHdG), concentrations were measured by liquid chromatography coupled to tandem mass spectrometry in the initial CSF of 79 children with BM and 10 without BM. All biomarkers, normalized with their corresponding precursors, showed higher median concentrations (p < 0.0001) in BM compared with controls, except 8OHdG/2dG. The ratios o-Tyr/Phe, 3Cl-Tyr/p-Tyr and 3NO₂-Tyr/p-Tyr were 570, 20 and 4.5 times as high, respectively. A significantly higher 3Cl-Tyr/p-Tyr ratio was found in BM caused by Streptococcus pneumoniae, than by Haemophilus influenzae type b, or Neisseria meningitidis (p = 0.002 for both). In conclusion, biomarkers indicating oxidative damage to proteins distinguished BM patients from non-BM, most clearly the o-Tyr/Phe ratio. The high 3Cl-Tyr/p-Tyr ratio in pneumococcal meningitis suggests robust inflammation because 3Cl-Tyr is a marker of MPO activation and, indirectly, of inflammation.

Overview of Brain-to-Gut Axis Exposed to Chronic CNS Bacterial Infection(s) and a Predictive Urinary Metabolic Profile of a Brain Infected by Mycobacterium tuberculosis

“…Each with their advantages and disadvantages is described by Winterbourn and Kettle (2000). Based on the analyses of CSF collected from 79 confirmed pediatric BM cases, Rugemalira et al (2019) indicated that elevated ratios of 3Cl-Tyr:para-tyrosine serves as a marker for MPO activation in CSF in pediatric BM cases, and potentially also for grading the severity of neuroinflammation. Furthermore, Rugemalira et al (2019) also proved that 3NO 2 -Tyr can be used as a biomarker for peroxynitrite formation and is associated with an unfavorable outcome of BM.…”

“…Based on the analyses of CSF collected from 79 confirmed pediatric BM cases, Rugemalira et al (2019) indicated that elevated ratios of 3Cl-Tyr:para-tyrosine serves as a marker for MPO activation in CSF in pediatric BM cases, and potentially also for grading the severity of neuroinflammation. Furthermore, Rugemalira et al (2019) also proved that 3NO 2 -Tyr can be used as a biomarker for peroxynitrite formation and is associated with an unfavorable outcome of BM. In a study of 59 children with confirmed BM (Mirić et al, 2010), CSF MPO activity, although relatively low, was significantly increased at baseline compared to controls (n = 23), increasing even further by day 5 of treatment.…”

Oxidative Stress-Generating Antimicrobials, a Novel Strategy to Overcome Antibacterial Resistance

“…The interaction between PRRs and PAMPs trigger the activation of the oxidative burst during phagocytosis, which is initially characterized by the activity of NADPH oxidases (NOX) that generate the superoxide anion (O2 − ). This free radical could be dismuted to hydrogen peroxide (H2O2) spontaneously, but superoxide dismutases do this more efficiently ( Figure 1B) [8,10,17]. The presence of NOX proteins is critical for the control of infections.…”

“…spontaneously, but superoxide dismutases do this more efficiently ( Figure 1B) [8,10,17]. The presence of NOX proteins is critical for the control of infections.…”

“…In addition, hypochlorous acid (HClO) is generated from H 2 O 2 and the chloride ion (Cl − ) by the action of myeloperoxidases ( Figure 1B), which are mainly expressed in macrophages and neutrophils [10,11,17,21]. HClO has a higher antibacterial activity than H 2 O 2 and it is more reactive with the sulfur contained in cysteines and methionines of essential proteins for the intracellular survival of the pathogen [9,22,23].…”