Biology subjects

Brouwer, M. C.

Publications and source records attributed to Brouwer, M. C..

4 recordsLinked to original sources

bioRxiv2025

Temporal Dynamics of Complement Activation and Outcome in Patients with Acute Ischemic Stroke

Immune-mediated inflammatory responses exacerbate brain injury and affect the prognosis in acute ischemic stroke (AIS). We characterized longitudinal complement activation after AIS using serial plasma samples from 10 patients and 8 controls. Initial markers of classical (C1q), lectin (mannose-binding lectin [MBL]), and alternative (Factor Bb [CFBb]) pathways, as well as regulatory (Factor H [CFH]) and downstream markers (C3a, C5a and C5b-9) were measured by ELISA at 9 time points. Stroke patients showed broad complement activation with increased C1q, MBL, CFBb, C3a, C5a, and C5b-9, and reduced CFH. C1q, MBL, and CFBb peaked around day 17. MBL was higher in patients with poor outcome, CFBb was higher with good outcome, and C5b-9 in severe strokes. These findings reveal pathway-specific complement dynamics after AIS and support complement as a target for stage-specific therapy.

neuroscience↗

bioRxiv2024

The Streptococcus pneumoniae transcriptome in patient cerebrospinal fluid identifies novel virulence factors required for meningitis

To better understand Streptococcus pneumoniae pathogenesis we performed RNA sequencing on cerebrospinal fluid (CSF) from meningitis patients to identify bacterial genes expressed during invasion of the central nervous system. Comparison to transcriptome data for serotype 1 S. pneumoniae cultured in ex vivo human CSF defined a subset of 57 genes with high expression during human meningitis. Deletion of two of the most highly expressed genetic loci, bgaA (encodes for a {beta}-galactosidase) or the SP_1801-5 putative stress response operon, resulted in S. pneumoniae strains still able to transmigrate the blood brain barrier but which were more susceptible to complement opsonisation and unable to maintain brain infection in a murine meningitis model. In 1144 meningitis patients, infection with bgaA containing S. pneumoniae strains was associated with a higher mortality (22% versus 14% p=0.02). These data demonstrate that direct bacterial RNAseq from CSF can identify previously undescribed S. pneumoniae virulence factors required for meningitis pathogenesis.

microbiology↗

bioRxiv2021

Pneumococcal genetic variability influences age-dependent bacterial carriage

The pneumococcal conjugate vaccine (PCV) primarily reduces disease burden in adults through a reduction in carriage prevalence of invasive serotypes in children. Current vaccine formulations are the same for both adults and children, but tailoring these formulations to age category could optimize vaccine efficacy. Identification of specific pneumococcal genetic factors associated with carriage in younger or older age groups may suggest alternative formulations and contribute to a better mechanistic understanding of immunity. Here, we used whole genome sequencing to dissect pneumococcal variation associated with age. We performed genome sequencing in a large carriage cohort, and conducted a meta-analysis with an existing carriage study. We compiled a dictionary of pathogen genetic variation including serotype, sequence cluster, sequence elements, SNPs, burden combined rare variants, and clusters of orthologous genes (COGs) for each cohort - all of which used in a genome-wide association with host age. Age-dependent colonization had some heritability, though this varied between cohorts (h2 = 0.10, 0.00 - 0.69 95% CI in the first; h2 = 0.46, 0.33 - 0.60 95% CI in the second cohort). We found that serotypes and genetic background (strain) explained most of the heritability in each cohort (h2serotype = 0.06 and h2GPSC = 0.04 in the first; h2 serotype = 0.20 and h2 GPSC = 0.23 in the second cohort). We found one candidate association (p = 1.2x10-9) upstream of an accessory Sec-dependent serine-rich glycoprotein adhesin. Overall, association with age was highly cohort and strain dependent, supporting proposals for a future vaccination strategy which is primarily targeted using serotypes rather than proteins, and is tailored towards specific pathogen populations.

microbiology↗

bioRxiv2018

Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis

Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. In a genome-wide association study of human and pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, and identified variants in CCDC33 associated with susceptibility. Pneumococcal variation explained a large amount of invasive potential, but serotype explained only half of this variation. Newly developed methods identified pneumococcal genes involved in invasiveness including pspC and zmpD, and allowed a human-bacteria interaction analysis, finding associations between pneumococcal lineage and STK32C.

genomics↗