Cerebrospinal fluid proteome maps detect pathogen-specific host response patterns in meningitis.

Anahita Bakochi,Paul Theodor Pyl,Adam Linder,Carlos Alberto Gueto-Tettay,Tirthankar Mohanty,Lars Malmström,Johan Malmström

doi:10.7554/elife.64159

Abstract

Meningitis is a potentially life-threatening infection characterized by the inflammation of the leptomeningeal membranes. Many different viral and bacterial pathogens can cause meningitis, with differences in mortality rates, risk of developing neurological sequelae, and treatment options. Here, we constructed a compendium of digital cerebrospinal fluid (CSF) proteome maps to define pathogen-specific host response patterns in meningitis. The results revealed a drastic and pathogen-type specific influx of tissue-, cell-, and plasma proteins in the CSF, where, in particular, a large increase of neutrophil-derived proteins in the CSF correlated with acute bacterial meningitis. Additionally, both acute bacterial and viral meningitis result in marked reduction of brain-enriched proteins. Generation of a multiprotein LASSO regression model resulted in an 18-protein panel of cell- and tissue-associated proteins capable of classifying acute bacterial meningitis and viral meningitis. The same protein panel also enabled classification of tick-borne encephalitis, a subgroup of viral meningitis, with high sensitivity and specificity. The work provides insights into pathogen-specific host response patterns in CSF from different disease etiologies to support future classification of pathogen type based on host response patterns in meningitis.

Highlights

Meningitis is a common condition with an estimated annual prevalence of 8.7 million cases globally (Kassebaum et al, 2017)
We developed a compendium of SWATH-MS cerebrospinal fluid (CSF) proteome maps to provide novel insights into central nervous system (CNS) functioning and host response in a cohort of patients with meningitis
CSF from each sample was digested, and peptides were analyzed by dependent acquisition (DDA)-MS for the construction of a CSF proteome assay library and data-independent acquisition (DIA)-MS to produce a compendium of proteome maps (Figure 1a)

Summary

Introduction

Meningitis is a common condition with an estimated annual prevalence of 8.7 million cases globally (Kassebaum et al, 2017). The different bacterial and viral pathogens are associated with specific virulence mechanisms that impact the molecular phenotype of the host immune response This information can be used to diagnose patients with meningitis, which routinely involves lumbar punctures to evaluate several parameters in the cerebrospinal fluid (CSF) such as the number of white blood cells (WBCs) as well as glucose and protein concentrations to differentiate between ABM and VM (Ross et al, 1988). These parameters are relatively non-specific yielding inconclusive diagnostic information (Garty et al, 1997; Lindquist et al, 1988; Nigrovic et al, 2002), and it currently remains unknown if different pathogens and pathogen types can evoke detectable differences in host response proteome

Methods

Results

Conclusion