Peripheral blood RNA gene expression in children with pneumococcal meningitis: a prospective case– control study

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), cytoskeletonassociated 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. IntrODuctIOn Streptococcus pneumoniae infection is a leading cause of pneumonia, meningitis and septicaemia worldwide, and results in approximately 1 million deaths in children under the age of 5 years annually. The overall burden of invasive pneumococcal disease (IPD) is increased 40-fold in HIV-infected compared with HIV-uninfected children. Pneumococcal meningitis is a life-threatening disease with poor prognosis associated with neurologic complications and a high case-fatality ratio in African children, which is further increased by HIV coinfection. What this study hopes to add? ► We demonstrate for the first time differences in transcriptional profiles between HIV-infected and HIV-uninfected children with pneumococcal meningitis (as a homogeneous disease entity of invasive pneumococcal disease and healthy