Proteomics

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CSF levels of Elongation Factor Tu is associated with increased mortality in human Streptococcus pneumoniae meningitis


ABSTRACT: 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.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo sapiens  

TISSUE(S): Cerebrospinal Fluid

DISEASE(S): Not Available

SUBMITTER: Philip Brownridge  

LAB HEAD: Emma Wall

PROVIDER: PXD021268 | Pride | 2020-11-09

REPOSITORIES: Pride

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