Biology subjects

van der Ende, A.

Publications and source records attributed to van der Ende, A..

4 recordsLinked to original sources

bioRxiv2022

Neisseria meningitidis sibling small regulatory RNAs connect metabolism with colonization by controlling propionate use.

Neisseria meningitidis (the meningococcus) colonizes the human nasopharynx, primarily as a commensal, but sporadically causing septicemia and meningitis. During colonization and invasion, it encounters different niches with specific nutrient compositions. Small non-coding RNAs (sRNAs) are used to fine-tune expression of genes allowing adaptation to their physiological differences. We have previously characterized sRNAs (Neisseria metabolic switch regulators [NmsRs]) controlling switches between cataplerotic and anaplerotic metabolism. Here we extend the NmsRs regulon by studying methylcitrate lyase (PrpF) and propionate kinase (AckA-1) involved in the methylcitrate cycle, and serine hydroxymethyltransferase (GlyA) and 3-hydroxyacid dehydrogenase (MmsB) involved in protein degradation. These proteins were previously shown to be dysregulated in a {Delta}nmsRs strain. Levels of transcription of target genes and NmsRs were assessed by RT-qPCR. We also used a novel gene-reporter system, in which the 5UTR of the target gene is fused to mcherry to study NmsRs-target gene interaction in the meningococcus. Under nutrient-rich conditions, NmsRs downregulate expression of PrpF and AckA-1, by direct interaction with the 5 UTR of their mRNA. Overexpression of NmsRs impaired growth under nutrient-limiting growth conditions with pyruvate and propionic acid as the only carbon sources. Our data strongly suggest that NmsRs downregulate propionate metabolism by lowering methylcitrate enzyme activity under nutrient-rich conditions. Under nutrient-poor conditions, NmsRs are downregulated, increasing propionate metabolism, resulting in higher tricarboxylic acid (TCA) activities. This allows metabolism to support nasopharynx colonization with breakdown products of amino acids functioning as anaplerotic substrates, as highlighted by NmsRs regulation of GlyA and MmsB. SIGNIFICANCENeisseria meningitidis colonizes the human adult nasopharynx, forming a reservoir for the sporadic occurrence of epidemic invasive meningococcal disease like septicemia and meningitis. Propionic acid generated by other bacteria that co-inhabit the human adolescent/adult nasopharynx can be utilized by meningococci for replication in this environment. Here we showed that the sibling small RNAs designated NmsRs (Neisseria metabolic switch regulators) riboregulate propionic acid utilization by meningococci, and thus, colonization. Under conditions mimicking the nasopharyngeal environment, NmsRs upregulated expression of enzymes of the methylcitrate cycle. This leads to the conversion of propionic acid to pyruvate and succinate, resulting in higher tricarboxylic acid cycle activity, allowing colonization of the nasopharynx. NmsRs link metabolic state with colonization, which is a crucial step on the trajectory to invasive meningococcal disease.

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

Temporal population structure of invasive Group B Streptococcus during a period of rising disease incidence shows expansion of a CC17 clone

Group B Streptococcus (GBS) is a major cause of neonatal invasive disease worldwide. In the Netherlands, the incidence of the disease increased, despite the introduction of prevention guidelines in 1999. This was accompanied by changes in pathogen genotype distribution, with a significant increase in the prevalence of isolates belonging to clonal complex (CC) 17. To better understand the mechanisms of temporal changes in the epidemiology of GBS genotypes that correlated with the rise in disease incidence, we applied whole genome sequencing (WGS) to study a national collection of invasive GBS isolates. A total of 1345 isolates from patients aged 0 - 89 days and collected between 1987 and 2016 in the Netherlands were sequenced and characterised. The GBS population contained 5 major lineages representing CC17 (39%), CC19 (25%), CC23 (18%), CC10 (9%), and CC1 (7%). There was a significant rise in the prevalence of isolates representing CC17 and CC23 among cases of early-and late-onset disease, due to expansion of discrete sub-lineages. The most prominent was shown by a CC17 sub-lineage, identified here as CC17-1A, which experienced a major clonal expansion at the end of the 1990s. The CC17-1A expansion correlated with the emergence of a novel phage carrying a gene encoding a putative adhesion protein, named here StrP. The first occurrence of this phage (designated phiStag1) within the collection in 1997, was followed by multiple, independent acquisitions by CC17 and parallel clonal expansions of CC17-1A and another cluster, CC17-1B. The CC17-1A clone was identified in external datasets, and represents a globally distributed invasive sub-lineage of CC17. Our work describes how a sudden change in the epidemiology of specific GBS sub-lineages, in particular CC17-1A, correlates with the rise in the disease incidence, and indicates a putative key role of a novel phage in driving the expansion of this CC17 clone.\n\nAuthor summaryGroup B Streptococcus (GBS) is a commensal organism of the gastrointestinal and genitourinary tracts. However, it is also an opportunistic pathogen and a major cause of neonatal invasive disease, which can be classified into early-onset (0 - 6 days of life) or late-onset (7 - 89 days of life). Current disease prevention strategy involves intrapartum antibiotic prophylaxis (IAP), which aims to prevent the transmission of GBS from mother to baby during labour. Many developed countries adapted national IAP guidelines. In the Netherlands, these were introduced in 1999. However, the incidence of GBS disease increased after IAP introduction. In this study we applied whole genome sequencing to characterise a nationwide collection of invasive GBS from cases of neonatal disease that occurred between 1987 and 2016. Analysis of GBS population structure involving phylogenetic partitioning of individual lineages revealed that the rise in disease incidence involved the expansion of specific clusters from two major GBS lineages, CC17 and CC23. Our study provides new insights into the recent evolution of the hypervirulent CC17 and describes a rapid expansion of a discrete, pre-existing sub-lineage that occurred after acquisition of a novel phage carrying a putative adhesion protein gene, underscoring the major role of CC17 in neonatal diseases.

genomics↗

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↗