CSF Levels of Elongation Factor Tu Is Associated With Increased Mortality in Malawian Adults With Streptococcus pneumoniae Meningitis

Wall, Emma C., Brownridge, Philip, Laing, Gavin, Terra, Vanessa S., Mlozowa, Veronica, Denis, Brigitte, Nyirenda, Mulinda, Allain, Theresa, Ramos-Sevillano, Elisa, Carrol, Enitan, Collins, Andrea, Gordon, Stephen ORCID: https://orcid.org/0000-0001-6576-1116, Lalloo, David ORCID: https://orcid.org/0000-0001-7680-2200, Wren, Brendan, Beynon, Robert, Heyderman, Robert S. and Brown, Jeremy S. (2020) 'CSF Levels of Elongation Factor Tu Is Associated With Increased Mortality in Malawian Adults With Streptococcus pneumoniae Meningitis'. Frontiers in Cellular and Infection Microbiology, Vol 10.

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Abstract

Background: Mortality from bacterial meningitis, predominately caused by Streptococcus pneumoniae, exceeds 50% in sub-Saharan African countries with high HIV prevalence. Underlying causes of high mortality are poorly understood. We examined the host and pathogen proteome in the CSF of adults with proven pneumococcal meningitis (PM), testing if there was an association between differentially expressed proteins and outcome.

Materials/Methods: CSF proteomes were analyzed by quantitative Mass-Spectrometry. Spectra were identified using the Swissprot human and TIGR4 pneumococcal protein libraries. Proteins were quantitated and analyzed against mortality. 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 neutrophil 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%). Three hundred sixty 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 in CSF.

Conclusions: Excessive S. pneumoniae EF-Tu protein in CSF was associated with reduced survival in meningitis in a high HIV prevalence population. We show EF-Tu may inhibit neutrophil mediated killing of S. pneumoniae in CSF. Further mechanistic work is required to better understand how S. pneumoniae avoids essential innate immune responses during PM through production of excess EF-Tu.

Item Type:	Article
Subjects:	QU Biochemistry > Genetics > QU 460 Genomics. Proteomics QW Microbiology and Immunology > Bacteria > QW 142 Gram-positive bacteria (General) WA Public Health > Health Problems of Special Population Groups > WA 395 Health in developing countries WL Nervous System > WL 200 Meninges. Blood-brain barrier
Faculty: Department:	Clinical Sciences & International Health > Clinical Sciences Department Clinical Sciences & International Health > Malawi-Liverpool-Wellcome Programme (MLW)
Digital Object Identifer (DOI):	https://doi.org/10.3389/fcimb.2020.603623
Depositing User:	Cathy Waldron
Date Deposited:	07 Jan 2021 16:25
Last Modified:	07 Jan 2021 16:25
URI:	https://archive.lstmed.ac.uk/id/eprint/16607

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