Dataset Information

Human Lyme Neuroborreliosis LC-MS (CSF)

ABSTRACT: Lyme neuroborreliosis (LNB) is a nervous system infection caused by tick-borne spirochetes of the Borrelia burgdorferi sensu lato complex and is one of the most frequent bacterial infections of the nervous system in Europe. Early diagnosis remains challenging due to limited sensitivity and specificity of current tests and the need for invasive lumbar punctures, highlighting the need for improved and potentially less invasive diagnostic tools. In this study, we used bottom-up proteomics to analyze 308 cerebrospinal fluid (CSF) samples and 207 plasma samples from well-characterized cohorts, including patients with LNB, viral meningitis, other manifestations of Lyme borreliosis without central nervous system involvement, and controls with normal CSF findings. We identified diagnostic panels of regulated proteins and evaluated their performance using machine learning–based classifiers. The resulting models distinguished LNB from viral meningitis and controls in CSF with areas under the ROC curve (AUC) of 0.92 and 0.90, respectively. In plasma, LNB was distinguished from controls with an AUC of 0.80. These findings suggest a potential diagnostic role for proteomics-based biomarker panels in LNB and provide a large-scale, publicly available proteomic resource for further biomarker discovery and validation studies. NB: the plasma submission is seperate to this CSF submission

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cerebrospinal Fluid

SUBMITTER: Annelaura Bach Nielsen

LAB HEAD: Nicolai J. Wewer Albrechtsen

PROVIDER: PXD067474 | Pride | 2025-09-30

REPOSITORIES: Pride

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			Action	DRS
	20210921_EXPL1_EvoPlateform_CR_LNBandViralMeningitis_Plate1_012000628091.raw	Raw
	20210921_EXPL1_EvoPlateform_CR_LNBandViralMeningitis_Plate1_012000628144.raw	Raw
	20210921_EXPL1_EvoPlateform_CR_LNBandViralMeningitis_Plate1_012000628271.raw	Raw
	20210921_EXPL1_EvoPlateform_CR_LNBandViralMeningitis_Plate1_012000628328.raw	Raw
	20210921_EXPL1_EvoPlateform_CR_LNBandViralMeningitis_Plate1_012000628455.raw	Raw

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Project description:Meningitis is a life-threatening condition characterized by the inflammation of the leptomeningeal membranes surrounding the brain and spinal cord. The term meningitis is an umbrella term and includes several different etiologies. The majorities of meningitis cases are caused by viruses (viral meningitis; VM) and are often associated with low mortality rates and low risk of developing neurological. In contrast, meningitis caused by some viral infections, such as tick-borne encephalitis (TBE), can be life-threatening when left untreated with increased risk of developing neurological sequelae. Acute bacterial meningitis (ABM), however, is one of the leading causes of death due to infectious diseases worldwide and is associated with rapid disease progression, high mortality rates and increased risk of long-term neurological sequelae in survivors. As meningitis is caused by numerous different pathogens, the host-response is typically highly variable and it is currently unknown if different pathogens can introduce specific proteome changes in the cerebrospinal fluid (CSF). In this study we applied DIA-MS to provide novel insights for in-depth understanding of central nervous system functioning and host response during meningitis in a cohort of patients with differential diagnosis of meningitis, to account for variability contributed by different disease-causing pathogens. The results reveal drastic changes in the CSF proteome during meningitis, where in particular a massive increase of neutrophil derived proteins in the CSF correlated with ABM, suggesting that activated neutrophils play a particular role in ABM. Additionally both ABM and VM result in marked reduction of brain-specific proteins in the CSF, which could be indicative of pathophysiological mechanisms leading to brain damage. Furthermore, generation of lasso regression model enables separation of ABM with high sensitivity and specificity, demonstrating that several proteins are required to confidently discriminate between ABM, VM and BM.

Project description:Background Mortality from bacterial meningitis, predominately caused by Streptococcus pneumoniae, exceeds 50% in low and middle income countries in sub-Saharan Africa with high HIV prevalence. Underlying causes of high mortality are poorly understood. We examined the host and pathogen proteome in adults with proven pneumococcal meningitis (PM), testing if differentially expressed proteins in CSF were implicated in outcome. Materials/methods CSF proteomes were analysed by quantitative Mass-Spectrometry. Spectra were identified using the Swissprot human and TIGR4 pneumococcal protein libraries. Proteins were quantitated and analysed against clinical outcome. Unique proteins in PM were identified against published normal CSF proteome. Random-Forest models were used to test for protein signatures discriminating outcome. Proteins of interest were tested for their effects on growth and opsonophagocytic killing of S. pneumoniae. Results CSF proteomes were available for 57 Adults with PM (median age 32 years, 60% male, 70% HIV-1 co-infected, mortality 63%). 360 individual human and 23 pneumococcal proteins were identified. Of the human protein hits, 30% were not expressed in normal CSF, and these were strongly associated with inflammation and primarily related to neutrophil activity. No human protein signature predicted outcome. However, expression of the essential S. pneumoniae protein Elongation Factor Tu (EF-Tu) was significantly increased in CSF of non-survivors (False Discovery Rate (q) <0.001). Expression of EF-Tu was negatively co-correlated against expression of Neutrophil defensin (r 0.4 p p<0.002), but not against complement proteins C3 or Factor H. In vitro, addition of EF-Tu protein impaired S. pneumoniae neutrophil killing when osponised with CSF. Conclusions Excessive CSF levels of S. pneumoniae EF-Tu protein was associated with reduced survival in human meningitis. Preliminary studies show EF-Tu inhibits neutrophil mediated killing of S. pneumoniae in CSF. Further functional studies are required to better understand the mechanistic role of EF-Tu during PM.

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Human Lyme Neuroborreliosis LC-MS (CSF)

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