Dataset Information

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

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cerebrospinal Fluid

DISEASE(S): Meningitis

SUBMITTER: Anahita Bakochi

LAB HEAD: Johan Malmstrom

PROVIDER: PXD023174 | Pride | 2021-04-12

REPOSITORIES: Pride

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

Bakochi Anahita A Mohanty Tirthankar T Pyl Paul Theodor PT Gueto-Tettay Carlos Alberto CA Malmström Lars L Linder Adam A Malmström Johan J

eLife 20210406

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 ...[more]

PMID: 33821792

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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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