Cerebrospinal fluid inflammome analysis identifies host-and pathogen-specific inflammatory profiles and signaling pathways in meningitis and predicts clinical outcome

Abstract

Increasing evidence indicate that individual host immune response to pathogens may be as important as virulence factors in determining the severity of infection. However, most available data on pathogen-host interactions are based on in vitro findings, neglecting the genetic complexity of the immune response. We conducted a comparative observational study of bacterial and viral meningitis to identify pathogen-specific and host-dependent inflammatory pathways that may predict the severity of infection by analysing 54 inflammatory factors using plexing technology. Infection severity and neurological disability were assessed using the modified RANKIN scale. To identify pathogen-specific and host-dependent pathways, plex data were entered into EMBiology(R) software and gene set enrichment analysis (GSEA) was performed. We also investigated pathogen- and host-dependent regulatory effects on blood-brain barrier function using human iPSC-derived endothelial cells as a model. BBB function was characterised at the level of transendothelial electrical resistance (TEER), endothelial apoptosis and drug transporter activity. We identified 36 factors that are highly differentially regulated in either bacterial or viral meningoencephalitis compared to healthy subjects, 15 of which have not been previously described. GSEA identified previously unknown pathogen-specific pathways including neurotrophin, NOTCH, immune tolerance, antiviral defence and tight junction signalling. As a key finding, we identified 15 host-dependent factors that correlated with the grade of disability and with blood-CSF barrier dysfunction. GSEA revealed stronger responses of neuroprotective (AKT/ERK), anti-apoptotic (Bcl-2/p53) and anti-inflammatory (JAK1/STAT1) pathways in patients with favourable course, whereas patients with severe infection show stronger pro-inflammatory STAT-activation, NKC/CTL-responses and NF{kappa}-B-associated neurotoxicity. BBB analysis supports these findings with dysregulation of TEER, drug transporter activity and induction of endothelial cell death in patients with severe infection. Our data highlight the need for future approaches to personalised medicine that go beyond traditional anti-infective therapy to target the individual immune response. Author SummeryInfections often cause personal suffering, but also high economic costs. Brain infections such as bacterial or viral meningitis are particularly serious and carry a high risk of death or permanent disability. At the same time, resistance to anti-infective drugs is increasing and fewer new antibiotics are being developed. As a result, there is a great need for translational research to develop new treatments beyond conventional anti-infectives. Due to its strict compartmentalisation, the brain is well suited to identify specific pathogen-dependent, but also host (patient) dependent inflammatory patterns in infections. Using a cohort of patients with a defined group of pathogen-specific meningitis, we investigated the inflammatory patterns in the cerebrospinal fluid and were able to describe new specific pathogen-dependent and new host-dependent immune responses and identify associated signalling pathways. We were also able to show how and at what cellular and molecular level the blood-brain barrier is disrupted by infection. The degree of damage to the blood-brain barrier is an important aspect and has major implications for the course and prognosis of brain infections. Once the pathogen- and host-specific aspects of the immune response are understood, new personalised therapeutic approaches can be developed that directly target the regulation of the individual immune response.