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Original article
Peripheral blood RNA gene expression in children with pneumococcal meningitis: a prospective case–control study
  1. Benard W Kulohoma1,
  2. Fiona Marriage2,
  3. Olga Vasieva3,
  4. Limangeni Mankhambo4,
  5. Kha Nguyen5,
  6. Malcolm E Molyneux4,
  7. Elizabeth M Molyneux6,
  8. Philip J R Day2,
  9. Enitan D Carrol4,5,6
  1. 1 Centre for Biotechnology and Bioinformatics, University of Nairobi, Nairobi, Kenya
  2. 2 Centre for Integrated Genomic Research, University of Manchester, Manchester, UK
  3. 3 Institute of Integrative Biology, University of Liverpool, Liverpool, UK
  4. 4 Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, Blantyre, Malawi
  5. 5 Institute of Infection and Global Health, University of Liverpool, Liverpool, UK
  6. 6 Department of Paediatrics, University of Malawi, College of Medicine, Blantyre, Malawi
  1. Correspondence to Professor Enitan D Carrol; edcarrol{at}liverpool.ac.uk

Abstract

Introduction Invasive pneumococcal disease (IPD), caused by Streptococcus pneumoniae, is a leading cause of pneumonia, meningitis and septicaemia worldwide, with increased morbidity and mortality in HIV-infected children.

Objectives We aimed to compare peripheral blood expression profiles between HIV-infected and uninfected children with pneumococcal meningitis and controls, and between survivors and non-survivors, in order to provide insight into the host inflammatory response leading to poorer outcomes.

Design and setting Prospective case–control observational study in a tertiary hospital in Malawi

Participants Children aged 2 months to 16 years with pneumococcal meningitis or pneumonia.

Methods We used the human genome HGU133A Affymetrix array to explore differences in gene expression between cases with pneumococcal meningitis (n=12) and controls, and between HIV-infected and uninfected cases, and validated gene expression profiles for 34 genes using real-time quantitative PCR (RT-qPCR) in an independent set of cases with IPD (n=229) and controls (n=13). Pathway analysis was used to explore genes differentially expressed.

Results Irrespective of underlying HIV infection, cases showed significant upregulation compared with controls of the following: S100 calcium-binding protein A12 (S100A12); vanin-1 (VNN1); arginase, liver (ARG1); matrix metallopeptidase 9 (MMP9); annexin A3 (ANXA3); interleukin 1 receptor, type II (IL1R2); CD177 molecule (CD177); endocytic adaptor protein (NUMB) and S100 calcium-binding protein A9 (S100A9), cytoskeleton-associated protein 4 (CKAP4); and glycogenin 1 (GYG1). RT-qPCR confirmed differential expression in keeping with microarray results. There was no differential gene expression in HIV-infected compared with HIV-uninfected cases, but there was significant upregulation of folate receptor 3 (FOLR3), S100A12 in survivors compared with non-survivors.

Conclusion Children with IPD demonstrated increased expression in genes regulating immune activation, oxidative stress, leucocyte adhesion and migration, arginine metabolism, and glucocorticoid receptor signalling.

  • differential expression
  • children
  • invasive pneumococcal disease
  • host response
  • pneumococcal meningitis

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

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Footnotes

  • Contributors FM, PJRD and EDC conceived and designed the study. LM and EDC collected the clinical samples. FM performed experiments. BWK, FM, OV, KN, PJRD and EDC performed the analysis. BWK, FM, PJRD and EDC wrote the first draft of the manuscript. BWK, FM, LM, KN, OV, MEM, EMM, PJRD and EDC contributed to writing the manuscript.

  • Funding EDC was supported by a Wellcome Trust Career Development Grant (068026). BWK was supported by a Wellcome Trust Major Overseas programme award (084679/Z/08/Z).

  • Disclaimer The funding bodies had no role in collection, analysis or interpretation of data or in writing the manuscript.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval College of Medicine Research Committee (COMREC), Malawi.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Transcription data are openly available.

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