The most common etiological agents of acute bacterial meningitis (ABM) are Streptococcus pneumoniae and Neisseria meningitidis. S. pneumoniae is associated with the highest mortality (up to 30%) and morbidity (up to 50%) despite advances in antimicrobial therapy and intensive care (reviewed in [1], [2]). Conversely, enteroviruses – the most frequent agents of viral meningitis - usually causes disease with an auto-limited course being less frequently associated with a bad prognostic [3], [4]. ABM causes cortical and hippocampal neuron loss leading to permanent neurological sequelae which include cognitive and sensory-motor deficits, seizure disorders, and cerebral palsy [5], [6], [7]. ABM-associated cortical injury consists of areas with morphologic evidence of neuronal necrosis [8], while apoptosis is the predominant form of neuronal injury in the hippocampus, affecting mainly progenitor cells and immature neurons in the inner layer of the dentate gyrus [9], [10], [11].

The inflammatory response to the infection in the central nervous system (CNS) determines the clinical outcome of acute meningitis, e.g., the associated mortality and the extent of brain injury. Bacterial components in the CNS trigger the production and release of inflammatory molecules such as cytokines and chemokines, reactive oxygen species (ROS), and reactive nitrogen species (RNS). They can directly cause brain injury, interact with each other modulating the inflammatory reaction, and induce secondary mechanisms capable of damaging the brain (reviewed in [12], [13], [14]). One such secondary mechanism involves the excessive activation of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP), which synthesizes ADP-ribose polymers in response to DNA damage [14]. This process comes at a very high-energy cost depleting NAD + and ATP and thereby causing cell death. PARP may provide a linkage between oxidative DNA damage and apoptosis or necrosis during ABM depending upon the severity of the ATP and NAD + withdrawal. The synthesis of NAD + by the nicotinamide pathway uses quinolinic acid (QUINA) as its only substrate. QUINA is the endpoint of the kynurenine (KYN) pathway, which is the major catabolic route of tryptophan (TRP) (Fig. 1).

Some KYN metabolites are neurotoxic, while others can be neuroprotective. Most important, kynurenic acid (KYNA) is an antagonist of the N-methyl-D-aspartate (NMDA) receptors, while quinolinic acid (QUINA) is agonist of such receptors (reviewed in: [15]). Neuron death in ABM involves the excessive activation of NMDA receptors [16], and exogenous KYNA protected neurons from excitotoxic brain damage in experimental ABM [17]. Furthermore, it has been previously shown that pneumococcal meningitis (PM) causes the accumulation of neurotoxic KYN metabolites in the brain regions more prone to neuron loss in infant rats [18]. However, no conclusive data is available on the specific patterns of KYN pathway modulation in humans in response to the most frequent forms of acute meningitis. The complete lack of data about QUINA in acute bacterial meningitis is significant.

This study aimed at investigating pathogen-specific patterns of KYN pathway modulation in the cerebrospinal fluid (CSF) of pediatric patients with acute meningococcal (MM), pneumococcal, and enteroviral (VM) meningitis. Combining Ultra-High-Performance Liquid Chromatography (uHPLC) with mass spectrometry to quantify TRP, KYN, KYNA, and QUINA, and machine learning algorithms for data mining, a specific pattern of KYN pathway modulation was found in patients with PM, which clearly distinguishes them from those with MM, VM, and controls without infection.